REACH failing files

PMC3420630.nxml

<?xml version="1.0" ?>
<!DOCTYPE pmc-articleset PUBLIC "-//NLM//DTD ARTICLE SET 2.0//EN" "https://dtd.nlm.nih.gov/ncbi/pmc/articleset/nlm-articleset-2.0.dtd">
<pmc-articleset><article xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" article-type="other">
  <?properties open_access?>
  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">Autism Res Treat</journal-id>
      <journal-id journal-id-type="iso-abbrev">Autism Res Treat</journal-id>
      <journal-id journal-id-type="publisher-id">AURT</journal-id>
      <journal-title-group>
        <journal-title>Autism Research and Treatment</journal-title>
      </journal-title-group>
      <issn pub-type="ppub">2090-1925</issn>
      <issn pub-type="epub">2090-1933</issn>
      <publisher>
        <publisher-name>Hindawi Publishing Corporation</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="pmid">22937259</article-id>
      <article-id pub-id-type="pmc">3420630</article-id>
      <article-id pub-id-type="doi">10.1155/2012/748467</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Clinical Study</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Visual Scanning in Very Young Children with Autism and Their Unaffected Parents</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Groen</surname>
            <given-names>Wouter B.</given-names>
          </name>
          <xref ref-type="aff" rid="I1">
<sup>1</sup>
</xref>
          <xref ref-type="aff" rid="I2">
<sup>2</sup>
</xref>
          <xref ref-type="aff" rid="I3">
<sup>3</sup>
</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rommelse</surname>
            <given-names>Nanda</given-names>
          </name>
          <xref ref-type="aff" rid="I1">
<sup>1</sup>
</xref>
          <xref ref-type="aff" rid="I2">
<sup>2</sup>
</xref>
          <xref ref-type="aff" rid="I3">
<sup>3</sup>
</xref>
          <xref ref-type="corresp" rid="cor1">*</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>de Wit</surname>
            <given-names>Tessa</given-names>
          </name>
          <xref ref-type="aff" rid="I3">
<sup>3</sup>
</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Zwiers</surname>
            <given-names>Marcel P.</given-names>
          </name>
          <xref ref-type="aff" rid="I2">
<sup>2</sup>
</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>van Meerendonck</surname>
            <given-names>Desley</given-names>
          </name>
          <xref ref-type="aff" rid="I2">
<sup>2</sup>
</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>van der Gaag</surname>
            <given-names>Rutger Jan</given-names>
          </name>
          <xref ref-type="aff" rid="I1">
<sup>1</sup>
</xref>
          <xref ref-type="aff" rid="I2">
<sup>2</sup>
</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Buitelaar</surname>
            <given-names>Jan K.</given-names>
          </name>
          <xref ref-type="aff" rid="I1">
<sup>1</sup>
</xref>
          <xref ref-type="aff" rid="I3">
<sup>3</sup>
</xref>
        </contrib>
      </contrib-group>
      <aff id="I1"><sup>1</sup>Karakter, Child and Adolescent Psychiatry University Center, 6525GC Nijmegen, The Netherlands</aff>
      <aff id="I2"><sup>2</sup>Radboud University Nijmegen Medical Center, 6500HB Nijmegen, The Netherlands</aff>
      <aff id="I3"><sup>3</sup>Center for Cognitive Neuroimaging, Radboud University Nijmegen, 6525EN Nijmegen, The Netherlands</aff>
      <author-notes>
        <corresp id="cor1">*Nanda Rommelse: <email>n.lambregts-rommelse@psy.umcn.nl</email></corresp>
        <fn fn-type="other">
          <p>Academic Editor: Elizabeth Aylward</p>
        </fn>
      </author-notes>
      <pub-date pub-type="ppub">
        <year>2012</year>
      </pub-date>
      <pub-date pub-type="epub">
        <day>26</day>
        <month>3</month>
        <year>2012</year>
      </pub-date>
      <volume>2012</volume>
      <elocation-id>748467</elocation-id>
      <history>
        <date date-type="received">
          <day>15</day>
          <month>7</month>
          <year>2011</year>
        </date>
        <date date-type="rev-recd">
          <day>18</day>
          <month>11</month>
          <year>2011</year>
        </date>
        <date date-type="accepted">
          <day>17</day>
          <month>1</month>
          <year>2012</year>
        </date>
      </history>
      <permissions>
        <copyright-statement>Copyright &#xA9; 2012 Wouter B. Groen et al.</copyright-statement>
        <copyright-year>2012</copyright-year>
        <license xlink:href="https://creativecommons.org/licenses/by/3.0/">
          <license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
        </license>
      </permissions>
      <abstract>
        <p>This study of gaze patterns in very young children with autism and their parents included 23 cases (with 16 fathers and 19 mothers) and 46 controls (with 14 fathers and 28 mothers). Children (mean age 3.3 &#xB1; 1.5
years) with autism met DSM-IV and ADOS-G diagnostic criteria. The participants' gaze patterns were recorded while they viewed four simple movies that did not feature people. In children, severity of autism is related to spending more time watching irrelevant regions in one of the four movies. The mothers of children with autism showed an atypical pattern for three movies, whereas the fathers of children with autism did not show an atypical gaze pattern. The gaze pattern of the mothers was positively correlated with that of their children. The atypical viewing pattern of autistic individuals appears not to be restricted to people and social situations but is also seen in other situations, suggesting that there is a perceptual broad autism phenotype.</p>
      </abstract>
    </article-meta>
  </front>
  <body>
    <sec id="sec1">
      <title>1. Introduction</title>
      <p>Autism spectrum disorders (ASDs) are a group of behaviorally defined disorders with impaired social interaction as a key feature, along with impairments in verbal and nonverbal communication and stereotyped and rigid patterns of behavior. There is evidence that these behavioral characteristics are accompanied by an atypical style of perception that is unique to autism [<xref rid="B1" ref-type="bibr">1</xref>&#x2013;<xref rid="B3" ref-type="bibr">3</xref>]. Unlike individuals with other brain disorders, people with autism perform better than controls on tasks that involve the perception of low-level stimuli, such as discriminating visual luminance contrasts [<xref rid="B2" ref-type="bibr">2</xref>] and pure tones [<xref rid="B3" ref-type="bibr">3</xref>], but have a poorer performance on tasks involving complex stimuli [<xref rid="B4" ref-type="bibr">4</xref>]. The asymmetric perceptual pattern in autism has been explained using different but converging theoretical frameworks, such as the Weak Central Coherence Theory [<xref rid="B5" ref-type="bibr">5</xref>] and the Enhanced Perceptual Functioning model [<xref rid="B6" ref-type="bibr">6</xref>]. The main theme of these theoretical frameworks is that people with autism have difficulty (or are less inclined to) processing complex dynamic stimuli but are superior in processing simple static stimuli, leading to an atypical perceptual style. This atypical perceptual style may lead to difficulties in everyday life [<xref rid="B7" ref-type="bibr">7</xref>] if people with autism fail to identify and pay attention to relevant aspects of their environment. Failure to notice these stimuli could lead to different experiences and subsequently to different cognitive processes and behaviors during development [<xref rid="B8" ref-type="bibr">8</xref>], which in turn could lead to different perceptual styles, thereby forming a vicious cycle. Klin and colleagues argue that different perceptual preferences in early life lead to a self-amplifying developmental derailment in autism [<xref rid="B8" ref-type="bibr">8</xref>]. A recent eye-tracking study provided empirical evidence that perceptual styles change during development and differently in individuals with autism [<xref rid="B9" ref-type="bibr">9</xref>]. Given that autism has its roots very early in development [<xref rid="B10" ref-type="bibr">10</xref>], it is important to study perception in very young children.</p>
      <p> A number of studies have used eye tracking to investigate perceptual patterns in toddlers with autism (see <xref ref-type="table" rid="tab1">Table 1</xref>); most studies investigated face processing [<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B11" ref-type="bibr">11</xref>&#x2013;<xref rid="B16" ref-type="bibr">16</xref>], but some investigated motion perception [<xref rid="B16" ref-type="bibr">16</xref>, <xref rid="B17" ref-type="bibr">17</xref>]. Results suggest that children with autism tend to focus on the area around the mouth rather than on the socially informative eye area [<xref rid="B14" ref-type="bibr">14</xref>] and on static objects rather than (moving) people [<xref rid="B16" ref-type="bibr">16</xref>, <xref rid="B17" ref-type="bibr">17</xref>]. Visual face processing appears to be affected early and becomes further compromised with age [<xref rid="B11" ref-type="bibr">11</xref>], which supports Klin and colleagues hypothesis of developmental derailment in autism [<xref rid="B8" ref-type="bibr">8</xref>, <xref rid="B17" ref-type="bibr">17</xref>].</p>
      <p>Eye tracking has also been used to study perceptual styles in the so-called broad autism phenotype. The broad autism phenotype includes subclinical impairments in language, communication, and social interaction that are found in unaffected family members of people with autism. Studies have shown that the broad autism phenotype is not limited to the triad of impairments but includes perceptual styles as well [<xref rid="B18" ref-type="bibr">18</xref>, <xref rid="B19" ref-type="bibr">19</xref>]. For instance, gaze fixation and brain function in response to images of human faces were different in unaffected siblings and typically developing controls [<xref rid="B20" ref-type="bibr">20</xref>]; processing of the eye region in faces was reduced whereas that of the mouth region was increased in the parents of children with autism, but only in parents who were assessed as being socially aloof [<xref rid="B21" ref-type="bibr">21</xref>]; the 6-month-old siblings of children with autism spent less time looking at their mothers' eyes than did control siblings [<xref rid="B22" ref-type="bibr">22</xref>]. Taken together, these studies suggest that atypical perceptual styles may also be present in family members with milder or no autism traits, suggesting perceptual styles may be fruitful in the search for susceptibility genes for autism by acting as endophenotypes (heritable vulnerability traits that increase the liability to develop ASD) [<xref rid="B23" ref-type="bibr">23</xref>]. In this study, we used eye-tracking technology to determine whether visual scanning patterns are different in very young children with autism and their parents compared with normally developing children and their parents. We investigated very young children to establish whether perceptual style is different at a relatively early stage of developmental derailment and included parents to investigate whether atypical perceptual styles are familial.</p>
    </sec>
    <sec id="sec2">
      <title>2. Materials and Methods</title>
      <sec sec-type="subsection" id="sec2.1">
        <title>2.1. Participants</title>
        <p>This study of gaze patterns in very young children with autism and their parents included 23 cases (with 16 fathers and 19 mothers) and 46 controls (with 14 fathers and 28 mothers). Children with autism had been referred to the outpatient unit of Karakter Child and Adolescent Psychiatry University Center Nijmegen. Children were included in the autism group if they met criteria for autism on the ADOS-G, a standardized instrument administered directly to children [<xref rid="B24" ref-type="bibr">24</xref>], and DSM-IV diagnostic criteria for autistic disorder [<xref rid="B25" ref-type="bibr">25</xref>]. The DSM-IV criteria were established during a series of clinical assessments that included a detailed developmental history, clinical observation, medical work-up by a child psychiatrist, and cognitive testing by a clinical child psychologist. The ADOS-G was administered by an independent trained clinician who had not been involved in the diagnostic process. To exclude mental retardation, a clinical child psychologist assessed the cognitive development of the children with autism, using the Psychoeducational Profile Revised (PEP-R). The PEP-R is an inventory of behaviors and skills and is designed to identify uneven and idiosyncratic learning patterns and provides information on developmental functioning in imitation, perception, fine motor, gross motor, eye-hand integration, cognitive performance, and cognitive verbal areas [<xref rid="B26" ref-type="bibr">26</xref>]. Control participants (children and their parents) were recruited from local daycare centers. To exclude psychiatric disorders or learning problems, parents completed the CBCL questionnaire [<xref rid="B27" ref-type="bibr">27</xref>]. None of the control participants had scores on the CBCL in the clinical range. To exclude mental retardation, the cognitive development of the control children was assessed with the Mullen Scales of Early Learning [<xref rid="B28" ref-type="bibr">28</xref>].</p>
        <p> The parents of control children and children with autism completed the Autism Spectrum Quotient questionnaire (AQ), which evaluates the presence of mild autistic traits in adults of normal intelligence (including social skills, attention switching, attention to detail, communication, and imagination) [<xref rid="B29" ref-type="bibr">29</xref>]. The AQ is a 50-item 4-point Likert scale in which incremental scores (ranging from 0 to 200) for correlation analysis or diagnostic scores (ranging from 0 to 50) for diagnostic purposes can be calculated (note that in <xref ref-type="table" rid="tab2">Table 2</xref> incremental scores are used). None of the parents had been diagnosed with an ASD, and only one parent (a father of a child with autism) scored above 32 on the AQ on the diagnostic scheme (which is a commonly used threshold for autism as the probability of someone without ASD, obtaining a score above 32 is just 2% [<xref rid="B29" ref-type="bibr">29</xref>]). Exclusion criteria for all participants were mental retardation, any general medical condition affecting brain function, neurologic disorders, and substance abuse. The study was approved by the local medical ethics committee. Informed consent was obtained from all parents.</p>
      </sec>
      <sec sec-type="subsection" id="sec2.2">
        <title>2.2. Procedure</title>
        <p>The participating children were invited to play with their parents and the third author (TW) for several minutes in the light-shielded, child-tailored research laboratory of Karakter Child and Adolescent Psychiatry University Center, so that they could become accustomed to the room and the Tobii Eye-tracking device. The third author (TW) then invited the child to &#x201C;watch TV&#x201D; on the 17-inch Tobii monitor, which resembled an ordinary flat-screen TV; the child sat in a child's chair. A 5-point eye-tracking calibration procedure was initiated. The calibration was repeated if necessary until all 5 calibration points were properly identified. The parents waited in another room, and the child then watched the four movies with only the third author present during the 15-minute period. After calibration, the parents then watched the same movies, again with only the third author present.</p>
        <p> All participants sat 70&#x2009;cm from the 1024 by 1280 pixel &#x201C;landscape&#x201D; monitor, in which the eye-tracking technology is invisibly integrated. Using infrared light, the Tobii T120 (Stockholm, Sweden) tracks pupil movements and size at 60&#x2009;Hz with a spatial resolution of 0.5&#xB0; using corneal reflection patterns. Thus, high-precision measurements could be made while participants were free to move (within a virtual cubic space of 44 &#xD7; 22 &#xD7; 30&#x2009;cm) and were not influenced by data acquisition through physical contact or feedback. Eye-tracking patterns (2-dimensional fixation coordinates of the left and right eye and pupil size) were recorded on line and later analyzed using Matlab 7.5 (MathWorks, Natick, MA). This allowed us to calculate the percentage of time per movie that participants looked at specific regions of interest. The spatial and temporal coordinates of the regions of interest were extracted using Clearview, Tobii's stimulus presentation software. The regions of interest differed for each movie and contained the elements essential for comprehension of the movie.</p>
        <p>All participants (children and parents) watched the same four movies, which were taken from popular children's TV shows. The movies were presented in a randomized order to counterbalance attention or learning effects. Importantly, parents and children were not instructed to attend to certain features in the movies, so that the watching paradigm provided a naturalistic instruction-free situation. This allowed us to measure tendencies rather than abilities, because this setup resembles daily life more closely than explicit tests.</p>
      </sec>
      <sec sec-type="subsection" id="sec2.3">
        <title>2.3. Materials</title>
        <p>The four movies were selected because they were easy to understand but provided a substantial amount of visual information; because they provided variable degrees of animation to provide for dynamic complex stimuli; because they did not contain actual people, as children with autism may actively avoid eye contact [<xref rid="B30" ref-type="bibr">30</xref>]. For all movies, the absolute and relative time participants spent watching regions of interest (ROIs) was calculated. Absolute time summed for all ROIs of a movie was calculated as &#x3A3; ((time tracked by the eye-tracker in the ROI/total time the ROI was visible) &#xD7; 100%). Relative time summed for all ROIs of a movie was calculated as &#x3A3; ((time tracked by the eye-tracker in the ROI/total time the ROI was visible) &#xD7; (100%/% of total time watched at the movie)). The ROIs were shaped in the form of a rectangle over the objects of interest. The position (on screen coordinates) and time window (time of onset and end time in ms) of the ROIs were obtained using Clearview (version 2.7.1); for moving ROIs, consecutive coordinates were obtained. Matlab (version 7.1) was used to calculate watching times within the ROIs, and SPSS (version 17) was for statistical testing.</p>
        <p>The Rabbit puzzle movie (duration: 33&#x2009;s) showed nine puzzle pieces that moved from the left and right side into the screen to form a photorealistic picture of a rabbit with a carrot (<xref ref-type="fig" rid="fig1">Figure 1</xref>). When the ninth piece moved into place at <italic>t</italic> = 24&#x2009;s, the picture unfroze and showed a rabbit eating the carrot. ROIs were the eye and the ears of the rabbit and the carrot. As the ears and the eye were visible from <italic>t</italic> = 10&#x2013;33&#x2009;s, their corresponding ROIs started at <italic>t</italic> = 10&#x2009;s and ended at <italic>t</italic> = 33&#x2009;s. The carrot ROI started at <italic>t</italic> = 15&#x2009;s and ended at <italic>t</italic> = 33&#x2009;s. As the picture of the rabbit unfroze at <italic>t</italic> = 24&#x2009;s, the ROIs positions moved to cover the eye, ear, and carrot from <italic>t</italic> = 24 to <italic>t</italic> = 33.</p>
        <p> The movie Trumpet (duration: 26&#x2009;s) featured a single puppet that moved from left to right and back while playing on his trumpet (<xref ref-type="fig" rid="fig1">Figure 1</xref>). At the end of the movie (at <italic>t</italic> = 21&#x2009;s), the puppet's position was static and it blew its trumpet: a large purple flower popped out of the trumpet. ROIs were the flower and face. The position of the face ROI moved horizontally from <italic>t</italic> = 0 to <italic>t</italic> = 21 to follow to puppet's movements and remained static from <italic>t</italic> = 21&#x2013;26&#x2009;s. The flower ROI was present from <italic>t</italic> = 21&#x2013;26&#x2009;s.</p>
        <p> The Teletubby movie (duration: 29&#x2009;s) showed 17 Teletubbies that subsequently appeared every few seconds and filled the screen (<xref ref-type="fig" rid="fig1">Figure 1</xref>). They moved as they stood, but they did not change their position on the screen. As several Teletubbies kept popping up, viewers do not usually spot newly appearing Teletubbies. Rather, people tend to pay attention to the central Teletubbies, to examine their appearance. The three central Teletubbies were combined into 1 ROI that was present from <italic>t</italic> = 4&#x2009;s to <italic>t</italic> = 29&#x2009;s. Also, the number of newly appearing targets spotted was calculated. Teletubbies could be spotted from the moment they appeared until a new Teletubby appeared.</p>
        <p> The Grandma Rabbit movie (duration: 1&#x2009;min 26&#x2009;s) consisted of eight drawings that showed a mother rabbit with her four children in their house (<xref ref-type="fig" rid="fig1">Figure 1</xref>). At <italic>t</italic> = 0&#x2009;s, 10&#x2009;s, 24&#x2009;s, 37&#x2009;s, 51&#x2009;s, 63&#x2009;s, 74&#x2009;s, and 83&#x2009;s, a new drawing appeared. In every drawing but the last, interesting objects such as a school bus or an ice-cream van could be seen through the window. In the last drawing, Grandma Rabbit could be seen through the window riding her motorbike. ROIs were the rabbits' faces and the window. The ROIs were present from <italic>t</italic> = 0&#x2013;80&#x2009;s. The ROIs were static most of the time, but as the transitions between drawings involved a limited amount of panning and zooming, the ROIs moved to follow the faces and the window during the transitions.</p>
      </sec>
      <sec sec-type="subsection" id="sec2.4">
        <title>2.4. Data Analyses</title>
        <p>Eye-tracking data were available for 22 of 23 children, 10 of 16 fathers, and 16 of 19 mothers from ASD families, and for 46 of 46 children, 12 of 14 fathers, and 26 of 28 mothers from control families. A minimum of 50% valid gaze time was required for analysis. Subjects were excluded if they had no valid data on any of the four movies, for example, due to excessive subject movement. Skewness and kurtosis were examined for each variable to test for normal distribution. To examine whether the facial fixation patterns of the children with autism and their fathers and mothers differed from those of the control children and their fathers and mothers, respectively, one-sided independent samples <italic>t</italic>-tests were performed with the percentage of absolute and relative time spent watching ROIs as dependent variables. If significant group differences were found between the ASD and control children, correlations were calculated between ADOS scores and the time spent watching the ROIs for the group of children with autism, to examine whether abnormal watching behavior was related to the severity of autism. Thereafter, to examine the relationship between parental and offspring watching behavior, generalized estimation equations (GEEs) were used with an exchangeable working correlation matrix, scale parameter method on deviance, and robust estimators. Family number was used as subject effect to account for clustered data (e.g., in several control families multiple children participated, resulting in clustered parent-offspring pairs). Independent variables were percentage of absolute time watching the ROIs for fathers and mothers separately. Diagnosis (ASD versus control) and sex of the child were also added as predictors. The percentage time the child spent watching the ROIs was dependent variable. Analyses were repeated for relative watching time. Analyses were carried out in SPSS version 17. For all analyses, correction for multiple testing using the 95% CI was performed, using the false discovery rate procedure.</p>
      </sec>
    </sec>
    <sec id="sec3">
      <title>3. Results and Discussion</title>
      <sec sec-type="subsection" id="sec3.1">
        <title>3.1. Results</title>
        <p>There were no significant age or sex differences between the ASD and control families (see <xref ref-type="table" rid="tab2">Table 2</xref>). The fathers, but not the mothers, of the children with autism reported slightly more problems on the imagination and the total scales of the AQ than did control fathers.</p>
        <p> Skewness and kurtosis were acceptably low for all variables. Independent sample <italic>t</italic>-tests (<xref ref-type="table" rid="tab3">Table 3</xref>) indicated that the children with autism spent less time than the control children watching the ROIs in the Grandma Rabbit movie, although this finding did not survive stringent correction for multiple testing. However, correlation analyses revealed medium to large correlations between watching parameters of the Grandma Rabbit movie and several ADOS scores (absolute time watching ROIs: play <italic>r</italic>
<sup>2</sup> = &#x2212;0.47, <italic>P</italic> = 0.05; relative time watching ROIs: play <italic>r</italic>
<sup>2</sup> = &#x2212;0.49, <italic>P</italic> = 0.04; social <italic>r</italic>
<sup>2</sup> = &#x2212;0.52, <italic>P</italic> = 0.02; time watching the movie: play <italic>r</italic>
<sup>2</sup> = &#x2212;0.44, <italic>P</italic> = 0.05), indicating that children with more severe autism (higher ADOS scores) spent less time watching the ROIs and the movie in general. The mothers of children with autism showed abnormal watching behavior, spending less time than control mothers watching the ROIs on three of the four movies (Puzzle Rabbit, Grandma Rabbit, and Teletubbies). These findings were still significant after correction for total watching time. The fathers from ASD families did not differ from the control fathers in their watching behavior. No group differences were found in the number of newly spotted Teletubbies in ASD versus controls, respectively (children <italic>M</italic> = 9.0 and <italic>M</italic> = 9.0, <italic>P</italic> = 0.49; fathers <italic>M</italic> = 11.3 and <italic>M</italic> = 13.4, <italic>P</italic> = 0.09; mothers <italic>M</italic> = 10.4 and <italic>M</italic> = 12.1, <italic>P</italic> = 0.13).</p>
        <p>GEE analyses were performed to investigate the relatedness of parent-offspring watching behavior. These analyses were performed for mother-child watching behavior (52 mother-child pairs were available for analyses) but not for father-child watching behavior, because too few father-child pairs were available for analysis (only 26 father-child pairs were available) and because the fathers of children with autism did not show abnormal watching behavior. The time (relative and absolute) mothers spent watching ROIs in the Teletubbies movie was positively correlated with the corresponding measures in their offspring (<italic>Wald <italic>&#x3C7;</italic>&#xB2;</italic> = 3.53, <italic>P</italic> = 0.05 and <italic>Wald <italic>&#x3C7;</italic>&#xB2;</italic> = 6.45, <italic>P</italic> = 0.01, resp.). No significant effects were found for the other movies.</p>
      </sec>
      <sec sec-type="subsection" id="sec3.2">
        <title>3.2. Discussion</title>
        <p>In the present study, we investigated free visual scanning in a large sample of very young (about 3 years of age) children with autism and their parents. As perceptual tendencies drive behaviors and behaviors drive perceptual tendencies, a circular process of developmental derailment may ensue in autism [<xref rid="B8" ref-type="bibr">8</xref>]. We studied very young child to investigate when this putative derailment occurs. We found subtle visual scanning differences between children with autism and control children for one of the four movies. Within the group of children with autism, higher ADOS scores related to more abnormal watching behavior. While the perceptual style of the fathers of children with autism was not different from that of the control fathers, the perceptual style of the mothers of children with autism was in the main atypical. These mothers spent less time than the control mothers watching the most relevant parts of the videos even after correction for the total watching time, suggesting that their attention and perceptual styles were different from those of control mothers. Lastly, direct parent-offspring associations in watching behavior showed that the children with autism and their mothers had similar gaze patterns, although this relation was significant for only one movie (Teletubbies), perhaps due to the limited sample size.</p>
        <p> The results suggest that the atypical perceptual style of autistic individuals and the perceptual broad autism phenotype are not restricted solely to the social domain, as the children with autisms paid less attention to relevant aspects of visual, nonhuman, stimuli. As people with autism may fail to identify and pay attention to relevant aspects of their environment, differences in perceptual tendencies may in part explain the often-observed discrepancy between their good performance on formal social-cognitive tests and their difficulties in everyday life [<xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B32" ref-type="bibr">31</xref>]. In an elegant study, Neumann and colleagues investigated which processes drive the abnormal perceptual style in people with autism [<xref rid="B33" ref-type="bibr">32</xref>]. Using eye tracking and faces with varying contrasts and intensities, they were able to model the contribution of bottom-up and top-down processes that drive eye gaze in autism. That is, simple features, such as high contrasts or motion, influence eye movements in a bottom-up fashion, while top-down modulation is based on stimulus meaning, learned associations, and expectations [<xref rid="B33" ref-type="bibr">32</xref>]. As they found only a low correlation between low-level visual saliency and gaze patterns, Neumann et al. argued that atypical perception in autism is mainly driven by an abnormal top-down strategy for allocating visual attention.</p>
        <p> Interestingly, the notion that mainly top-down processes, such as learned associations and expectations, drive the perceptual style in autism is consistent with the hypothesis of self-amplifying developmental derailment in autism, in which early atypical perceptual styles give rise to more atypical perceptual styles in later life. Low-level saliency is less likely to change during development than are top-down processes, because top-down processes are the product of learned associations. Of note, a study of temporospatial gaze patterns in children and adults with and without autism, using multidimensional scaling [<xref rid="B9" ref-type="bibr">9</xref>], showed that children's and adults' temporospatial gaze patterns clustered differently, indicating that gaze behaviors developed or changed over time. Post hoc analyses revealed that typical children preferred to watch the mouth rather than the eyes during speech, while adults preferred to watch the eyes rather than the mouth. This difference was not seen in children and adults with autism. Longitudinal studies of child-parent watching behavior would add a wealth of empirical data to the developmental derailment hypothesis. One would expect that the mothers who exhibited the most atypical watching behavior would have children whose watching behavior would develop atypically over time. The observation that the children with autism and their mothers showed atypical perceptual patterns provides some empirical evidence for the hypothesis of developmental derailment in autism. However, as the parents did not have an ASD, the current study design does not allow for solid inferences on perceptual styles in adults with autism.</p>
        <p> Another important implication of the current findings is that while the parents of children with autism were not impaired clinically, the mothers showed perceptual patterns similar to those seen in individuals with autism. This suggests that atypical perceptual patterns are an endophenotypic trait. The current findings therefore validate the concept of the perceptual broad autism phenotype [<xref rid="B19" ref-type="bibr">19</xref>] and underline the usefulness of this endophenotypic trait for brain and genetic studies.</p>
        <p> The eye-tracking data furthermore suggest that the broader autism phenotype not only applies to siblings [<xref rid="B20" ref-type="bibr">20</xref>] but to mothers as well. This is important since it is often suggested that the broad autism phenotype is found in the fathers but not the mothers of children with autism [<xref rid="B34" ref-type="bibr">33</xref>]. It is remarkable that the mothers' visual scan patterns were affected the most, since their AQ scores did not differ from the scores of the control mothers. The fathers of children with autism, on the other hand, ascribed more autistic traits to themselves in the total AQ score and the imagination subscore specifically. Only one other study has previously used the AQ with the parents of children with autism [<xref rid="B34" ref-type="bibr">33</xref>]. The authors also reported that the mothers of children with autism had lower AQ scores than the control parents, which the authors interpreted as showing that the mothers of children with autism are reluctant to ascribe autistic traits to themselves. Self-report questionnaires of autistic traits may thus underestimate autistic traits in mothers. Given our results of impaired perceptual styles in these self-reported unimpaired mothers, it seems vital to include non-self-report measures of autistic traits in mothers of children with autism when studying the familiality of autism.</p>
        <p>Some limitations need to be taken into account. First, the cognitive development of the children with autism and the control children was assessed using different tests, which prevents direct comparison of the children's cognitive skills. Second, although the total number of participants was relatively large for an eye-tracking study, the number of parent-offspring pairs and the size of the autism sample overall were relatively limited, reducing statistical power. Third, alternative explanations for the gaze pattern differences between the mothers of children with autism and the control mothers cannot be ruled out. Having a child with autism may cause differences in eye gaze patterns as a result of another process such as stress. As the mothers of autistic children may experience more stress than the fathers, our finding of differences between mothers but not fathers might be due to greater levels of maternal stress. This explanation is, however, not in line with findings of increased perceptual abilities in people with autism that cannot be accounted for by greater stress [<xref rid="B2" ref-type="bibr">2</xref>].</p>
      </sec>
    </sec>
    <sec id="sec4">
      <title>4. Conclusions</title>
      <p>The current findings suggest that the atypical perceptual style in autism is not solely limited to the social domain and validate the concept of a perceptual broad autism phenotype. The results are in line with the hypothesis of developmental derailment, in which early atypical perceptual styles give rise to more atypical perceptual styles in later life. Converging evidence suggests that atypical perceptual patterns reflect the developmental unfolding of selective learning profiles in children with autism [<xref rid="B17" ref-type="bibr">17</xref>]. Combining the perceptual endophenotype with genetic studies may shed light on the genetic and neurobiological anomalies in autism.</p>
    </sec>
  </body>
  <back>
    <ack>
      <title>Conflict of Interests</title>
      <p>All the authors declare no competing interests.</p>
    </ack>
    <ack>
      <title>Author's Contributions</title>
      <p>The first two authors are contributed equally.</p>
    </ack>
    <glossary>
      <title>Abbreviations</title>
      <def-list>
        <def-item>
          <term>ASD:</term>
          <def>
            <p>Autism spectrum disorders</p>
          </def>
        </def-item>
        <def-item>
          <term>AQ:</term>
          <def>
            <p>Autism Spectrum Quotient questionnaire</p>
          </def>
        </def-item>
        <def-item>
          <term>ROIs:</term>
          <def>
            <p>Regions of interest.</p>
          </def>
        </def-item>
      </def-list>
    </glossary>
    <ref-list>
      <ref id="B1">
        <label>1</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Samson</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Mottron</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Jemel</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Belin</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Ciocca</surname>
              <given-names>V</given-names>
            </name>
          </person-group>
          <article-title>Can spectro-temporal complexity explain the autistic pattern of performance on auditory tasks?</article-title>
          <source>
            <italic>Journal of Autism and Developmental Disorders</italic>
          </source>
          <year>2006</year>
          <volume>36</volume>
          <issue>1</issue>
          <fpage>65</fpage>
          <lpage>76</lpage>
          <pub-id pub-id-type="pmid">16382329</pub-id>
        </element-citation>
      </ref>
      <ref id="B2">
        <label>2</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bertone</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Mottron</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Jelenic</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Faubert</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Enhanced and diminished visuo-spatial information processing in autism depends on stimulus complexity</article-title>
          <source>
            <italic>Brain</italic>
          </source>
          <year>2005</year>
          <volume>128</volume>
          <issue>10</issue>
          <fpage>2430</fpage>
          <lpage>2441</lpage>
          <pub-id pub-id-type="pmid">15958508</pub-id>
        </element-citation>
      </ref>
      <ref id="B3">
        <label>3</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bonnel</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Mottron</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Peretz</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Trudel</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Gallun</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Bonnel</surname>
              <given-names>AM</given-names>
            </name>
          </person-group>
          <article-title>Enhanced pitch sensitivity in individuals with autism: a signal detection analysis</article-title>
          <source>
            <italic>Journal of Cognitive Neuroscience</italic>
          </source>
          <year>2003</year>
          <volume>15</volume>
          <issue>2</issue>
          <fpage>226</fpage>
          <lpage>235</lpage>
          <pub-id pub-id-type="pmid">12676060</pub-id>
        </element-citation>
      </ref>
      <ref id="B4">
        <label>4</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Groen</surname>
              <given-names>WB</given-names>
            </name>
            <name>
              <surname>van Orsouw</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Huurne</surname>
              <given-names>N</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Intact spectral but abnormal temporal processing of auditory stimuli in autism</article-title>
          <source>
            <italic>Journal of Autism and Developmental Disorders</italic>
          </source>
          <year>2009</year>
          <volume>39</volume>
          <issue>5</issue>
          <fpage>742</fpage>
          <lpage>750</lpage>
          <pub-id pub-id-type="pmid">19148738</pub-id>
        </element-citation>
      </ref>
      <ref id="B5">
        <label>5</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Happ&#xE9;</surname>
              <given-names>FG</given-names>
            </name>
          </person-group>
          <article-title>Studying weak central coherence at low levels: children with autism do not succumb to visual illusions. A research note</article-title>
          <source>
            <italic>Journal of Child Psychology and Psychiatry and Allied Disciplines</italic>
          </source>
          <year>1996</year>
          <volume>37</volume>
          <issue>7</issue>
          <fpage>873</fpage>
          <lpage>877</lpage>
        </element-citation>
      </ref>
      <ref id="B6">
        <label>6</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mottron</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Dawson</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Souli&#xE8;res</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Hubert</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Burack</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Enhanced perceptual functioning in autism: an update, and eight principles of autistic perception</article-title>
          <source>
            <italic>Journal of Autism and Developmental Disorders</italic>
          </source>
          <year>2006</year>
          <volume>36</volume>
          <issue>1</issue>
          <fpage>27</fpage>
          <lpage>43</lpage>
          <pub-id pub-id-type="pmid">16453071</pub-id>
        </element-citation>
      </ref>
      <ref id="B7">
        <label>7</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Klin</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Jones</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Schultz</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Volkmar</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Cohen</surname>
              <given-names>D</given-names>
            </name>
          </person-group>
          <article-title>Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism</article-title>
          <source>
            <italic>Archives of General Psychiatry</italic>
          </source>
          <year>2002</year>
          <volume>59</volume>
          <issue>9</issue>
          <fpage>809</fpage>
          <lpage>816</lpage>
          <pub-id pub-id-type="pmid">12215080</pub-id>
        </element-citation>
      </ref>
      <ref id="B8">
        <label>8</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Klin</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Jones</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Schultz</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Volkmar</surname>
              <given-names>F</given-names>
            </name>
          </person-group>
          <article-title>The enactive mind, or from actions to cognition: lessons from autism</article-title>
          <source>
            <italic>Philosophical Transactions of the Royal Society B</italic>
          </source>
          <year>2003</year>
          <volume>358</volume>
          <issue>1430</issue>
          <fpage>345</fpage>
          <lpage>360</lpage>
        </element-citation>
      </ref>
      <ref id="B9">
        <label>9</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nakano</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Tanaka</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Endo</surname>
              <given-names>Y</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Atypical gaze patterns in children and adults with autism spectrum disorders dissociated from developmental changes in gaze behaviour</article-title>
          <source>
            <italic>Proceedings of the Royal Society B</italic>
          </source>
          <year>2010</year>
          <volume>277</volume>
          <issue>1696</issue>
          <fpage>2935</fpage>
          <lpage>2943</lpage>
          <pub-id pub-id-type="pmid">20484237</pub-id>
        </element-citation>
      </ref>
      <ref id="B10">
        <label>10</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Landa</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Holman</surname>
              <given-names>KC</given-names>
            </name>
            <name>
              <surname>Garrett-Mayer</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title>Social and communication development in toddlers with early and later diagnosis of autism spectrum disorders</article-title>
          <source>
            <italic>Archives of General Psychiatry</italic>
          </source>
          <year>2007</year>
          <volume>64</volume>
          <issue>7</issue>
          <fpage>853</fpage>
          <lpage>864</lpage>
          <pub-id pub-id-type="pmid">17606819</pub-id>
        </element-citation>
      </ref>
      <ref id="B11">
        <label>11</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Chawarska</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Shic</surname>
              <given-names>F</given-names>
            </name>
          </person-group>
          <article-title>Looking but not seeing: atypical visual scanning and recognition of faces in 2 and 4-Year-old children with Autism spectrum disorder</article-title>
          <source>
            <italic>Journal of Autism and Developmental Disorders</italic>
          </source>
          <year>2009</year>
          <volume>39</volume>
          <issue>12</issue>
          <fpage>1663</fpage>
          <lpage>1672</lpage>
          <pub-id pub-id-type="pmid">19590943</pub-id>
        </element-citation>
      </ref>
      <ref id="B12">
        <label>12</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Chawarska</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Volkmar</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Klin</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title>Limited attentional bias for faces in toddlers with autism spectrum disorders</article-title>
          <source>
            <italic>Archives of General Psychiatry</italic>
          </source>
          <year>2010</year>
          <volume>67</volume>
          <issue>2</issue>
          <fpage>178</fpage>
          <lpage>185</lpage>
          <pub-id pub-id-type="pmid">20124117</pub-id>
        </element-citation>
      </ref>
      <ref id="B13">
        <label>13</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Falck-Ytter</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Fernell</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Gillberg</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Von Hofsten</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <article-title>Face scanning distinguishes social from communication impairments in autism</article-title>
          <source>
            <italic>Developmental Science</italic>
          </source>
          <year>2010</year>
          <volume>13</volume>
          <issue>6</issue>
          <fpage>864</fpage>
          <lpage>875</lpage>
          <pub-id pub-id-type="pmid">20977557</pub-id>
        </element-citation>
      </ref>
      <ref id="B14">
        <label>14</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Jones</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Carr</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Klin</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title>Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder</article-title>
          <source>
            <italic>Archives of General Psychiatry</italic>
          </source>
          <year>2008</year>
          <volume>65</volume>
          <issue>8</issue>
          <fpage>946</fpage>
          <lpage>954</lpage>
          <pub-id pub-id-type="pmid">18678799</pub-id>
        </element-citation>
      </ref>
      <ref id="B15">
        <label>15</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Young</surname>
              <given-names>GS</given-names>
            </name>
            <name>
              <surname>Merin</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Rogers</surname>
              <given-names>SJ</given-names>
            </name>
            <name>
              <surname>Ozonoff</surname>
              <given-names>S</given-names>
            </name>
          </person-group>
          <article-title>Gaze behavior and affect at 6 months: predicting clinical outcomes and language development in typically developing infants and infants at risk for autism</article-title>
          <source>
            <italic>Developmental Science</italic>
          </source>
          <year>2009</year>
          <volume>12</volume>
          <issue>5</issue>
          <fpage>798</fpage>
          <lpage>814</lpage>
          <pub-id pub-id-type="pmid">19702771</pub-id>
        </element-citation>
      </ref>
      <ref id="B16">
        <label>16</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Klin</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Jones</surname>
              <given-names>W</given-names>
            </name>
          </person-group>
          <article-title>Altered face scanning and impaired recognition of biological motion in a 15-month-old infant with autism</article-title>
          <source>
            <italic>Developmental Science</italic>
          </source>
          <year>2008</year>
          <volume>11</volume>
          <issue>1</issue>
          <fpage>40</fpage>
          <lpage>46</lpage>
          <pub-id pub-id-type="pmid">18171365</pub-id>
        </element-citation>
      </ref>
      <ref id="B17">
        <label>17</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Klin</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Lin</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Gorrindo</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Ramsay</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Jones</surname>
              <given-names>W</given-names>
            </name>
          </person-group>
          <article-title>Two-year-olds with autism orient to non-social contingencies rather than biological motion</article-title>
          <source>
            <italic>Nature</italic>
          </source>
          <year>2009</year>
          <volume>459</volume>
          <issue>7244</issue>
          <fpage>257</fpage>
          <lpage>261</lpage>
          <pub-id pub-id-type="pmid">19329996</pub-id>
        </element-citation>
      </ref>
      <ref id="B18">
        <label>18</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Losh</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Piven</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Social-cognition and the broad autism phenotype: identifying genetically meaningful phenotypes</article-title>
          <source>
            <italic>Journal of Child Psychology and Psychiatry and Allied Disciplines</italic>
          </source>
          <year>2007</year>
          <volume>48</volume>
          <issue>1</issue>
          <fpage>105</fpage>
          <lpage>112</lpage>
        </element-citation>
      </ref>
      <ref id="B19">
        <label>19</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Losh</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Adolphs</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Poe</surname>
              <given-names>MD</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Neuropsychological profile of autism and the broad autism phenotype</article-title>
          <source>
            <italic>Archives of General Psychiatry</italic>
          </source>
          <year>2009</year>
          <volume>66</volume>
          <issue>5</issue>
          <fpage>518</fpage>
          <lpage>526</lpage>
          <pub-id pub-id-type="pmid">19414711</pub-id>
        </element-citation>
      </ref>
      <ref id="B20">
        <label>20</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Dalton</surname>
              <given-names>KM</given-names>
            </name>
            <name>
              <surname>Nacewicz</surname>
              <given-names>BM</given-names>
            </name>
            <name>
              <surname>Alexander</surname>
              <given-names>AL</given-names>
            </name>
            <name>
              <surname>Davidson</surname>
              <given-names>RJ</given-names>
            </name>
          </person-group>
          <article-title>Gaze-fixation, brain activation, and amygdala volume in unaffected siblings of individuals with autism</article-title>
          <source>
            <italic>Biological Psychiatry</italic>
          </source>
          <year>2007</year>
          <volume>61</volume>
          <issue>4</issue>
          <fpage>512</fpage>
          <lpage>520</lpage>
          <pub-id pub-id-type="pmid">17069771</pub-id>
        </element-citation>
      </ref>
      <ref id="B21">
        <label>21</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Adolphs</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Spezio</surname>
              <given-names>ML</given-names>
            </name>
            <name>
              <surname>Parlier</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Piven</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Distinct face-processing strategies in parents of autistic children</article-title>
          <source>
            <italic>Current Biology</italic>
          </source>
          <year>2008</year>
          <volume>18</volume>
          <issue>14</issue>
          <fpage>1090</fpage>
          <lpage>1093</lpage>
          <pub-id pub-id-type="pmid">18635351</pub-id>
        </element-citation>
      </ref>
      <ref id="B22">
        <label>22</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Merin</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Young</surname>
              <given-names>GS</given-names>
            </name>
            <name>
              <surname>Ozonoff</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Rogers</surname>
              <given-names>SJ</given-names>
            </name>
          </person-group>
          <article-title>Visual fixation patterns during reciprocal social interaction distinguish a subgroup of 6-month-old infants at-risk for autism from comparison infants</article-title>
          <source>
            <italic>Journal of Autism and Developmental Disorders</italic>
          </source>
          <year>2007</year>
          <volume>37</volume>
          <issue>1</issue>
          <fpage>108</fpage>
          <lpage>121</lpage>
          <pub-id pub-id-type="pmid">17191096</pub-id>
        </element-citation>
      </ref>
      <ref id="B23">
        <label>23</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Gottesman</surname>
              <given-names>II</given-names>
            </name>
            <name>
              <surname>Gould</surname>
              <given-names>TD</given-names>
            </name>
          </person-group>
          <article-title>The endophenotype concept in psychiatry: etymology and strategic intentions</article-title>
          <source>
            <italic>American Journal of Psychiatry</italic>
          </source>
          <year>2003</year>
          <volume>160</volume>
          <issue>4</issue>
          <fpage>636</fpage>
          <lpage>645</lpage>
          <pub-id pub-id-type="pmid">12668349</pub-id>
        </element-citation>
      </ref>
      <ref id="B24">
        <label>24</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Lord</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Risi</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Lambrecht</surname>
              <given-names>L</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism</article-title>
          <source>
            <italic>Journal of Autism and Developmental Disorders</italic>
          </source>
          <year>2000</year>
          <volume>30</volume>
          <issue>3</issue>
          <fpage>205</fpage>
          <lpage>223</lpage>
          <pub-id pub-id-type="pmid">11055457</pub-id>
        </element-citation>
      </ref>
      <ref id="B25">
        <label>25</label>
        <element-citation publication-type="book">
          <collab>American Psychiatric Association</collab>
          <source>
            <italic>Diagnostic and Statistical Manual of Mental Disorders</italic>
          </source>
          <year>1994</year>
          <publisher-loc>Washington, DC, USA</publisher-loc>
          <publisher-name>American Psychiatric Association</publisher-name>
        </element-citation>
      </ref>
      <ref id="B26">
        <label>26</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Schopler</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <source>
            <italic>Individualized Assessment and Treatment for Autistic and Developmentally Disabled Children: Psychoeducational Profile-Revised (Pep-R)</italic>
          </source>
          <year>1990</year>
          <publisher-loc>Austin, Tex, USA</publisher-loc>
          <publisher-name>Pro-Ed</publisher-name>
        </element-citation>
      </ref>
      <ref id="B27">
        <label>27</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Achenbach</surname>
              <given-names>TM</given-names>
            </name>
          </person-group>
          <source>
            <italic>Manual for the Child Behavior Checklist</italic>
          </source>
          <year>1991</year>
          <publisher-loc>Burlington, Mass, USA</publisher-loc>
          <publisher-name>University of Vermont</publisher-name>
        </element-citation>
      </ref>
      <ref id="B28">
        <label>28</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Mullen</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <source>
            <italic>Mullen Scales of Early Learning</italic>
          </source>
          <year>1995</year>
          <publisher-loc>Circle Pines, Minn, USA</publisher-loc>
          <publisher-name>American Guidance Service</publisher-name>
        </element-citation>
      </ref>
      <ref id="B29">
        <label>29</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Baron-Cohen</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Wheelwright</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Skinner</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Martin</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Clubley</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title>The autism-spectrum quotient (AQ): evidence from asperger syndrome/high-functioning autism, males and females, scientists and mathematicians</article-title>
          <source>
            <italic>Journal of Autism and Developmental Disorders</italic>
          </source>
          <year>2001</year>
          <volume>31</volume>
          <issue>1</issue>
          <fpage>5</fpage>
          <lpage>17</lpage>
          <pub-id pub-id-type="pmid">11439754</pub-id>
        </element-citation>
      </ref>
      <ref id="B30">
        <label>30</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Senju</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Johnson</surname>
              <given-names>MH</given-names>
            </name>
          </person-group>
          <article-title>Atypical eye contact in autism: models, mechanisms and development</article-title>
          <source>
            <italic>Neuroscience and Biobehavioral Reviews</italic>
          </source>
          <year>2009</year>
          <volume>33</volume>
          <issue>8</issue>
          <fpage>1204</fpage>
          <lpage>1214</lpage>
          <pub-id pub-id-type="pmid">19538990</pub-id>
        </element-citation>
      </ref>
      <ref id="B32">
        <label>31</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Klin</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Jones</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Schultz</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Volkmar</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Cohen</surname>
              <given-names>D</given-names>
            </name>
          </person-group>
          <article-title>Defining and quantifying the social phenotype in autism</article-title>
          <source>
            <italic>American Journal of Psychiatry</italic>
          </source>
          <year>2002</year>
          <volume>159</volume>
          <issue>6</issue>
          <fpage>895</fpage>
          <lpage>908</lpage>
          <pub-id pub-id-type="pmid">12042174</pub-id>
        </element-citation>
      </ref>
      <ref id="B33">
        <label>32</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Neumann</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Spezio</surname>
              <given-names>ML</given-names>
            </name>
            <name>
              <surname>Piven</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Adolphs</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title>Looking you in the mouth: abnormal gaze in autism resulting from impaired top-down modulation of visual attention</article-title>
          <source>
            <italic>Social Cognitive and Affective Neuroscience</italic>
          </source>
          <year>2006</year>
          <volume>1</volume>
          <issue>3</issue>
          <fpage>194</fpage>
          <lpage>202</lpage>
          <pub-id pub-id-type="pmid">18985106</pub-id>
        </element-citation>
      </ref>
      <ref id="B34">
        <label>33</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Scheeren</surname>
              <given-names>AM</given-names>
            </name>
            <name>
              <surname>Stauder</surname>
              <given-names>JEA</given-names>
            </name>
          </person-group>
          <article-title>Broader autism phenotype in parents of autistic children: reality or myth?</article-title>
          <source>
            <italic>Journal of Autism and Developmental Disorders</italic>
          </source>
          <year>2008</year>
          <volume>38</volume>
          <issue>2</issue>
          <fpage>276</fpage>
          <lpage>287</lpage>
          <pub-id pub-id-type="pmid">17588199</pub-id>
        </element-citation>
      </ref>
    </ref-list>
  </back>
  <floats-group>
    <fig id="fig1" position="float">
      <label>Figure 1</label>
      <caption>
        <p>Clockwise, starting upper left: Puzzle Rabbit movie, Trumpet movie, Grandma Rabbit movie, and Teletubbies movie.</p>
      </caption>
      <graphic xlink:href="AURT2012-748467.001"/>
    </fig>
    <table-wrap id="tab1" position="float">
      <label>Table 1</label>
      <caption>
        <p>Overview of recent influential eye-tracking studies in very young children.</p>
      </caption>
      <table frame="hsides" rules="groups">
        <thead>
          <tr>
            <th align="left" rowspan="1" colspan="1">Study</th>
            <th align="center" rowspan="1" colspan="1">Age (y)</th>
            <th align="center" rowspan="1" colspan="1">N (a&#x2013;c)</th>
            <th align="center" rowspan="1" colspan="1">Method</th>
            <th align="left" rowspan="1" colspan="1">Main results and conclusions</th>
          </tr>
        </thead>
        <tbody>
          <tr>
            <td align="left" rowspan="1" colspan="1">Chawarska and Shic 2009 [<xref rid="B11" ref-type="bibr">11</xref>]</td>
            <td align="center" rowspan="1" colspan="1">2&#x2013;4</td>
            <td align="center" rowspan="1" colspan="1">44&#x2013;30</td>
            <td align="center" rowspan="1" colspan="1">Visual scanning and recognition of faces</td>
            <td align="left" rowspan="1" colspan="1">R: children with autism looked increasingly away from faces with age and atypically attended to key features of faces<break/>C: face processing is affected early and becomes further compromised with age</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Chawarska et al. 2010 [<xref rid="B12" ref-type="bibr">12</xref>]</td>
            <td align="center" rowspan="1" colspan="1">2&#x2013;4</td>
            <td align="center" rowspan="1" colspan="1">42&#x2013;46</td>
            <td align="center" rowspan="1" colspan="1">Attentional bias associated with faces and nonfacial stimuli</td>
            <td align="left" rowspan="1" colspan="1">R: controls had more difficulties disengaging visual attention from faces but not objects than children with autism<break/>C: the neural attentional mechanism that supports deep processing of faces is disrupted in autism</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Falck-Ytter et al. 2010 [<xref rid="B13" ref-type="bibr">13</xref>]</td>
            <td align="center" rowspan="1" colspan="1">4&#x2013;6</td>
            <td align="center" rowspan="1" colspan="1">15-15</td>
            <td align="center" rowspan="1" colspan="1">Visual scanning of faces</td>
            <td align="left" rowspan="1" colspan="1">R: children with autism who are better at socioemotional skills than nonverbal communication skills look more at the eyes than the mouth, and vice versa<break/>C: separate neural systems underlie these skills</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Jones et al. 2008 [<xref rid="B14" ref-type="bibr">14</xref>]</td>
            <td align="center" rowspan="1" colspan="1">2</td>
            <td align="center" rowspan="1" colspan="1">15&#x2013;36</td>
            <td align="center" rowspan="1" colspan="1">Visual scanning of an actress playing the role of caregiver</td>
            <td align="left" rowspan="1" colspan="1">R: looking at the eyes of others was decreased in children with autism, while looking at mouths was increased<break/>C: looking at the eyes is derailed early offering a potential biomarker quantifying syndrome manifestation</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Klin and Jones 2008 [<xref rid="B16" ref-type="bibr">16</xref>]</td>
            <td align="center" rowspan="1" colspan="1">1</td>
            <td align="center" rowspan="1" colspan="1">1&#x2013;0</td>
            <td align="center" rowspan="1" colspan="1">Visual scanning of naturalistic and ambiguous social stimuli</td>
            <td align="left" rowspan="1" colspan="1">R: viewing patterns of a child with autism were driven by the physical contingencies of the stimuli rather than by their social context<break/>C: mechanisms of social development are developmentally derailed in children with autism</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Klin et al. 2009 [<xref rid="B17" ref-type="bibr">17</xref>]</td>
            <td align="center" rowspan="1" colspan="1">1&#x2013;3</td>
            <td align="center" rowspan="1" colspan="1">21&#x2013;39</td>
            <td align="center" rowspan="1" colspan="1">Visual scanning of point-light (inverted) displays of biological motion</td>
            <td align="left" rowspan="1" colspan="1">R: children with autism fail to orient towards point-light displays of biological motion<break/> C: early developmental derailment leads to an altered neurodevelopmental trajectory of brain specialization in autism</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Nakano et al. 2010 [<xref rid="B9" ref-type="bibr">9</xref>]</td>
            <td align="center" rowspan="1" colspan="1">2&#x2013;9; <break/>&gt;25</td>
            <td align="center" rowspan="1" colspan="1">25-25<break/>27-27</td>
            <td align="center" rowspan="1" colspan="1">Temporospatial gaze patterns of visual scanning of video clips</td>
            <td align="left" rowspan="1" colspan="1">R: typical infants preferred to watch the mouth rather than the eyes, which reversed with development (eyes rather than mouth)<break/> C: research in gaze behavior should take the effect of development into account</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Young et al. 2009 [<xref rid="B15" ref-type="bibr">15</xref>]</td>
            <td align="center" rowspan="1" colspan="1">0.5</td>
            <td align="center" rowspan="1" colspan="1">33&#x2013;25</td>
            <td align="center" rowspan="1" colspan="1">Live interaction with video-transmitted mothers' face</td>
            <td align="left" rowspan="1" colspan="1">R and C: eye contact did not predict autism at follow up; greater amounts attention to the mother's mouth predicted higher levels of expressive language at follow up</td>
          </tr>
        </tbody>
      </table>
      <table-wrap-foot>
        <fn>
          <p>a: autism spectrum disorder group; c: controls; C: conclusions; R: results.</p>
        </fn>
      </table-wrap-foot>
    </table-wrap>
    <table-wrap id="tab2" position="float">
      <label>Table 2</label>
      <caption>
        <p>Participant characteristics.</p>
      </caption>
      <table frame="hsides" rules="groups">
        <thead>
          <tr>
            <th align="left" rowspan="1" colspan="1">
</th>
            <th align="center" colspan="3" rowspan="1">Children</th>
            <th align="center" colspan="3" rowspan="1">Fathers</th>
            <th align="center" colspan="3" rowspan="1">Mothers</th>
          </tr>
          <tr>
            <th align="left" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">Autism <italic>N</italic> = 23</th>
            <th align="center" rowspan="1" colspan="1">Control <italic>N</italic> = 46</th>
            <th align="center" rowspan="1" colspan="1">
<italic>t</italic>/<italic><italic>&#x3C7;</italic>&#xB2;, P </italic>
</th>
            <th align="center" rowspan="1" colspan="1">Autism <italic>N</italic> = 16</th>
            <th align="center" rowspan="1" colspan="1">Control <italic>N</italic> = 14</th>
            <th align="center" rowspan="1" colspan="1">
<italic>t, P </italic>
</th>
            <th align="center" rowspan="1" colspan="1">Autism <italic>N</italic> = 19</th>
            <th align="center" rowspan="1" colspan="1">Control <italic>N</italic> = 28</th>
            <th align="center" rowspan="1" colspan="1">
<italic>t, P</italic>
</th>
          </tr>
        </thead>
        <tbody>
          <tr>
            <td align="left" rowspan="1" colspan="1">Age in years</td>
            <td align="center" rowspan="1" colspan="1">3.1 (1.0&#x2013;5.2)</td>
            <td align="center" rowspan="1" colspan="1">3.6 (1.1&#x2013;6.8)</td>
            <td align="center" rowspan="1" colspan="1">1.34, .19</td>
            <td align="center" rowspan="1" colspan="1">37.7 (30.8&#x2013;48.1)</td>
            <td align="center" rowspan="1" colspan="1">40.8 (35.4&#x2013;47.3)</td>
            <td align="center" rowspan="1" colspan="1">&#x2212;1.48,&#x2009;&#x2009;0.15</td>
            <td align="center" rowspan="1" colspan="1">34.3 (27.1&#x2013;40.1)</td>
            <td align="center" rowspan="1" colspan="1">36.5 (31.4&#x2013;46.0)</td>
            <td align="center" rowspan="1" colspan="1">1.70,&#x2009;&#x2009;0.10</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Sex (<italic>N</italic>, %&#x2642;)</td>
            <td align="center" rowspan="1" colspan="1">16 (72.7)</td>
            <td align="center" rowspan="1" colspan="1">26 (56.5)</td>
            <td align="center" rowspan="1" colspan="1">1.10, .30</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">ADOS</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Communication</td>
            <td align="center" rowspan="1" colspan="1">22.3 (10.4)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Social reciprocal interaction</td>
            <td align="center" rowspan="1" colspan="1">10.7 (4.4)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Play</td>
            <td align="center" rowspan="1" colspan="1">3.2 (1.8)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Stereotyped behaviors and restricted interests</td>
            <td align="center" rowspan="1" colspan="1">3.1 (2.0)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" colspan="3" rowspan="1">Autism Spectrum Quotient</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Social skills</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">20.9 (7.7)</td>
            <td align="center" rowspan="1" colspan="1">16.8 (3.4)</td>
            <td align="center" rowspan="1" colspan="1">1.72, 0.10</td>
            <td align="center" rowspan="1" colspan="1">17.0 (5.1)</td>
            <td align="center" rowspan="1" colspan="1">15.8 (4.9)</td>
            <td align="center" rowspan="1" colspan="1">0.71,&#x2009;&#x2009;0.48</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Attention switching</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">24.6 (8.2)</td>
            <td align="center" rowspan="1" colspan="1">20.1 (4.3)</td>
            <td align="center" rowspan="1" colspan="1">1.50,&#x2009;&#x2009;0.15</td>
            <td align="center" rowspan="1" colspan="1">17.4 (5.1)</td>
            <td align="center" rowspan="1" colspan="1">19.4 (4.4)</td>
            <td align="center" rowspan="1" colspan="1">&#x2212;1.31,&#x2009;&#x2009;0.20</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Attention to detail</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">23.5 (7.7)</td>
            <td align="center" rowspan="1" colspan="1">22.6 (3.6)</td>
            <td align="center" rowspan="1" colspan="1">0.40,&#x2009;&#x2009;0.70</td>
            <td align="center" rowspan="1" colspan="1">19.7 (6.8)</td>
            <td align="center" rowspan="1" colspan="1">22.8 (4.2)</td>
            <td align="center" rowspan="1" colspan="1">&#x2212;1.73,&#x2009;&#x2009;0.09</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Communication</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">20.4 (6.4)</td>
            <td align="center" rowspan="1" colspan="1">17.0 (3.8)</td>
            <td align="center" rowspan="1" colspan="1">1.64,&#x2009;&#x2009;0.12</td>
            <td align="center" rowspan="1" colspan="1">16.1 (3.6)</td>
            <td align="center" rowspan="1" colspan="1">16.9 (4.4)</td>
            <td align="center" rowspan="1" colspan="1">&#x2212;0.62, &#x2009;0.54</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Imagination</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">22.9 (5.8)</td>
            <td align="center" rowspan="1" colspan="1">18.1 (2.7)</td>
            <td align="center" rowspan="1" colspan="1">
<bold>2.71,</bold>&#x2009;&#x2009;
<bold>0.01</bold>
</td>
            <td align="center" rowspan="1" colspan="1">15.2 (4.1)</td>
            <td align="center" rowspan="1" colspan="1">17.6 (3.8)</td>
            <td align="center" rowspan="1" colspan="1">&#x2212;1.88,&#x2009;&#x2009;0.07</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Total</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">115.9 (31.2)</td>
            <td align="center" rowspan="1" colspan="1">94.0 (9.0)</td>
            <td align="center" rowspan="1" colspan="1">
<bold>2.40,</bold>&#x2009;&#x2009;
<bold>0.03</bold>
</td>
            <td align="center" rowspan="1" colspan="1">83.0 (19.3)</td>
            <td align="center" rowspan="1" colspan="1">92.6 (14.8)</td>
            <td align="center" rowspan="1" colspan="1">&#x2212;1.67,&#x2009;&#x2009;0.11</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">Mullen T-scores</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Expressive language</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">55.4 (9.7)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Receptive language</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">50.8 (6.7)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Fine motor</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">50.0 (10.9)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Visual reception</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">57.0 (9.5)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">PEP-R</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="10" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Imitation</td>
            <td align="center" rowspan="1" colspan="1">20.1 (6.3)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Perception</td>
            <td align="center" rowspan="1" colspan="1">33.8 (12.4)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Fine motor</td>
            <td align="center" rowspan="1" colspan="1">25.6 (7.0)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Gross motor</td>
            <td align="center" rowspan="1" colspan="1">25.1 (7.6)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Eye-hand integration</td>
            <td align="center" rowspan="1" colspan="1">26.6 (4.9)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Cognitive performance</td>
            <td align="center" rowspan="1" colspan="1">14.4 (5.4)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Cognitive verbal</td>
            <td align="center" rowspan="1" colspan="1">16.1 (7.9)</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
        </tbody>
      </table>
    </table-wrap>
    <table-wrap id="tab3" position="float">
      <label>Table 3</label>
      <caption>
        <p>Percentage of absolute and relative time watched at regions of interest (ROIs) in children with ASD and control children and their fathers and mothers.</p>
      </caption>
      <table frame="hsides" rules="groups">
        <thead>
          <tr>
            <th align="left" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" colspan="4" rowspan="1">Absolute time in %</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" colspan="4" rowspan="1">Relative time in %</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
          </tr>
          <tr>
            <th align="left" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" colspan="2" rowspan="1">Autism</th>
            <th align="center" colspan="2" rowspan="1">Controls</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" colspan="2" rowspan="1">Autism</th>
            <th align="center" colspan="2" rowspan="1">Controls</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">Orientation to ROIs</th>
          </tr>
          <tr>
            <th align="left" rowspan="1" colspan="1">
</th>
            <th align="center" rowspan="1" colspan="1">Range</th>
            <th align="center" rowspan="1" colspan="1">
<italic>M</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>SD</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>M</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>SD</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>P</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>d</italic>
</th>
            <th align="center" rowspan="1" colspan="1">Range</th>
            <th align="center" rowspan="1" colspan="1">
<italic>M</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>SD</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>M</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>SD</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>P</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
<italic>d</italic>
</th>
            <th align="center" rowspan="1" colspan="1">
</th>
          </tr>
        </thead>
        <tbody>
          <tr>
            <td align="left" rowspan="1" colspan="1">Children</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" colspan="2" rowspan="1">
<italic>N</italic> = 22</td>
            <td align="center" colspan="2" rowspan="1">
<italic>N</italic> = 46</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="16" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Puzzle Rabbit</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;61</td>
            <td align="center" rowspan="1" colspan="1">22.4</td>
            <td align="center" rowspan="1" colspan="1">17.8</td>
            <td align="center" rowspan="1" colspan="1">26.8</td>
            <td align="center" rowspan="1" colspan="1">15.3</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;66</td>
            <td align="center" rowspan="1" colspan="1">26.2</td>
            <td align="center" rowspan="1" colspan="1">18.4</td>
            <td align="center" rowspan="1" colspan="1">31.1</td>
            <td align="center" rowspan="1" colspan="1">15.6</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Trumpet</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;70</td>
            <td align="center" rowspan="1" colspan="1">32.5</td>
            <td align="center" rowspan="1" colspan="1">22.8</td>
            <td align="center" rowspan="1" colspan="1">24.5</td>
            <td align="center" rowspan="1" colspan="1">22.1</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;100</td>
            <td align="center" rowspan="1" colspan="1">39.0</td>
            <td align="center" rowspan="1" colspan="1">28.4</td>
            <td align="center" rowspan="1" colspan="1">31.0</td>
            <td align="center" rowspan="1" colspan="1">27.9</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Teletubbies</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;47</td>
            <td align="center" rowspan="1" colspan="1">18.3</td>
            <td align="center" rowspan="1" colspan="1">8.4</td>
            <td align="center" rowspan="1" colspan="1">21.2</td>
            <td align="center" rowspan="1" colspan="1">12.6</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.2</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;57</td>
            <td align="center" rowspan="1" colspan="1">24.6</td>
            <td align="center" rowspan="1" colspan="1">9.5</td>
            <td align="center" rowspan="1" colspan="1">26.3</td>
            <td align="center" rowspan="1" colspan="1">12.5</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.2</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Grandma Rabbit</td>
            <td align="center" rowspan="1" colspan="1">1&#x2013;72</td>
            <td align="center" rowspan="1" colspan="1">32.1</td>
            <td align="center" rowspan="1" colspan="1">20.7</td>
            <td align="center" rowspan="1" colspan="1">42.8</td>
            <td align="center" rowspan="1" colspan="1">19.1</td>
            <td align="center" rowspan="1" colspan="1">0.02</td>
            <td align="center" rowspan="1" colspan="1">0.5</td>
            <td align="center" rowspan="1" colspan="1">10&#x2013;100</td>
            <td align="center" rowspan="1" colspan="1">45.4</td>
            <td align="center" rowspan="1" colspan="1">17.5</td>
            <td align="center" rowspan="1" colspan="1">54.8</td>
            <td align="center" rowspan="1" colspan="1">20.0</td>
            <td align="center" rowspan="1" colspan="1">0.04</td>
            <td align="center" rowspan="1" colspan="1">0.5</td>
            <td align="center" rowspan="1" colspan="1">Autism &#x2193; Controls</td>
          </tr>
          <tr>
            <td align="left" colspan="16" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Mothers</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" colspan="2" rowspan="1">
<italic>N</italic> = 16</td>
            <td align="center" colspan="2" rowspan="1">
<italic>N</italic> = 26</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="16" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Puzzle Rabbit</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;56</td>
            <td align="center" rowspan="1" colspan="1">
<bold>19.1</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>11.6</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>30.3</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>13.4</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>&lt;0.01</bold>
</td>
            <td align="center" rowspan="1" colspan="1">0.9</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;58</td>
            <td align="center" rowspan="1" colspan="1">
<bold>24.0</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>13.2</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>32.9</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>13.8</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>0.02</bold>
</td>
            <td align="center" rowspan="1" colspan="1">0.7</td>
            <td align="center" rowspan="1" colspan="1">Autism &#x2193; Controls</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Trumpet</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;84</td>
            <td align="center" rowspan="1" colspan="1">32.5</td>
            <td align="center" rowspan="1" colspan="1">21.8</td>
            <td align="center" rowspan="1" colspan="1">44.3</td>
            <td align="center" rowspan="1" colspan="1">26.1</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.5</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;88</td>
            <td align="center" rowspan="1" colspan="1">40.0</td>
            <td align="center" rowspan="1" colspan="1">22.5</td>
            <td align="center" rowspan="1" colspan="1">46.7</td>
            <td align="center" rowspan="1" colspan="1">26.5</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">Autism &#x2193; Controls</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Teletubbies</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;71</td>
            <td align="center" rowspan="1" colspan="1">
<bold>19.3</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>13.2</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>28.8</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>13.5</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>0.02</bold>
</td>
            <td align="center" rowspan="1" colspan="1">0.7</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;72</td>
            <td align="center" rowspan="1" colspan="1">25.7</td>
            <td align="center" rowspan="1" colspan="1">12.6</td>
            <td align="center" rowspan="1" colspan="1">31.5</td>
            <td align="center" rowspan="1" colspan="1">13.0</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.4</td>
            <td align="center" rowspan="1" colspan="1">Autism &#x2193; Controls</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Grandma Rabbit</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;69</td>
            <td align="center" rowspan="1" colspan="1">
<bold>31.5</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>21.0</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>53.5</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>11.6</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>&lt;0.001</bold>
</td>
            <td align="center" rowspan="1" colspan="1">1.4</td>
            <td align="center" rowspan="1" colspan="1">3&#x2013;88</td>
            <td align="center" rowspan="1" colspan="1">
<bold>50.3</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>18.7</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>61.0</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>11.0</bold>
</td>
            <td align="center" rowspan="1" colspan="1">
<bold>0.01</bold>
</td>
            <td align="center" rowspan="1" colspan="1">0.7</td>
            <td align="center" rowspan="1" colspan="1">Autism &#x2193; Controls</td>
          </tr>
          <tr>
            <td align="left" colspan="16" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Fathers</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" colspan="2" rowspan="1">
<italic>N</italic> = 10</td>
            <td align="center" colspan="2" rowspan="1">
<italic>N</italic> = 12</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" colspan="16" rowspan="1">
<hr/>
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Puzzle Rabbit</td>
            <td align="center" rowspan="1" colspan="1">0&#x2013;53</td>
            <td align="center" rowspan="1" colspan="1">27.8</td>
            <td align="center" rowspan="1" colspan="1">15.3</td>
            <td align="center" rowspan="1" colspan="1">30.5</td>
            <td align="center" rowspan="1" colspan="1">11.2</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.2</td>
            <td align="center" rowspan="1" colspan="1">2&#x2013;56</td>
            <td align="center" rowspan="1" colspan="1">32.7</td>
            <td align="center" rowspan="1" colspan="1">14.3</td>
            <td align="center" rowspan="1" colspan="1">36.1</td>
            <td align="center" rowspan="1" colspan="1">12.7</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Trumpet</td>
            <td align="center" rowspan="1" colspan="1">3&#x2013;69</td>
            <td align="center" rowspan="1" colspan="1">27.7</td>
            <td align="center" rowspan="1" colspan="1">20.7</td>
            <td align="center" rowspan="1" colspan="1">33.0</td>
            <td align="center" rowspan="1" colspan="1">18.8</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">7&#x2013;71</td>
            <td align="center" rowspan="1" colspan="1">33.0</td>
            <td align="center" rowspan="1" colspan="1">20.1</td>
            <td align="center" rowspan="1" colspan="1">34.5</td>
            <td align="center" rowspan="1" colspan="1">18.7</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.1</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Teletubbies</td>
            <td align="center" rowspan="1" colspan="1">4&#x2013;49</td>
            <td align="center" rowspan="1" colspan="1">22.0</td>
            <td align="center" rowspan="1" colspan="1">11.4</td>
            <td align="center" rowspan="1" colspan="1">25.1</td>
            <td align="center" rowspan="1" colspan="1">11.3</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">10&#x2013;52</td>
            <td align="center" rowspan="1" colspan="1">27.8</td>
            <td align="center" rowspan="1" colspan="1">10.6</td>
            <td align="center" rowspan="1" colspan="1">27.3</td>
            <td align="center" rowspan="1" colspan="1">10.9</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.05</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
          <tr>
            <td align="left" rowspan="1" colspan="1">Movie Grandma Rabbit</td>
            <td align="center" rowspan="1" colspan="1">6&#x2013;64</td>
            <td align="center" rowspan="1" colspan="1">44.2</td>
            <td align="center" rowspan="1" colspan="1">18.3</td>
            <td align="center" rowspan="1" colspan="1">48.8</td>
            <td align="center" rowspan="1" colspan="1">10.6</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.3</td>
            <td align="center" rowspan="1" colspan="1">26&#x2013;98</td>
            <td align="center" rowspan="1" colspan="1">60.9</td>
            <td align="center" rowspan="1" colspan="1">17.9</td>
            <td align="center" rowspan="1" colspan="1">56.5</td>
            <td align="center" rowspan="1" colspan="1">6.7</td>
            <td align="center" rowspan="1" colspan="1">ns</td>
            <td align="center" rowspan="1" colspan="1">0.4</td>
            <td align="center" rowspan="1" colspan="1">
</td>
          </tr>
        </tbody>
      </table>
      <table-wrap-foot>
        <fn>
          <p>Groups compared with one-sided independent samples <italic>t</italic>-tests. Ns: not significant. Findings printed in bold were significant after correction for multiple testing.</p>
        </fn>
      </table-wrap-foot>
    </table-wrap>
  </floats-group>
</article>
</pmc-articleset>

PMC5109642.nxml

<?xml version="1.0" ?>
<!DOCTYPE pmc-articleset PUBLIC "-//NLM//DTD ARTICLE SET 2.0//EN" "https://dtd.nlm.nih.gov/ncbi/pmc/articleset/nlm-articleset-2.0.dtd">
<pmc-articleset><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" article-type="research-article">
  <?properties open_access?>
  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">BMC Psychol</journal-id>
      <journal-id journal-id-type="iso-abbrev">BMC Psychol</journal-id>
      <journal-title-group>
        <journal-title>BMC Psychology</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2050-7283</issn>
      <publisher>
        <publisher-name>BioMed Central</publisher-name>
        <publisher-loc>London</publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="pmid">27842603</article-id>
      <article-id pub-id-type="pmc">5109642</article-id>
      <article-id pub-id-type="publisher-id">165</article-id>
      <article-id pub-id-type="doi">10.1186/s40359-016-0165-9</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Study Protocol</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Simulated Partners and Collaborative Exercise (SPACE) to boost motivation for astronauts: study protocol</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author" corresp="yes">
          <name>
            <surname>Feltz</surname>
            <given-names>Deborah L.</given-names>
          </name>
          <address>
            <email>dfeltz@msu.edu</email>
          </address>
          <xref ref-type="aff" rid="Aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Ploutz-Snyder</surname>
            <given-names>Lori</given-names>
          </name>
          <address>
            <email>lori.ploutz-snyder-1@nasa.gov</email>
          </address>
          <xref ref-type="aff" rid="Aff4">4</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Winn</surname>
            <given-names>Brian</given-names>
          </name>
          <address>
            <email>winnb@msu.edu</email>
          </address>
          <xref ref-type="aff" rid="Aff3">3</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Kerr</surname>
            <given-names>Norbert L.</given-names>
          </name>
          <address>
            <email>kerr@msu.edu</email>
          </address>
          <xref ref-type="aff" rid="Aff2">2</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pivarnik</surname>
            <given-names>James M.</given-names>
          </name>
          <address>
            <email>jimpiv@msu.edu</email>
          </address>
          <xref ref-type="aff" rid="Aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Ede</surname>
            <given-names>Alison</given-names>
          </name>
          <address>
            <email>alison.ede@csulb.edu</email>
          </address>
          <xref ref-type="aff" rid="Aff5">5</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Hill</surname>
            <given-names>Christopher</given-names>
          </name>
          <address>
            <email>hillch12@msu.edu</email>
          </address>
          <xref ref-type="aff" rid="Aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Samendinger</surname>
            <given-names>Stephen</given-names>
          </name>
          <address>
            <email>sfs62@drexel.edu</email>
          </address>
          <xref ref-type="aff" rid="Aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Jeffery</surname>
            <given-names>William</given-names>
          </name>
          <address>
            <email>jefferyw@msu.edu</email>
          </address>
          <xref ref-type="aff" rid="Aff3">3</xref>
        </contrib>
        <aff id="Aff1"><label>1</label>Department of Kinesiology, Michigan State University, East Lansing, MI 48824 USA </aff>
        <aff id="Aff2"><label>2</label>Department of Psychology, Michigan State University, East Lansing, MI USA </aff>
        <aff id="Aff3"><label>3</label>Department of Media and Information, Michigan State University, East Lansing, MI USA </aff>
        <aff id="Aff4"><label>4</label>Universities Space Research Association, Houston, TX USA </aff>
        <aff id="Aff5"><label>5</label>Department of Kinesiology, California State University, Long Beach, CA USA </aff>
      </contrib-group>
      <pub-date pub-type="epub">
        <day>14</day>
        <month>11</month>
        <year>2016</year>
      </pub-date>
      <pub-date pub-type="pmc-release">
        <day>14</day>
        <month>11</month>
        <year>2016</year>
      </pub-date>
      <pub-date pub-type="collection">
        <year>2016</year>
      </pub-date>
      <volume>4</volume>
      <elocation-id>54</elocation-id>
      <history>
        <date date-type="received">
          <day>21</day>
          <month>10</month>
          <year>2016</year>
        </date>
        <date date-type="accepted">
          <day>5</day>
          <month>11</month>
          <year>2016</year>
        </date>
      </history>
      <permissions>
        <copyright-statement>&#xA9; The Author(s). 2016</copyright-statement>
        <license license-type="OpenAccess">
          <license-p>
<bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p>
        </license>
      </permissions>
      <abstract id="Abs1">
        <sec>
          <title>Background</title>
          <p>Astronauts may have difficulty adhering to exercise regimens at vigorous intensity levels during long space missions. Vigorous exercise is important for aerobic and musculoskeletal health during space missions and afterwards. A key impediment to maintaining vigorous exercise is motivation. Finding ways to motivate astronauts to exercise at levels necessary to mitigate reductions in musculoskeletal health and aerobic capacity have not been explored. The focus of Simulated Partners and Collaborative Exercise (SPACE) is to use recently documented motivation gains in task groups to heighten the exercise experience for participants, similar in age and fitness to astronauts, for vigorous exercise over a 6-month exercise regimen. A secondary focus is to determine the most effective features in simulated exercise partners for enhancing enjoyment, self-efficacy, and social connectedness. The aims of the project are to (1) Create software-generated (SG) exercise partners and interface software with a cycle ergometer; (2) Pilot test design features of SG partners within a video exercise game (exergame), and (3) Test whether exercising with an SG partner over 24-week time period, compared to exercising alone, leads to greater work effort, aerobic capacity, muscle strength, exercise adherence, and enhanced psychological parameters.</p>
        </sec>
        <sec>
          <title>Methods/Design</title>
          <p>This study was approved by the Institutional Review Board (IRB). Chronic exercisers, between the ages 30 and 62, were asked to exercise on a cycle ergometer 6&#xA0;days per week for 24&#xA0;weeks using a routine consisting of alternating between moderate-intensity continuous and high-intensity interval sessions. Participants were assigned to one of three conditions: no partner (control), always faster SG partner, or SG partner who was not always faster. Participants were told they could vary cycle ergometer output to increase or decrease intensity during the sessions. Mean change in cycle ergometer power (watts) from the initial continuous and 4&#xA0;min. interval sessions was the primary dependent variable reflecting work effort. Measures of physiological, strength, and psychological parameters were also taken.</p>
        </sec>
        <sec>
          <title>Discussion</title>
          <p>This paper describes the rationale, development, and methods of the SPACE exergame. We believe this will be a viable intervention that can be disseminated for astronaut use and adapted for use by other populations.</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="en">
        <title>Keywords</title>
        <kwd>Behavioral health</kwd>
        <kwd>Exercise</kwd>
        <kwd>Exergames</kwd>
        <kwd>Fitness</kwd>
        <kwd>K&#xF6;hler effect</kwd>
        <kwd>Motivation</kwd>
        <kwd>Relational agent</kwd>
        <kwd>Software-generated partner</kwd>
        <kwd>Virtual reality</kwd>
      </kwd-group>
      <funding-group>
        <award-group>
          <funding-source>
            <institution-wrap>
              <institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100008898</institution-id>
              <institution>National Space Biomedical Research Institute</institution>
            </institution-wrap>
          </funding-source>
          <award-id>MA03401</award-id>
        </award-group>
      </funding-group>
      <custom-meta-group>
        <custom-meta>
          <meta-name>issue-copyright-statement</meta-name>
          <meta-value>&#xA9; The Author(s) 2016</meta-value>
        </custom-meta>
      </custom-meta-group>
    </article-meta>
  </front>
  <body>
    <sec id="Sec1">
      <title>Background</title>
      <p>Astronauts need to adhere to high intensity exercise regimens to mitigate reductions in muscle strength and endurance, bone density, and reduced aerobic capacity that occur during long space missions. Exercise is also considered a key psychological countermeasure to risks of adverse behavioral health although much less is known about the dose-response relationship between exercise intensity and behavioral outcomes. While most astronauts are able to sustain high intensity exercise programs over a 4&#x2013;6 month period (the average International Space Station mission duration), there is concern that for longer duration missions, such as Mars, a key impediment to maintaining intense exercise levels is motivation. Identifying motivational strategies and technologies to support high intensity exercise over long durations has not been explored. Exercise video games (exergames) have been marketed as a way to increase motivation and enjoyment of exercise by being entertaining, engaging and providing a means to interact with other players. Although many exergames involve competition among players, there has been little attempt to analyze what game features and interpersonal interactions would best motivate users to continue exercising with these games.</p>
      <p>National Aeronautics and Space Administration&#x2019;s (NASA) research is evaluating a new high intensity integrated resistance and aerobic training program (SPRINT) during 6&#xA0;months of spaceflight on the International Space Station (ISS) (ongoing) and during 70&#xA0;days of bed rest (which simulates a reduced gravity environment) [<xref ref-type="bibr" rid="CR1">1</xref>]. Preliminary evidence from bed rest research studies suggests that a vigorous intensity exercise program during bed rest is very effective. However, bed rest studies involve SPRINT training for ~100&#xA0;days during bed rest and the ISS study requires training for ~180&#xA0;days. Eventual space exploration missions will require compliance with an exercise program for 2&#x2013;3 years. Motivation and adherence to high intensity exercise, coupled with a socially isolating environment with atypical access to social support may compromise compliance, especially if astronauts&#x2019; regimens become monotonous. Exercise programs that enhance enjoyment, self-efficacy, and a sense of social connectedness may mitigate decrements in mood and feelings of social isolation [<xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR3">3</xref>].</p>
      <p>Group dynamics, using social psychological mechanisms such as social comparison and indispensability to group achievement, may be a useful means to address lack of motivation (i.e., the level of effort) for vigorous physical exercise [<xref ref-type="bibr" rid="CR4">4</xref>]. Our research is designed to determine whether astronauts&#x2019; motivation to exercise at intense levels repeatedly over long durations can be improved using a virtual, software-generated (SG) partner--one that is anthropomorphic but clearly artificial and synthetic. People can respond socially to computers/software agents (also referred to as relational or social agents) and apply social rules much as if they were human. There is a strong research base suggesting humans can establish significant social relationships (e.g., keep promises and perceive virtual characters as teammates) with SG partners [<xref ref-type="bibr" rid="CR5">5</xref>&#x2013;<xref ref-type="bibr" rid="CR8">8</xref>].</p>
      <p>Traditional group or partner exercise leads to higher adherence than individualized exercise programs [<xref ref-type="bibr" rid="CR9">9</xref>, <xref ref-type="bibr" rid="CR10">10</xref>], but structured group exercise is not possible for astronauts during space missions due to limited space and exercise equipment. In addition, exercising in pairs may be difficult to coordinate. Exercising with an SG partner offers several advantages (e.g., availability, flexibility, autonomy) over a live human partner. An SG partner&#x2019;s abilities can be adjusted automatically over time to attain a level that may be the most motivating to the player, thereby hypothetically, keeping the player engaged and active. Additionally, exercising with an SG partner has the potential to make workout sessions more enjoyable, improve self-efficacy regarding physical performance capability and adherence to the regimen, and create a sense of social connectedness with the virtual character. The effects of an SG partner may be even stronger when used in socially isolated environments where there is little human interaction.</p>
      <p>Active video games (i.e., exergames) have become increasingly popular and have been marketed as a fun way to increase people&#x2019;s motivation to exercise [<xref ref-type="bibr" rid="CR11">11</xref>]. Several studies have found that people are motivated to exercise with active games that are entertaining, engaging, and interactive [<xref ref-type="bibr" rid="CR12">12</xref>]. However, even exergames can become boring within a short period of time if played in isolation [<xref ref-type="bibr" rid="CR13">13</xref>]. Few exergames take advantage of the potential of group dynamics to motivate physically active play, and there has been little attempt to analyze what interpersonal interactions would best motivate people to use and continue exercising with these games [<xref ref-type="bibr" rid="CR11">11</xref>].</p>
      <p>Recent research has shown that an SG partner, who was moderately more capable than the participant in an exergame, increased the player&#x2019;s physical activity persistence more than playing the game alone [<xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR7">7</xref>]. This research is based on group motivation dynamics principles that stress upward social comparison and a sense of indispensability of one&#x2019;s efforts to their more capable partner under conjunctive task conditions [<xref ref-type="bibr" rid="CR14">14</xref>]. Under such conditions, the dyad team can persist no longer than its weaker partner--when the weaker member stops, it was impossible for the stronger partner to continue. Thus, motivation is likely to be enhanced when one sees his/her efforts as being highly instrumental in achieving team success [<xref ref-type="bibr" rid="CR14">14</xref>]. However, to date, the motivating benefits of an SG partner have not been explored with physical exertion tasks over an extended period of time and at high exercise intensities required of astronauts. Further, whether the motivating benefits of exercising with an SG partner who is continually superior will attenuate over long-term intense exercise has not been explored. This gap in the literature is important because the full promise of an SG partner in exercise games for long-term exercise (e.g., simplicity of manipulating relative ability over time; and avoiding scheduling conflicts with a live partner) hinges on this question. Given previous research suggesting that humans will establish significant social relationships with SG partners [<xref ref-type="bibr" rid="CR5">5</xref>, <xref ref-type="bibr" rid="CR15">15</xref>], we sought to explore related questions in the context of exercising with an SG partner over a period of 24&#xA0;weeks.</p>
      <sec id="Sec2">
        <title>Specific aims and hypotheses</title>
        <p>The primary aim of Simulated Partners and Collaborative Exercise (SPACE) was to determine whether recently documented motivation gains in task groups (dyads in particular) can be harnessed to improve motivation in an interactive exergame using SG partners. Aim 1 involved the development of software to create SG exercise partners and interface with cycle ergometers. The SG partner features were tested with focus groups of astronauts and NASA physical trainers and piloted with a convenience sample of physically active kinesiology students. After the SG exercise partners and games were developed, the design features of the SG partners, the exergame, and the questionnaires were pilot tested (Aim 2), using a short duration training study with master&#x2019;s athletes and fitness club members who are similar in age and fitness to experienced astronauts. Aim 3 tested the long-term (i.e., 24&#xA0;weeks) effectiveness of the SG partner in maintaining participants&#x2019; prescribed fitness goals, greater workout effort, physiological parameters (viz., aerobic capacity, ventilatory threshold, and musculoskeletal fitness), self-efficacy, enjoyment, interest in continuing the game, and perceptions of social connectedness compared to exercising alone (See Fig.&#xA0;<xref rid="Fig1" ref-type="fig">1</xref> for an overview of the different aims and flowchart through phases). The following hypotheses were tested in Aim 3:<fig id="Fig1"><label>Fig. 1</label><caption><p>Overview of the aims and flowchart through phases of SPACE study</p></caption><graphic xlink:href="40359_2016_165_Fig1_HTML" id="MO1"/></fig>
<list list-type="bullet"><list-item><p>H1: Exercising with a conjunctive SG partner over 24-week time period, compared to exercising alone, leads to greater workout effort and adherence.</p></list-item><list-item><p>H2: Exercising with a conjunctive SG partner over 24-week time period, compared to exercising alone, leads to better aerobic capacity, higher ventilatory threshold, and greater thigh muscle strength.</p></list-item><list-item><p>H3: Exercising with a conjunctive SG partner over 24-week time period, compared to exercising alone, leads to greater enjoyment in the activity, self-efficacy, interest in continuing the exergame, and sense of social connectedness.</p></list-item></list>
</p>
      </sec>
    </sec>
    <sec id="Sec3">
      <title>Method</title>
      <sec id="Sec4">
        <title>Study design</title>
        <p>SPACE is a 6-month randomized control trial design. To better simulate actual astronauts, participants were middle-aged adults who are competitive athletes or highly physically active exercisers, recruited from mid-Michigan. Participants were assigned to one of three conditions: no partner individual control, an always superior SG partner, or an SG partner who was not always superior. Participants were asked to exercise on a cycle ergometer 6&#xA0;days per week for 24&#xA0;weeks using a routine consisting of alternating between days of moderate-intensity continuous (at or above 75% of their maximum heart rate) and three types of high-intensity interval sessions: (a) long, 4&#x2009;&#xD7;&#x2009;4 min intervals at or above 90% HRmax with 3&#xA0;min active rest (i.e., cycling at a recovery rate), (b) medium 6&#x2009;&#xD7;&#x2009;2 min intervals at 70, 80, 90, 100, 90, 80% of HRmax, respectively with 2&#xA0;min active rest, and (c) short, 30&#xA0;s max sprint intervals with 20&#xA0;s active rest. The design consists of a 3 (Exercise condition) &#xD7; 2 (Participant gender) &#xD7; 4 (Training regimens: Continuous, Interval sprint, Interval 2-min, Interval 4-min.) &#xD7; 24 (Weeks) mixed design with repeated measures on the last two factors. Participants were able to vary cycle ergometer wattage to increase or decrease intensity only during the continuous and 4-min. interval sessions. We did not want the participants to overexert on the first half of the ladder on the 2-min intervals, and the sprint intervals were already set for maximum intensity. Table&#xA0;<xref rid="Tab1" ref-type="table">1</xref> contains details of the exercise regimen.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Weekly exercise regimen for 24-week study</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Day</th><th>Workout</th><th>Description</th></tr></thead><tbody><tr><td>1</td><td>Continuous</td><td>5&#xA0;min. warm-up starting at 50% of HRmax and progressing in intensity until Ss reach an effort that will elicit 75% max HR, followed by 30&#xA0;min. of continuous cycling at or above 75% max HR. Ss are allowed to increase or decrease their work intensity.</td></tr><tr><td>2</td><td>Long intervals</td><td>5&#xA0;min. warm-up starting at 50% of HR max. and progressing in intensity until Ss reach an effort that will elicit 90% max HR, followed by 4&#x2009;&#xD7;&#x2009;4 min intervals at or above 90% max HR with 3&#xA0;min. active rest (at 50% HR max). Ss are allowed to increase or decrease their work intensity.</td></tr><tr><td>3</td><td>Continuous</td><td/></tr><tr><td>4</td><td>Medium intervals</td><td>5&#xA0;min. warm-upstarting at 50% of HR max. and progressing in intensity until Ss reach an effort that will elicit 70% max HR, followed by 6&#x2009;&#xD7;&#x2009;2 min intervals at 70, 80, 90, 100, 90, 80% max HR with 2&#xA0;min. active rest (at 50% HR max). Ss are not allowed to increase or decrease their work intensity.</td></tr><tr><td>5</td><td>Continuous</td><td/></tr><tr><td>6</td><td>Short, sprint intervals</td><td>After 10&#xA0;min. warm-up, progressing in intensity until Ss reach an effort that will elicit max HR (100%), Ss pedal at that same workload for 8&#x2009;&#xD7;&#x2009;30 s sprint intervals with 20&#xA0;s active rest. Ss are not allowed to increase or decrease their work intensity.</td></tr></tbody></table></table-wrap>
</p>
        <p>Prior to conducting the intervention, we conducted focus groups of astronauts, astronaut trainers, and highly physically active middle-aged adults. In addition, pilot tests were carried out to refine the exergame and assessments. In the 6-month study, assessments were made on numerous physiological, performance, and psychological variables. This protocol paper adheres to the SPIRIT guidelines.</p>
      </sec>
      <sec id="Sec5">
        <title>Participants</title>
        <sec id="Sec6">
          <title>Recruitment and eligibility criteria</title>
          <p>There were three phases of recruitment: focus groups, piloting testing, and the 24-week intervention study. Each involved separate criteria.</p>
        </sec>
        <sec id="Sec7">
          <title>Focus group recruitment</title>
          <p>Recruitment of astronauts and astronaut trainers took place at the Johnson Space Center in Houston, TX. Eligibility for astronauts included long-duration flight and exercise experience and availability for interviews. Astronaut trainers at the Johnson Space Center were recruited based on availability in their schedules. No incentives were provided for participation. We prioritized for equal numbers of men and women.</p>
          <p>A separate focus group of highly active middle-aged adults was recruited from the local community through the first author&#x2019;s personal knowledge of local master&#x2019;s athletes. Participants were required to be between 35 and 60&#xA0;years of age and exercise at least four times per week at moderate to high intensity. One-half of the group was required to be female. No incentives were provided for participation. Two co-investigators (1 female), with focus group experience, conducted all focus group interviews.</p>
        </sec>
        <sec id="Sec8">
          <title>Pilot testing recruitment</title>
          <p>A convenience sample of university kinesiology majors, who were physically active and at least 18&#xA0;years of age, were recruited to test the game and mechanics of the cycle ergometer-game interface for six sessions within a 2-week period. Flyers were posted throughout the kinesiology building and announcements were made in kinesiology classes. We attempted to recruit for equal numbers of men and women. Participants were told that they would be given a &#x201C;Training Like an Astronaut&#x201D; t-shirt for their participation. Testing was conducted by members of the research team.</p>
          <p>Solicitation of participants for the 6-day pilot (Aim 2) was for those who were 30&#x2013;62 years of age who would like to improve fitness and who exercise at least 30&#xA0;min. per day, three times per week at moderate to high intensity. We strived for a mean age of 48&#xA0;years for the sample, the mean age of an experienced astronaut. Participants were recruited from the local community through flyers posted at races, fitness centers, and athletic shops; through emails to running, triathlete, and cycling clubs; and through employee fitness programs. Compensation for the study included a &#x201C;Training Like an Astronaut&#x201D; t-shirt and $6.00 per session to cover mileage and parking to be received at the end of the study. Payment was not contingent on exercise performance.</p>
          <p>Potential participants were screened using the Physical Activity Readiness Questionnaire (i.e., and excluded if they answered &#x2018;yes&#x2019; to anyone of the following: have a heart condition that precludes participating in moderate to vigorous physical activity; feel chest pain during physical activity; feel chest pain while resting; lose balance because of dizziness, lose consciousness; have joint or bone problems that could be made worse by physical activity; if a doctor is currently prescribing medication for blood pressure or heart condition; or if there are any known reasons why the participant should not do physical activity). Also, all men over 44&#xA0;years. had to obtain physician consent prior to participating.</p>
          <p>Potential participants were also screened by self-reported physical activity levels. Eligibility required at least 30&#xA0;min. of physical activity per day, three times per week at moderate to high intensity. Those who met the initial qualifications were given an incremental exercise test (cycle ergometer) in order to estimate their maximal oxygen consumption (VO<sub>2</sub> max). Participants were required to reach an estimated VO<sub>2</sub> max value of 35&#xA0;ml/kg/min or achieve the 150-watt stage of the test. Any potential participants who did not meet the aforementioned requirements were excluded from the study. A total of six participants either self-selected out of the study after the incremental exercise test or did not qualify.</p>
        </sec>
        <sec id="Sec9">
          <title>Twenty-four week intervention study recruitment</title>
          <p>Solicitation of participants for the 24-week intervention study (Aim 3) was similar to the 6-day pilot study. However, recruitment has been conducted in two separate cohorts across 2&#xA0;years because of space limitations to conduct the intervention. Compensation for the study included the same &#x201C;Training Like an Astronaut&#x201D; t-shirt and $6.95 per session. Participants received payment only for the number of days they complete for a potential total of $1000. Payment was provided on a monthly basis but was not contingent on performance. Instead of a graded exercise test, potential participants performed the same test as previously described for the six-day pilot study, but expired respiratory gases were collected during this test so VO<sub>2</sub> was measured, rather than estimated. As was the case with the 6-day pilot study, participants had to reach at least 35&#xA0;ml/kg/min or make it through 150 Watt stage of max test to qualify for this phase of the study. The astronaut average VO<sub>2</sub> max is ~42&#xA0;ml/kg/min. and we strived for that as a sample mean.</p>
        </sec>
        <sec id="Sec10">
          <title>Study samples</title>
          <p>The study sample for Aim 1 included two focus groups. The first group comprised four experienced astronauts (2 female) and three astronaut personal trainers (1 female). Participants reviewed the prototype design of the male and female SG partners and provided feedback on facial features and expressions, somatotype, voice, and verbal interactions. They also provided feedback on the features of the game, including the variety of exercise terrain, workout summary (average RPM, distance traveled, etc.), and the virtual trainer who provided game instructions. Based on feedback from the first focus group, a second focus group of four highly active male and female athletes/exercisers, over 35&#xA0;years of age, reviewed a second version of the SG partner (more muscular, more expressive) and game (more varied terrain) that had been developed to further refine the appearance of the SG partners, exergame interface, and the nature and quality of interactions between participants and their SG partners (e.g., detail of introductions, greetings). After conducting focus groups, the game was pilot tested on a convenience sample of six highly active kinesiology students (2 female) at the university. They rode a stationary cycle on a simulated bike path for 30&#xA0;min. for 6&#xA0;days within 2&#xA0;weeks to test game mechanics and protocol.</p>
          <p>The study sample for Aim 2 consisted of 82 highly physically active adults, ages 30 &#x2013; 62&#xA0;years. These were participants who would be of similar age and fitness levels to those who would be recruited for the full intervention study.</p>
          <p>For the long-term intervention (Aim 3), a total of 419 participants expressed interest in enrolling in the study. Of those, 221 completed a screening survey on Qualtrics. A final sample of 41 highly physically active adults, (18 female, 44%; one Hispanic) enrolled in the study in two cohorts. The first cohort of participants included 11 women, 12 men (<italic>M</italic> age&#x2009;=&#x2009;46.74&#x2009;&#xB1;&#x2009;6.98). The second cohort included 7 women, 11 men (M age&#x2009;=&#x2009;44.17&#x2009;&#xB1;&#x2009;9.31). We have strived for equal numbers of males and females, but in any case, insured proportional numbers of males and females in each condition.</p>
          <p>Power analyses were performed using G*Power software (see <ext-link ext-link-type="uri" xlink:href="http://gpower.hhu.de">gpower.hhu.de</ext-link>). To examine effects within and between treatment groups for the primary effort dependent variable, a repeated-measures ANOVA of three measurement blocks (for averaged exercise session data), with a moderate correlation among repeated measures (&#x3C1;&#x2009;=&#x2009;0.3), suggested we would detect a moderate effect (f&#x2009;=&#x2009;.35) with the sample size of 13 individuals per group (total N&#x2009;=&#x2009;39) with a probability of .95. These projections were consistent with previous conjunctive-partnered studies conducted by the research group that have shown large treatment effects (e.g., <italic>d</italic>&#x2009;=&#x2009;.99 [<xref ref-type="bibr" rid="CR4">4</xref>]; <italic>d</italic>&#x2009;=&#x2009;1.38 [<xref ref-type="bibr" rid="CR16">16</xref>]).</p>
        </sec>
      </sec>
      <sec id="Sec11">
        <title>Description of SPACE exergame, cycle ergometer interface, and testing facility</title>
        <p>The exergame, developed specifically for this study, incorporated the exercise regimen of continuous and interval training and included a series of different bike paths for each of the 6&#xA0;days. SPACE includes a same-sex SG trainer who provides instructions for all of the workouts. In the partnered conditions, the game includes a same-sex SG partner who is introduced by the SG trainer as a teammate</p>
        <p>Participants can view workout information on the screen, such as current intensity level, (measured in watts), RPMs, the distance cycled, whether they are above or below their target watts, and a clock that counts down from 30&#xA0;min for the continuous workout protocol or for the specific interval time they are working on for interval days. Participants can change intensity or bike speed (+/- 5, 10, or 20 watts) by selecting the appropriate buttons on their keypad. Because of the design of the cycle ergometer, participants cannot change their intensity by pedaling faster or slower &#x2014;for example, pedaling more slowly results in an increase in resistance, keeping the overall intensity constant.</p>
        <p>SPACE is interfaced with the Monark LC4 cycle ergometer (with adjustable seat and handle bar) and is used in conjunction with a PC, monitor, and numeric keypad. Participants pedal the cycle ergometer at a fixed wattage based on a prescribed percentage of their target HR<sub>max</sub> while viewing their gameplay via the computer monitor. The testing facility has six exercise cubicles and can accommodate up to six participants at a time. There is a separate room to perform pre- and post-session measures (e.g., blood pressure). Additionally, another lab in the building houses all physiological equipment relevant to the current investigation, including an isokinetic machine (Biodex 3 dynamometer), body composition (Bodpod), and metabolic carts (Parvo).</p>
      </sec>
      <sec id="Sec12">
        <title>Intervention</title>
        <p>All qualified participants had 6&#xA0;days of baseline cycling in Week 1, using the 6-day exercise regimen, to adjust their work intensity (as set in watts) without the SPACE game. In Week 2, all participants were introduced to the SPACE game, known to them as &#x201C;Training Like and Astronaut&#x201D; and went through the no-partner Control condition of the 6-day exercise regimen at their target watts intensity, where an SG same-sex trainer appeared on the monitor and provided instructions for the workouts. After Week 2, the project manager randomized participants, balanced for gender, to one of three conditions: no-partner Control, Always superior partner (AWS), or Not always superior partner (NAS). Participants were blinded to the conditions they were in and were told not to discuss their exercise with anyone who might be in the study. Although experimenters were not blind to conditions, they were unaware of the experimental hypotheses.</p>
        <sec id="Sec13">
          <title>Control</title>
          <p>In the individual control condition, participants cycled under the same conditions and instructions as in the previous week. They must try to cycle at their target watts or higher for the Continuous 30-min. and 4-min intervals sessions; however, if they feel they cannot cycle at that intensity, they can lower their watts. They received feedback, prior to each session, on their previous workout performance for the type of workout they have that day (i.e., continuous 30-min, 4-min interval, etc.).</p>
        </sec>
        <sec id="Sec14">
          <title>Always superior partner (AWS)</title>
          <p>Participants were told that they will be cycling for the rest of the study with an SG partner who will be their teammate. They were told that their teammate, named Chris (always same sex as participant), is programmed to be slightly more fit than they are, but that he/she is designed to respond to a workout as any person would, and can experience fatigue at some point during the exercise session. This was manifested in two ways: (a) false feedback on potential initial, baseline performance from Week 2 (the SG partner was alleged to have been programmed to cycle about 1.15 times faster than the participant) and (b) during the exercise session, the image of the SG partner was shown on the video monitor starting out at the same pace as the participant but quickly moving into a faster pace and then always be shown to be outperforming the participant. The 15% discrepancy between participant and SG partner was determined from feedback in focus-group testing.</p>
          <p>The SG trainer explained the nature of the conjunctive task (i.e., that they are working together toward a team workout score, which is determined by whoever bikes the shorter distance). Further, they were told that they and their teammate are linked together, so that if one of them cycles too far ahead AND the other is below their target watts, the team member who is ahead will be slowed down, until the gap has lessened. When this happens, they will also see a red hue on the bottom of the screen, indicating that their teammate has had to slow down.</p>
          <p>In order to build rapport with the SG partner, participants were introduced to him/her, through a guided dialogue-tree interface which allows participants to respond to questions posed by their SG partner by selecting from several pre-programmed responses on screen. Examples include asking if the participant is from Michigan with response choices of &#x201C;Yeah, I&#x2019;m a Michigander&#x201D; or &#x201C;Actually, I&#x2019;m not from around here.&#x201D; Depending on the choice option chosen, the SG partner responds with appropriate follow-up dialogue and additional questions. There are five question and response interactions. The type of personal information exchanged was developed through focus group testing as part of the SG development the SG partner.</p>
          <p>In terms of continued rapport-building, the SG partner comments periodically throughout the 24-week intervention, either before or after the workout. This occurs a total of 32 times with comments such as, &#x201C;Ready&#x201D;; &#x201C;Good work&#x201D;; and &#x201C;I&#x2019;m looking forward to our workout.&#x201D; In addition to the introductory dialogue, there are three other occasions where a dialogue-tree format occurs: (a) in Week 13 at the halfway point of the study, (b) in Week 21 with 1&#xA0;month to go, and (c) on the last day, where the SG partner thanks the participant for working out with him/her and says goodbye and the participant is then given the option to reply.</p>
          <p>As a part of designing the SG partner to have human qualities but still be recognized as a computer, there are two separate weeks when he/she is not available. In Week 9, the SG partner is sick with a software &#x201C;virus&#x201D; for 4&#xA0;days, and in Week 19, he/she has an injury and is out for the week.</p>
          <p>Just before participants begin the game after meeting their SG partner for the first time, the SG trainer explains that they can see their average watts and the distance they biked in their first session (Week 2 baseline) compared with their SG partner&#x2019;s average watts and distance. The SG partner&#x2019;s performance also shows a 15% better score. They are then reminded that their workout score for this session is determined by whoever cycles the shorter distance in 30&#xA0;min. continuous workout (or 4-min interval) and, that on the screen, they will be able to see both their own score and the team score. They were instructed that if they finished ahead of the SG partner, the partner&#x2019;s score would be the team score. If the SG partner finished ahead of them, their own score would be the team score. At any time that the participant is ahead of the SG partner, the partner is visible in a profile view in the corner of the screen. As in the Control condition, participants receive feedback, prior to each session, on their own previous workout performance for the type of workout they have that day.</p>
        </sec>
        <sec id="Sec15">
          <title>Not always superior partner (NAS)</title>
          <p>All information provided to the NAS participants is the same as that provided to those in the AWS condition. The only difference in the two conditions is that the participant was sometimes be able to surpass the SG partner. This happened on 17 of the possible 117 occasions (15%) where participants cycled with a partner. The 15% was a best guess on how to both maintain the impression of partner superiority and minimize participant discouragement based on focus group responses. There are eight times during continuous sessions and three times during each of the interval sessions. During these occasions, the NAS partner says things like, &#x201C;Sorry, I just couldn&#x2019;t keep up today&#x201D; or &#x201C;Those sprints were tough!&#x201D;.</p>
        </sec>
      </sec>
      <sec id="Sec16">
        <title>Procedures</title>
        <p>Prior to the start of the study, participants were invited to an information and orientation session in the facility where the study would be conducted. The session provided information on the pretest measures that would be conducted (VO<sub>2</sub> max test, muscular strength test of quadriceps and hamstrings, body composition), compensation for participation, and the schedule. Participants could choose either a Sunday through Friday or a Monday through Saturday time schedule. Participants were then scheduled for their pretest assessments. Descriptions of these pretest measures are detailed under Measures.</p>
        <sec id="Sec17">
          <title>Pretest assessments</title>
          <p>Pretest assessments were scheduled 1 to 3&#xA0;weeks prior to the first week of the study. Participants came to the exercise testing lab and were first administered the informed consent to participate in the study. If participants consented, they then were given the instructions and were evaluated for body composition and performed the VO<sub>2</sub> max test. After the completion of the VO<sub>2</sub> max test, researchers indicated whether participants met the eligibility criteria for VO<sub>2</sub> max. If participants met criteria, they were scheduled for a second lab visit where their lower body muscular strength was measured. After the second testing visit was completed participants were then ready to begin participating with the exergame.</p>
        </sec>
        <sec id="Sec18">
          <title>Week 1</title>
          <p>During the first week of the study, participants came to the exercise facility to get accustomed to the 6-day exercise regimen, outlined in Table&#xA0;<xref rid="Tab1" ref-type="table">1</xref>. Exercise was initially prescribed based on percentages of VO<sub>2</sub>max and was monitored by HR. For example, the HR and workload corresponding to 90% of VO<sub>2</sub>max during the initial max test was recorded as the training target for the 4&#x2009;&#xD7;&#x2009;4 min intervals. Participants performed all of the workouts under the supervision of research staff with an exercise physiology background and the research staff adjusted the participant&#x2019;s work intensity if necessary based on the HR. If adjustments to participants&#x2019; cycle power output were made by the research staff, the adjusted watts were used for all subsequent sessions. Participants were not exposed to the game in this adjustment week. Prior to the start of each session (during this week and throughout the entire study), participants were fitted with a Polar HR monitor and a blood pressure cuff for pre-exercise cardiovascular measurements.</p>
        </sec>
        <sec id="Sec19">
          <title>Week 2: baseline</title>
          <p>As described previously, during Week 2, all participants cycled in the Control condition, which includes having an SG trainer to provide instructions. Participants were instructed to wear the headphones provided or to bring their own so that they could hear the instructions and not overhear participants in adjacent exercise stations. HR, blood pressure, and rating of perceived exertion (RPE) measures were taken during each session of baseline and continued throughout the study. During the continuous workout, HR was collected at 10, 20, and 30&#xA0;min. RPE was collected at the end of the workout (30&#xA0;min. mark). HR and RPE were taken at the end of each 4&#x2009;&#xD7;&#x2009;4 min. interval (4, 11, 17, and 25&#xA0;min.). During the sprint workout, RPE was collected at the end of the 10&#xA0;min. warm up and at the end of the 8<sup>th</sup> sprint. HR was collected at the end of the warm-up and after each of the 8 intervals in the sprint workout. HR was collected at the end of each of the 6&#x2009;&#xD7;&#x2009;2 min. intervals and RPE was collected at the end of the 4<sup>th</sup> and 6<sup>th</sup> intervals. At the end of the workouts, participants were required to cool-down for 3&#xA0;min. or until HR was below 130 beats per min. Blood pressure was taken after the workout and the participant was given a survey if there was one for the day they just completed.</p>
        </sec>
        <sec id="Sec20">
          <title>Week 3 through 24</title>
          <p>Starting in Week 3, participants were randomly assigned to one of the three conditions. All procedures remained the same. During Week 13, participants completed midpoint VO<sub>2</sub> max, body composition, and leg strength testing using the same protocol from the beginning of the study. Using the fitness data from the VO<sub>2</sub> max test, adjustments could be made to prescribed watts for participants if training effects had occurred. If participants improved their VO<sub>2</sub> max, prescribed watts were adjusted to the new regression line that predicts their performance at a variety of intensities.</p>
          <p>Strategies to improve adherence to the intervention included follow-up phone calls if participants missed a session to try to minimize any drop out or adherence problems. Occasional nonparticipation was anticipated as inevitable and managed afterward in missing data analysis. The project manager also established a secure and direct online communication with all participants to encourage proactive notification and management of any potential issues with scheduled session appointments. This deterred missed appointments that occur due to multiple inherent, non-study personal schedule conflicts. Adherence to the protocol was monitored in the lab by staff. Participation would be discontinued for any individual who incurred an injury, within or outside of the exercise sessions that could be aggravated by continuing the exercise program.</p>
        </sec>
      </sec>
      <sec id="Sec21">
        <title>Measures</title>
        <p>Mean change in cycle ergometer workload (Watts) from the initial continuous and 4&#xA0;min. interval session is the primary dependent variable reflecting motivational effort. Measures of physiological, strength, and psychological parameters (perceived effort, enjoyment, self-efficacy, and social connectedness) were also obtained. A schedule of the frequency of measures administered is contained in Table&#xA0;<xref rid="Tab2" ref-type="table">2</xref>.<table-wrap id="Tab2"><label>Table 2</label><caption><p>Frequency of measures</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Measure</th><th>Applicable workouts</th><th>Frequency</th></tr></thead><tbody><tr><td>Fitness variables:<break/>&#x2003;VO2 max<break/>&#x2003;Ventilatory threshold<break/>&#x2003;Thigh strength<break/>&#x2003;Body composition</td><td>Not specific to a workout</td><td>Weeks 1, 12, and 24</td></tr><tr><td>Free-living physical activity</td><td>Not specific to a workout</td><td>Weekly</td></tr><tr><td>Rating of perceived exertion</td><td>Continuous<break/>Sprint intervals<break/>Short intervals<break/>Long intervals</td><td>Daily during sessions</td></tr><tr><td>Heart rate</td><td>Continuous<break/>Sprint intervals<break/>Short intervals<break/>Long intervals</td><td>Daily during sessions</td></tr><tr><td>Blood pressure</td><td>Not specific to a workout</td><td>Before and after each session</td></tr><tr><td>Self-efficacy</td><td>Continuous<break/>Long intervals</td><td>Weeks 2, 4, 8, 12, 17, 20, 24</td></tr><tr><td>Enjoyment</td><td>Continuous<break/>Sprint intervals<break/>Short intervals<break/>Long intervals</td><td>Weeks 1, 2, 3, 9, 24</td></tr><tr><td>Social connectedness</td><td>Not specific to a workout</td><td>Weeks 12, 24</td></tr><tr><td>Team perceptions</td><td>Not specific to a workout</td><td>Weeks 3, 12, 24</td></tr><tr><td>Alternative Godspeed Indices</td><td>Not specific to a workout</td><td>Weeks 3, 12, 24</td></tr><tr><td>Game interest</td><td>Not specific to a workout</td><td>Week 24</td></tr></tbody></table></table-wrap>
</p>
        <sec id="Sec22">
          <title>Primary measures</title>
          <sec id="FPar1">
            <title>Effort</title>
            <p>Mean change in cycle ergometer workload (watts) from each participant&#x2019;s initial targeted workload (individually determined during max testing), as well as mean change in workload over 24&#xA0;weeks from baseline are the primary dependent variables reflecting work effort for both the continuous and 4-min. interval sessions. Without missing data, there are a total of 66 Continuous, 22 4&#x2009;&#xD7;&#x2009;4 min interval, 22 6&#x2009;&#xD7;&#x2009;2 min interval, and 22 sprint interval effort measures. Effort to persist in the 2-min interval workouts was measured in the number of seconds completed without decreasing intensity. Effort to persist was also measured in the sprint workouts by the number of intervals completed (up to a maximum of 8). Participant-controlled changes in watts above the target were not allowed in the 2-min interval workout, though they could decrease their watts if the workout at their prescribed watts was too difficult. In the sprint interval, participants could not decrease watts, but they could stop if unable to continue.</p>
          </sec>
          <sec id="FPar2">
            <title>Rating of perceived exertion (RPE)</title>
            <p>Along with an objective measure of effort, participants reported their subjective evaluation of effort levels throughout exercise, using the 15-point version of the Borg RPE scale (minimal effort&#x2009;=&#x2009;6; maximum effort&#x2009;=&#x2009;20, which when multiplied by 10 corresponds to an estimate of heart rate). Ratings were then averaged for each experimental session. We assessed RPE because perceptions of exertion also may influence one&#x2019;s motivation to persist at a taxing task [<xref ref-type="bibr" rid="CR17">17</xref>].</p>
          </sec>
          <sec id="FPar3">
            <title>VO<sub>2</sub>max. and ventilatory threshold</title>
            <p>The test was conducted using an electronic cycle ergometer, and expired respiratory gases were collected using a Parvo metabolic cart. The test ended when participants reached volitional exhaustion and stopped pedaling or were instructed to stop when they reached two out of three criteria indicating that they had achieved VO<sub>2</sub>max (i.e., plateau in VO<sub>2</sub> occurred, heart rate was higher than 95% of predicted, and respiratory exchange rate was over 1.05.) Ventilatory threshold values were calculated from the VO<sub>2</sub>max test data by identifying the breakpoint of pulmonary ventilation (VE) from VO<sub>2</sub> as described by Amann et al. These tests were measured at the time of screening, at Week 13, and at posttest [<xref ref-type="bibr" rid="CR18">18</xref>].</p>
          </sec>
          <sec id="FPar4">
            <title>Quadriceps and hamstring strength</title>
            <p>Isometric muscular strength was measured at the right knee (45&#xA0;deg, 5&#xA0;s contraction) including peak torque extension and peak torque flexion using the Biodex 3 dynamometer. Participants warmed-up with four repetitions of extension and flexion, followed by 3 repetitions each for the actual test. These tests were performed at the time of screening, at Week 12, and at posttest.</p>
          </sec>
          <sec id="FPar5">
            <title>Body composition</title>
            <p>Each participant&#x2019;s body density was measured via air displacement plethysmography (BodPod), and %fat and fat free mass were calculated according to standard equations.</p>
          </sec>
        </sec>
        <sec id="Sec23">
          <title>Secondary measures</title>
          <p>A number of psychological measures were taken to assess participants&#x2019; enjoyment, self-efficacy, social connectedness, and interest in the game. In addition, measures of participants&#x2019; perceptions of the SG partner were assessed for those in the partnered conditions.</p>
          <sec id="FPar6">
            <title>Enjoyment, social connectedness, and interest in the game</title>
            <p>Enjoyment was assessed with a 5-item version of the Physical Activity Enjoyment Scale [<xref ref-type="bibr" rid="CR19">19</xref>] regarding &#x201C;how you feel at the moment about the physical activity you have been doing.&#x201D; The Social Connectedness Scale [<xref ref-type="bibr" rid="CR20">20</xref>] was adapted to include six items to measure participants&#x2019; sense, in general, of companionship, togetherness, and relatedness during the exercise sessions. Game interest was assessed on the final day with a single item that asked participants to rate their interest in playing an exercise video.</p>
          </sec>
          <sec id="FPar7">
            <title>Self-efficacy</title>
            <p>Self-efficacy beliefs were measured pre- and post session for the continuous and 4-min interval workouts only. Pre-session efficacy was rated in terms of the up-coming workout and post-session efficacy was rated regarding beliefs about the next time the participant engaged in that workout. Participants rated their confidence on an 11-point probability scale that they could cycle for 30&#xA0;min (continuous workout) at six different intensities, starting at 75% of the participant&#x2019;s VO<sub>2</sub>max and increasing by 5% for each item up to 100%. For the 4-min interval workout, participants rated their confidence on the same scale that they could complete all four, 4-min intervals (4-min interval workout) starting at 90% of their VO<sub>2</sub> max and increasing by 5% up to 100% (i.e., 3 items).</p>
          </sec>
          <sec id="FPar8">
            <title>Additional perceptual measures</title>
            <p>To check for perceptions of the SG partner&#x2019;s humanness, participants in partnered conditions completed a questionnaire that used the Alternative Godspeed Indices [<xref ref-type="bibr" rid="CR21">21</xref>]. To check for participants&#x2019; perceptions of their partner as a teammate, partnered participants completed a 5-item questionnaire that assessed their perceptions of the working relationship with their partner (e.g., I felt I was part of a team) [<xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR23">23</xref>].</p>
          </sec>
          <sec id="FPar9">
            <title>Monitored measures</title>
            <p>Blood pressure and HR were monitored for safety. Blood pressure was measured using a GE Dinamap automatic blood pressure monitor. HR was measured using the Polar HR monitor during each exercise session. Additionally, participants were asked to recall any outside activity and record the activity and the duration they participated in the activity to account for any outside influences on performance and fitness measures.</p>
          </sec>
        </sec>
      </sec>
      <sec id="Sec24">
        <title>Statistical analyses</title>
        <p>For the continuous and 4-min. sessions, a blocked session repeated-measures analyses of variance (ANOVA) will be utilized to examine the effect of treatment on the primary motivational effort measure (mean change in power output) across conditions and across the study. Group and individual linear trend analyses and growth curve modeling will be applied to assess potential inter- versus intra-individual variability trajectories and patterns of change over the 24&#xA0;weeks. ANOVA will be used to analyze the mean differences for percent of cycling 2-min. intervals and 30-s. sprints at or above targeted level of effort. In all analyses of these measures, baseline performance measures will also be covaried to control for pre-program levels of fitness. Missing data will be evaluated for randomness and a within-subjects, same-session type linear interpolation will be used to impute the data set. Interpolation of missing data was chosen due to the nature of the effort measure (i.e., longitudinal objective measure of exercise effort).</p>
        <p>Hypotheses related to the effect of treatment on objective measures of fitness (e.g., VO<sub>2</sub>max measures; ventilatory threshold; isokinetic strength) will be tested using ANOVA at the pre, mid, and post-study time points.</p>
        <p>Given that prior research has found little evidence that enhanced effort achieved with conjunctive exercise partners is accompanied by any aversion to the exercise task, loss in self-efficacy, or rise in subjectively experienced exertion, we will check to see if these patterns replicate in this study. We will also examine self-reports of social connectedness both generally and toward the SG partner, in terms of feeling like a teammate. For each variable, we will use a general linear model to analyze means across the multiple time points administered and for the entire study, as well as correlations to blocked means for effort measures. We also will check for sex and age differences.</p>
      </sec>
    </sec>
    <sec id="Sec25">
      <title>Discussion</title>
      <p>This paper describes the rationale, development, and methods of the SPACE exergame program. This intervention was designed to maintain intense levels of exercise for astronauts and other adults who need to exercise at vigorous levels for health and performance purposes. We believe this will be a viable sustainable intervention that can be disseminated for astronaut use and adapted by other populations. The strengths of the study include the strong conceptual basis of group dynamics, using social psychological mechanisms such as social comparison and indispensability to group achievement to boost motivation (i.e., the level of effort) for vigorous physical exercise [<xref ref-type="bibr" rid="CR4">4</xref>]. In addition, the use of an SG partner embedded in an exergame has several practical advantages over a live human partner for astronauts as well as other populations. For instance, an SG partner&#x2019;s abilities can be adjusted automatically over time to perform at a level that is always challenging to the player, thereby keeping the player engaged and active.</p>
      <p>The study also has some limitations. The exercise program uses only the aerobic segment of NASA&#x2019;s SPRINT exercise regimen. Including the weight training component would provide a more thorough test of the effectiveness of an SG partner to sustain motivation in a vigorous exercise program. Additionally, participants did not live in an isolated environment, similar to what astronauts experience at the ISS or on deep space missions. The effects of an SG partner may be even stronger when used in an environment where inhabitants are socially isolated, especially in testing its social connections effects. Further, the interactions with the SG partner were relatively superficial and limited by the software. Having an SG partner with some artificial intelligence capabilities could enrich the social interaction such that the SG partner is more than just a cycling partner but also a relational agent.</p>
      <p>The authors plan to communicate results to participants and through a local community presentation. We plan to communicate scientific results through presentations at professional conferences and through publications in scientific journals.</p>
    </sec>
  </body>
  <back>
    <glossary>
      <title>Abbreviations</title>
      <def-list>
        <def-item>
          <term>AWS</term>
          <def>
            <p>Always superior condition</p>
          </def>
        </def-item>
        <def-item>
          <term>HR<sub>max</sub></term>
          <def>
            <p>Maximum heart rate</p>
          </def>
        </def-item>
        <def-item>
          <term>IRB</term>
          <def>
            <p>Institutional Review Board</p>
          </def>
        </def-item>
        <def-item>
          <term>ISS</term>
          <def>
            <p>International Space Station</p>
          </def>
        </def-item>
        <def-item>
          <term>ml/kg/min</term>
          <def>
            <p>Milliliters per kilogram per minute</p>
          </def>
        </def-item>
        <def-item>
          <term>NAS</term>
          <def>
            <p>Not always superior condition</p>
          </def>
        </def-item>
        <def-item>
          <term>NASA</term>
          <def>
            <p>National Aeronautics and Space Administration</p>
          </def>
        </def-item>
        <def-item>
          <term>NSBRI</term>
          <def>
            <p>National Space Biomedical Research Institute</p>
          </def>
        </def-item>
        <def-item>
          <term>PAES</term>
          <def>
            <p>Physical Activity Enjoyment Scale</p>
          </def>
        </def-item>
        <def-item>
          <term>RPE</term>
          <def>
            <p>Rating of perceived exertion</p>
          </def>
        </def-item>
        <def-item>
          <term>SG</term>
          <def>
            <p>Software-generated</p>
          </def>
        </def-item>
        <def-item>
          <term>SPACE</term>
          <def>
            <p>Simulated Partners and Collaborative Exercise</p>
          </def>
        </def-item>
        <def-item>
          <term>SPRINT</term>
          <def>
            <p>NASA&#x2019;s high intensity integrated resistance and aerobic training program</p>
          </def>
        </def-item>
        <def-item>
          <term>VE</term>
          <def>
            <p>Volume of expired respiratory gases</p>
          </def>
        </def-item>
        <def-item>
          <term>VO<sub>2</sub> max</term>
          <def>
            <p>Maximum rate of oxygen consumption</p>
          </def>
        </def-item>
      </def-list>
    </glossary>
    <ack>
      <sec id="FPar10">
        <title>Funding</title>
        <p>Space is funded by NASA/National Space Biomedical Research Institute, MA03401. The funding source has had no role in the design of the study and collection, analysis, and interpretation of data, nor in writing the manuscript.</p>
      </sec>
      <sec id="FPar11">
        <title>Availability of data and materials</title>
        <p>The dataset that will be analyzed during the current study will be available from the corresponding author on reasonable request. There will be no personal identification of participants in the data set.</p>
      </sec>
      <sec id="FPar12">
        <title>Authors&#x2019; contributions</title>
        <p>DF drafted the manuscript, conceived of the study, and was principal investigator of the study design. LPS and NK conceived of the study, contributed to the study design, and draft of the manuscript. BW, JP, and AE contributed to the study design and draft of the manuscript. WJ contributed to the study design. CH and SS contributed to the draft of the manuscript. All authors read and approved the final manuscript.</p>
      </sec>
      <sec id="FPar13">
        <title>Competing interests</title>
        <p>The authors declare that they have no competing interests.</p>
      </sec>
      <sec id="FPar14">
        <title>Consent for publication</title>
        <p>Not applicable.</p>
      </sec>
      <sec id="FPar15">
        <title>Ethics approval and consent to participate</title>
        <p>The Social Science Behavioral/Education Institutional Review Board of the Human Research Protection Programs at Michigan State University approved this study (reference number: 13-554). Members of the research team obtained written informed consent from participants. Potential participants could decide whether to participate in the study after reading the consent form and asking questions. Prior to enrollment of participants, guidelines were established for identifying adverse events and serious adverse events. Data have been handled in strict confidence and stored anonymously by identification code only. There will be no personal identification of participants in scientific communications. Records will be kept in locked file cabinets and secure computer files at the University, and only the principal investigator, project manager, and formal, Institutional Review Board (IRB), research team members will have access to the data set. Any adverse events or serious adverse events will be communicated immediately to the IRB.</p>
      </sec>
    </ack>
    <ref-list id="Bib1">
      <title>References</title>
      <ref id="CR1">
        <label>1.</label>
        <mixed-citation publication-type="other">Ploutz-Snyder LL, Downs M, Ryder J, Hackney K, Scott J, Buxton R, Goetchius E, Crowell B. Integrated resistance and aerobic exercise protects fitness during bed rest. Med Sci Sports Exerc. 2014;358-68. doi:10.1249/MSS.0b013e3182a62f85.</mixed-citation>
      </ref>
      <ref id="CR2">
        <label>2.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Byrne</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Byrne</surname>
              <given-names>DG</given-names>
            </name>
          </person-group>
          <article-title>The effect of exercise on depression, anxiety and other mood states: a review</article-title>
          <source>J Psychosom Res</source>
          <year>1993</year>
          <volume>37</volume>
          <fpage>565</fpage>
          <lpage>74</lpage>
          <pub-id pub-id-type="doi">10.1016/0022-3999(93)90050-P</pub-id>
          <pub-id pub-id-type="pmid">8410742</pub-id>
        </element-citation>
      </ref>
      <ref id="CR3">
        <label>3.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>McAuley</surname>
              <given-names>EB</given-names>
            </name>
            <name>
              <surname>Blissmer</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Marquez</surname>
              <given-names>DX</given-names>
            </name>
            <name>
              <surname>Jerome</surname>
              <given-names>GJ</given-names>
            </name>
            <name>
              <surname>Kramer</surname>
              <given-names>AF</given-names>
            </name>
            <name>
              <surname>Katula</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Social relations, physical activity, and well-being in older adults</article-title>
          <source>Prev Med</source>
          <year>2000</year>
          <volume>31</volume>
          <fpage>608</fpage>
          <lpage>17</lpage>
          <pub-id pub-id-type="doi">10.1006/pmed.2000.0740</pub-id>
          <pub-id pub-id-type="pmid">11071843</pub-id>
        </element-citation>
      </ref>
      <ref id="CR4">
        <label>4.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Feltz</surname>
              <given-names>DL</given-names>
            </name>
            <name>
              <surname>Kerr</surname>
              <given-names>NL</given-names>
            </name>
            <name>
              <surname>Irwin</surname>
              <given-names>BC</given-names>
            </name>
          </person-group>
          <article-title>Buddy up: the Kohler effect applied to health games</article-title>
          <source>J Sport Exerc Psychol</source>
          <year>2011</year>
          <volume>33</volume>
          <fpage>506</fpage>
          <lpage>26</lpage>
          <pub-id pub-id-type="doi">10.1123/jsep.33.4.506</pub-id>
          <pub-id pub-id-type="pmid">21808077</pub-id>
        </element-citation>
      </ref>
      <ref id="CR5">
        <label>5.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bickmore</surname>
              <given-names>TW</given-names>
            </name>
            <name>
              <surname>Picard</surname>
              <given-names>RW</given-names>
            </name>
          </person-group>
          <article-title>Establishing and maintaining long-term human-computer relationships</article-title>
          <source>ACM Trans Comput Hum Interact</source>
          <year>2005</year>
          <volume>12</volume>
          <fpage>293</fpage>
          <lpage>327</lpage>
          <pub-id pub-id-type="doi">10.1145/1067860.1067867</pub-id>
        </element-citation>
      </ref>
      <ref id="CR6">
        <label>6.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Feltz</surname>
              <given-names>DL</given-names>
            </name>
            <name>
              <surname>Forlenza</surname>
              <given-names>ST</given-names>
            </name>
            <name>
              <surname>Winn</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Kerr</surname>
              <given-names>NL</given-names>
            </name>
          </person-group>
          <article-title>Cyber buddy is better than no buddy: A test of the K&#xF6;hler motivation effect in exergame</article-title>
          <source>Games Health J</source>
          <year>2014</year>
          <volume>3</volume>
          <fpage>98</fpage>
          <lpage>105</lpage>
          <pub-id pub-id-type="doi">10.1089/g4h.2013.0088</pub-id>
          <pub-id pub-id-type="pmid">26196051</pub-id>
        </element-citation>
      </ref>
      <ref id="CR7">
        <label>7.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Max</surname>
              <given-names>EJ</given-names>
            </name>
            <name>
              <surname>Samendinger</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Winn</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Kerr</surname>
              <given-names>NL</given-names>
            </name>
            <name>
              <surname>Pfeiffer</surname>
              <given-names>KA</given-names>
            </name>
            <name>
              <surname>Feltz</surname>
              <given-names>DL</given-names>
            </name>
          </person-group>
          <article-title>Enhancing aerobic exercise with a novel virtual exercise buddy based on the K&#xF6;hler effect</article-title>
          <source>Games Health J</source>
          <year>2016</year>
          <volume>5</volume>
          <fpage>1</fpage>
          <lpage>6</lpage>
          <pub-id pub-id-type="doi">10.1089/g4h.2016.0018</pub-id>
          <pub-id pub-id-type="pmid">26262772</pub-id>
        </element-citation>
      </ref>
      <ref id="CR8">
        <label>8.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nass</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Moon</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Carney</surname>
              <given-names>P</given-names>
            </name>
          </person-group>
          <article-title>Are people polite to computers? Responses to computer-based interviewing systems</article-title>
          <source>J Appl Soc Psychol</source>
          <year>1999</year>
          <volume>29</volume>
          <issue>5</issue>
          <fpage>1093</fpage>
          <lpage>110</lpage>
          <pub-id pub-id-type="doi">10.1111/j.1559-1816.1999.tb00142.x</pub-id>
        </element-citation>
      </ref>
      <ref id="CR9">
        <label>9.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Burke</surname>
              <given-names>SM</given-names>
            </name>
            <name>
              <surname>Carron</surname>
              <given-names>AV</given-names>
            </name>
            <name>
              <surname>Eys</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Ntoumanis</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Estabrooks</surname>
              <given-names>PA</given-names>
            </name>
          </person-group>
          <article-title>Group versus individual approach? A meta-analysis of the effectiveness of interventions to promote physical activity</article-title>
          <source>Sport Exerc Psychol Rev</source>
          <year>2006</year>
          <volume>2</volume>
          <issue>1</issue>
          <fpage>13</fpage>
          <lpage>29</lpage>
        </element-citation>
      </ref>
      <ref id="CR10">
        <label>10.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Dishman</surname>
              <given-names>RK</given-names>
            </name>
            <name>
              <surname>Buckworth</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Increasing physical activity: a quantitative synthesis</article-title>
          <source>Med Sci Sports Exerc</source>
          <year>1996</year>
          <volume>28</volume>
          <fpage>706</fpage>
          <lpage>19</lpage>
          <pub-id pub-id-type="doi">10.1097/00005768-199606000-00010</pub-id>
          <pub-id pub-id-type="pmid">8784759</pub-id>
        </element-citation>
      </ref>
      <ref id="CR11">
        <label>11.</label>
        <mixed-citation publication-type="other">Yim J, Graham TCN. Using games to increase exercise motivation. Paper presented at: Conference on Future Play 2007; New York.</mixed-citation>
      </ref>
      <ref id="CR12">
        <label>12.</label>
        <mixed-citation publication-type="other">Lieberman DA. Dance games and other exergames: What the research says. 2006. <ext-link ext-link-type="uri" xlink:href="http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=0E6FFDAB4AB375D49E2696948FEFE8E3?doi=10.1.1.403.8924&amp;rep=rep1&amp;type=pdf">http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=0E6FFDAB4AB375D49E2696948FEFE8E3?doi=10.1.1.403.8924&amp;rep=rep1&amp;type=pdf</ext-link>.</mixed-citation>
      </ref>
      <ref id="CR13">
        <label>13.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Madsen</surname>
              <given-names>KA</given-names>
            </name>
            <name>
              <surname>Yen</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Wlasiuk</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Newman</surname>
              <given-names>TB</given-names>
            </name>
            <name>
              <surname>Lustig</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title>Feasability of a dance videogame to promote weight loss among overweight children and adolescents</article-title>
          <source>Arch Pediatr Adolesc Med</source>
          <year>2007</year>
          <volume>161</volume>
          <fpage>105</fpage>
          <lpage>7</lpage>
          <pub-id pub-id-type="doi">10.1001/archpedi.161.1.105-c</pub-id>
          <pub-id pub-id-type="pmid">17199076</pub-id>
        </element-citation>
      </ref>
      <ref id="CR14">
        <label>14.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Weber</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Hertel</surname>
              <given-names>G</given-names>
            </name>
          </person-group>
          <article-title>Motivation gains of inferior group members: a meta-analytical review</article-title>
          <source>J Pers Soc Psychol</source>
          <year>2007</year>
          <volume>93</volume>
          <issue>6</issue>
          <fpage>973</fpage>
          <lpage>93</lpage>
          <pub-id pub-id-type="doi">10.1037/0022-3514.93.6.973</pub-id>
          <pub-id pub-id-type="pmid">18072849</pub-id>
        </element-citation>
      </ref>
      <ref id="CR15">
        <label>15.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Parise</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Kiesler</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Sproull</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Waters</surname>
              <given-names>K</given-names>
            </name>
          </person-group>
          <article-title>Cooperating with life-like interface agents</article-title>
          <source>Comput Hum Behav</source>
          <year>1999</year>
          <volume>15</volume>
          <fpage>123</fpage>
          <lpage>42</lpage>
          <pub-id pub-id-type="doi">10.1016/S0747-5632(98)00035-1</pub-id>
        </element-citation>
      </ref>
      <ref id="CR16">
        <label>16.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Irwin</surname>
              <given-names>BC</given-names>
            </name>
            <name>
              <surname>Scorniaenchi</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Kerr</surname>
              <given-names>NL</given-names>
            </name>
            <name>
              <surname>Eisenmann</surname>
              <given-names>JC</given-names>
            </name>
            <name>
              <surname>Feltz</surname>
              <given-names>DL</given-names>
            </name>
          </person-group>
          <article-title>Aerobic exercise is promoted when individual performance affects the group: a test of the Kohler motivation gain effect</article-title>
          <source>Ann Behav Med</source>
          <year>2012</year>
          <volume>44</volume>
          <fpage>151</fpage>
          <lpage>9</lpage>
          <pub-id pub-id-type="doi">10.1007/s12160-012-9367-4</pub-id>
          <pub-id pub-id-type="pmid">22576339</pub-id>
        </element-citation>
      </ref>
      <ref id="CR17">
        <label>17.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Borg</surname>
              <given-names>GAV</given-names>
            </name>
          </person-group>
          <article-title>Psychophysical bases of perceived exertion</article-title>
          <source>Med Sci Sports Exerc</source>
          <year>1982</year>
          <volume>14</volume>
          <issue>5</issue>
          <fpage>377</fpage>
          <lpage>81</lpage>
          <pub-id pub-id-type="doi">10.1249/00005768-198205000-00012</pub-id>
          <pub-id pub-id-type="pmid">7154893</pub-id>
        </element-citation>
      </ref>
      <ref id="CR18">
        <label>18.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Amann</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Subudhi</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Foster</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <article-title>Influence of testing protocol on ventilatory thresholds and cycling performance</article-title>
          <source>Med Sci Sports Exer</source>
          <year>2004</year>
          <volume>36</volume>
          <fpage>613</fpage>
          <lpage>22</lpage>
          <pub-id pub-id-type="doi">10.1249/01.MSS.0000122076.21804.10</pub-id>
        </element-citation>
      </ref>
      <ref id="CR19">
        <label>19.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Raedeke</surname>
              <given-names>TD</given-names>
            </name>
            <name>
              <surname>Amorose</surname>
              <given-names>AJ</given-names>
            </name>
          </person-group>
          <article-title>A psychometric evaluation of a short exercise enjoyment measure</article-title>
          <source>J Sport Exerc Psychol</source>
          <year>2013</year>
          <volume>35</volume>
          <fpage>S110</fpage>
          <pub-id pub-id-type="doi">10.1123/jsep.35.1.110</pub-id>
        </element-citation>
      </ref>
      <ref id="CR20">
        <label>20.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Lee</surname>
              <given-names>RM</given-names>
            </name>
            <name>
              <surname>Robbins</surname>
              <given-names>SB</given-names>
            </name>
          </person-group>
          <article-title>Measuring belongingness: the Social Connectedness and Social Assurance Scale</article-title>
          <source>J Couns Psychol</source>
          <year>1995</year>
          <volume>42</volume>
          <fpage>232</fpage>
          <lpage>41</lpage>
          <pub-id pub-id-type="doi">10.1037/0022-0167.42.2.232</pub-id>
        </element-citation>
      </ref>
      <ref id="CR21">
        <label>21.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ho</surname>
              <given-names>CC</given-names>
            </name>
            <name>
              <surname>MacDorman</surname>
              <given-names>KF</given-names>
            </name>
          </person-group>
          <article-title>Revisiting the uncanny valley theory: Developing and validating an alternative to the Godspeed indices</article-title>
          <source>Comput Hum Behav</source>
          <year>2010</year>
          <volume>26</volume>
          <fpage>1508</fpage>
          <lpage>18</lpage>
          <pub-id pub-id-type="doi">10.1016/j.chb.2010.05.015</pub-id>
        </element-citation>
      </ref>
      <ref id="CR22">
        <label>22.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Irwin</surname>
              <given-names>BC</given-names>
            </name>
            <name>
              <surname>Feltz</surname>
              <given-names>DL</given-names>
            </name>
            <name>
              <surname>Kerr</surname>
              <given-names>NL</given-names>
            </name>
          </person-group>
          <article-title>Silence is golden: effect of encouragement in motivating the weak link in an online exercise video game</article-title>
          <source>J Med Internet Res</source>
          <year>2013</year>
          <volume>15</volume>
          <issue>6</issue>
          <fpage>e104</fpage>
          <pub-id pub-id-type="doi">10.2196/jmir.2551</pub-id>
          <pub-id pub-id-type="pmid">23732514</pub-id>
        </element-citation>
      </ref>
      <ref id="CR23">
        <label>23.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Reeves</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Nass</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <source>The media equation</source>
          <year>1996</year>
          <publisher-loc>Stanford</publisher-loc>
          <publisher-name>CSLI Publicaqtions</publisher-name>
        </element-citation>
      </ref>
    </ref-list>
  </back>
</article>
</pmc-articleset>

PMC6588870.nxml

<?xml version="1.0" ?>
<!DOCTYPE pmc-articleset PUBLIC "-//NLM//DTD ARTICLE SET 2.0//EN" "https://dtd.nlm.nih.gov/ncbi/pmc/articleset/nlm-articleset-2.0.dtd">
<pmc-articleset><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" article-type="research-article">
  <?properties open_access?>
  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">BMC Psychol</journal-id>
      <journal-id journal-id-type="iso-abbrev">BMC Psychol</journal-id>
      <journal-title-group>
        <journal-title>BMC Psychology</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2050-7283</issn>
      <publisher>
        <publisher-name>BioMed Central</publisher-name>
        <publisher-loc>London</publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="pmid">31227016</article-id>
      <article-id pub-id-type="pmc">6588870</article-id>
      <article-id pub-id-type="publisher-id">310</article-id>
      <article-id pub-id-type="doi">10.1186/s40359-019-0310-3</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Research Article</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Offering mental health first aid to a person with depression: a Delphi study to re-develop the guidelines published in 2008</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author" corresp="yes">
          <contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5577-2292</contrib-id>
          <name>
            <surname>Bond</surname>
            <given-names>Kathy S.</given-names>
          </name>
          <address>
            <email>kathybond@mhfa.com.au</email>
          </address>
          <xref ref-type="aff" rid="Aff1">1</xref>
          <xref ref-type="aff" rid="Aff2">2</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cottrill</surname>
            <given-names>Fairlie A.</given-names>
          </name>
          <address>
            <email>fairliec@mhfa.com.au</email>
          </address>
          <xref ref-type="aff" rid="Aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Blee</surname>
            <given-names>Fiona L.</given-names>
          </name>
          <address>
            <email>fionalblee@gmail.com</email>
          </address>
          <xref ref-type="aff" rid="Aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Kelly</surname>
            <given-names>Claire M.</given-names>
          </name>
          <address>
            <email>clairek@mhfa.com.au</email>
          </address>
          <xref ref-type="aff" rid="Aff1">1</xref>
          <xref ref-type="aff" rid="Aff3">3</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Kitchener</surname>
            <given-names>Betty A.</given-names>
          </name>
          <address>
            <email>betty.kitchener@deakin.edu.au</email>
          </address>
          <xref ref-type="aff" rid="Aff3">3</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Jorm</surname>
            <given-names>Anthony F.</given-names>
          </name>
          <address>
            <email>ajorm@unimelb.edu.au</email>
          </address>
          <xref ref-type="aff" rid="Aff2">2</xref>
        </contrib>
        <aff id="Aff1"><label>1</label>Mental Health First Aid Australia, Parkville, Victoria Australia </aff>
        <aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2179 088X</institution-id><institution-id institution-id-type="GRID">grid.1008.9</institution-id><institution>Centre for Mental Health, Melbourne School of Population and Global Health, </institution><institution>University of Melbourne, </institution></institution-wrap>Parkville, Victoria Australia </aff>
        <aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0526 7079</institution-id><institution-id institution-id-type="GRID">grid.1021.2</institution-id><institution>Department of Psychology, Faculty of Health, </institution><institution>Deakin University, </institution></institution-wrap>Burwood, Victoria Australia </aff>
      </contrib-group>
      <pub-date pub-type="epub">
        <day>21</day>
        <month>6</month>
        <year>2019</year>
      </pub-date>
      <pub-date pub-type="pmc-release">
        <day>21</day>
        <month>6</month>
        <year>2019</year>
      </pub-date>
      <pub-date pub-type="collection">
        <year>2019</year>
      </pub-date>
      <volume>7</volume>
      <elocation-id>37</elocation-id>
      <history>
        <date date-type="received">
          <day>2</day>
          <month>10</month>
          <year>2018</year>
        </date>
        <date date-type="accepted">
          <day>31</day>
          <month>5</month>
          <year>2019</year>
        </date>
      </history>
      <permissions>
        <copyright-statement>&#xA9; The Author(s). 2019</copyright-statement>
        <license license-type="OpenAccess">
          <license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p>
        </license>
      </permissions>
      <abstract id="Abs1">
        <sec>
          <title>Background</title>
          <p id="Par1">Depressive disorder is ranked as the largest contributor to non-fatal health burden. However, with prompt treatment, outcomes can improve. Family and friends are well placed to recognise the signs of depression and encourage early help seeking. Guidelines about how members of the public can provide mental health first aid to someone who is experiencing depression were developed in 2008. A Delphi study was conducted to re-develop these guidelines to ensure they are current and reflect best practice.</p>
        </sec>
        <sec>
          <title>Methods</title>
          <p id="Par2">A survey was developed using the 2008 depression mental health first aid guidelines and a systematic search of grey and academic literature. The questionnaire contained items about providing mental health first aid to a person with depression. These items were rated by two international expert panels &#x2013; a lived experience panel (consumers and carers) and a professional panel.</p>
        </sec>
        <sec>
          <title>Results</title>
          <p id="Par3">Three hundred and fifty-two items were rated by 53 experts (36 with lived experience and 17 professionals) according to whether they should be included in the revised guidelines. There were 183 items that met the criteria to be included in the updated guidelines.</p>
        </sec>
        <sec>
          <title>Conclusions</title>
          <p id="Par4">This re-development has added detail to the previous version of the guidelines, giving more guidance on the role of the first aider and allowing for a more nuanced approach to providing first aid to someone with depression. These guidelines are available to the public and will be used to update the Mental Health First Aid courses.</p>
        </sec>
        <sec>
          <title>Electronic supplementary material</title>
          <p>The online version of this article (10.1186/s40359-019-0310-3) contains supplementary material, which is available to authorized users.</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="en">
        <title>Keywords</title>
        <kwd>Depression</kwd>
        <kwd>Mental health first aid</kwd>
        <kwd>Delphi study</kwd>
      </kwd-group>
      <custom-meta-group>
        <custom-meta>
          <meta-name>issue-copyright-statement</meta-name>
          <meta-value>&#xA9; The Author(s) 2019</meta-value>
        </custom-meta>
      </custom-meta-group>
    </article-meta>
  </front>
  <body>
    <sec id="Sec1">
      <title>Background</title>
      <p id="Par6">In 2015 it was estimated that 4.4% of the world&#x2019;s population experienced a depressive disorder in the past year, and these disorders were ranked as the largest contributor to non-fatal health burden [<xref ref-type="bibr" rid="CR1">1</xref>]. If depression is not treated promptly, outcomes tend to be worse and the person is more likely to have subsequent and worse episodes of depression [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>].</p>
      <p id="Par7">Family and friends are well placed to recognise the signs of depression and assist a person with depression to get early help. While the public&#x2019;s knowledge about depression is higher than for other mental health conditions, such as anxiety disorder and psychosis [<xref ref-type="bibr" rid="CR3">3</xref>], this does not necessarily translate into knowing what actions to take to support a person with depression [<xref ref-type="bibr" rid="CR4">4</xref>]. For this reason, the Mental Health First Aid (MHFA)&#xA0;course was developed [<xref ref-type="bibr" rid="CR5">5</xref>]. The course teaches adults how to recognise when someone is developing a mental health problem or crisis and to assist them by offering mental health first aid. Similar to physical first aid, mental health first aid is offered by members of the public to their friends, family, co-workers, etc. and is defined as [<xref ref-type="bibr" rid="CR6">6</xref>]:<disp-quote><p id="Par8">
<italic>The help offered to a person developing a mental health problem, experiencing a worsening of an existing mental health problem or in a mental health crisis. The first aid is given until appropriate professional help is received or until the crisis resolves.</italic>
</p></disp-quote>The MHFA&#xA0;course has been extensively evaluated and shown to improve knowledge about mental health problems, the ability to recognise a mental health problem and confidence in the ability to help a person with a mental health problem [<xref ref-type="bibr" rid="CR7">7</xref>].</p>
      <p id="Par9">The content of this course is based on a series of expert consensus guidelines developed using the Delphi method (e.g. [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR9">9</xref>]), including guidelines on how to provide mental health first aid for depression, developed in 2008 [<xref ref-type="bibr" rid="CR10">10</xref>]. These guidelines were used to inform the content of the 2nd, 3rd and 4th editions of the Australian MHFA course, which is the parent of MHFA courses internationally [<xref ref-type="bibr" rid="CR5">5</xref>, <xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR12">12</xref>]. These guidelines are available on the MHFA Australia website. The usefulness of these guidelines to people who download them from the website was evaluated by Hart and colleagues [<xref ref-type="bibr" rid="CR13">13</xref>]. They found that the guidelines contributed to a meaningful conversation about the person&#x2019;s mental health problems, and in some cases the person sought professional help. The users of the guidelines stated they were able to assist in a way that was knowledgeable and supportive. The guidelines are a general set of recommendations, and because each person is unique, the guidelines may not be suitable to every situation. However, they are designed to be useful for most people, most of the time. To ensure that the guidelines are current and reflect best practice, they are updated on a regular schedule, similar to clinical practice guidelines being regularly updated (e.g. [<xref ref-type="bibr" rid="CR14">14</xref>]). With the MHFA Australia guidelines, this re-development is carried out at least every 10 years, using the Delphi method. The mental health first aid guidelines for suicidal thoughts and behaviours, and non-suicidal self-injury were the first guidelines to be revised using the Delphi method and significant revisions were indicated, specifically a number of&#xA0;more detailed and specific first aid actions were recommended [<xref ref-type="bibr" rid="CR15">15</xref>, <xref ref-type="bibr" rid="CR16">16</xref>] further justifying the need to regularly revise the full suite of guidelines.</p>
      <p id="Par10">The Delphi method is a systematic way of determining expert consensus [<xref ref-type="bibr" rid="CR17">17</xref>] and it is often used to develop guidelines using practice-based evidence. It is considered an ethical and feasible way to develop guidelines on a topic that is not amenable to evaluation using other methods, e.g. randomised controlled trials. The method can be implemented online, allowing expert consensus to be obtained from participants located in many countries. Development of the current guidelines followed the protocol of similar Delphi studies conducted on topics such as mental health first aid guidelines for non-suicidal self-injury and assisting Australians with mental health problems and financial difficulties [<xref ref-type="bibr" rid="CR18">18</xref>].</p>
      <p id="Par11">The aim of this study was to re-develop the 2008 Mental Health First Aid Guidelines for Depression [<xref ref-type="bibr" rid="CR10">10</xref>] using the Delphi method to ascertain the consensus of international experts from high-income western countries. As expertise on how to give mental health first aid may come from either professional or personal experience, the study required the consensus of panels of consumers, carers and mental health professionals.</p>
    </sec>
    <sec id="Sec2">
      <title>Methods</title>
      <p id="Par12">This Delphi study was conducted in four steps: (1) recruit expert panel members (participants), (2) conduct literature search and develop survey, (3) collect and analyse data and (4) re-develop the 2008 guidelines.</p>
      <sec id="Sec3">
        <title>Step 1: recruit expert panels</title>
        <p id="Par13">People from high-income countries that have licenced the Mental Health First Aid program (Australia, Canada, Denmark, England, Finland, Ireland, The Netherlands, New Zealand, Northern Ireland, Scotland, Sweden, The United States and Wales) were invited to join one of three expert panels: Consumer, Carer or Professional. Researchers aimed to recruit at least 30 participants to each panel to allow for attrition and produce stable results [<xref ref-type="bibr" rid="CR17">17</xref>].</p>
        <p id="Par14">Participants were recruited by sending a flyer to Australian and international networks, instructors associated with MHFA Australia, and to Australian and international mental health promotion and professional organisations, peak bodies, and advocacy and carer groups. Participants were asked to pass the flyer on to anyone they thought might be interested in participating.</p>
        <p id="Par15">As per previous Delphi studies (e.g. [<xref ref-type="bibr" rid="CR19">19</xref>]), participants had to be 18&#x2009;years or older. The specific expert panel selection criteria were:<list list-type="bullet"><list-item><p id="Par16">Consumer panel &#x2013; Have a lived experience of depression with the depression being currently well managed <bold>AND</bold> be involved in activities that expose the participant to&#xA0;a broader experience of depression, e.g. advisory or advocacy group, peer support, etc.</p></list-item><list-item><p id="Par17">Carer panel &#x2013; Have experience in providing day-to-day support to someone with depression <bold>AND</bold> be involved in activities that expose the participant to&#xA0;a broader experience of depression, e.g. advisory or advocacy group, peer support, etc.</p></list-item><list-item><p id="Par18">Professional panel &#x2013; have at least 2&#x2009;years&#x2019; experience as a mental health professional or researcher in the field of depression.</p></list-item></list></p>
      </sec>
      <sec id="Sec4">
        <title>Step 2: literature search and survey development</title>
        <p id="Par19">The first author conducted a literature search of both the &#x2018;grey&#x2019; and academic literature in May 2016 to gather statements about how to provide mental health first aid to a person with depression. The literature search was conducted using Google Australia, Google USA, Google UK, Google Books and Google Scholar. Google Scholar was the only academic search engine used because it has a much broader interdisciplinary coverage than other databases and also covers grey academic literature. Our previous experience has been that searches of other databases covering research and professional literature rarely produce information relevant to lay mental health first aid strategies. The key search terms were &#x2018;depression&#x2019;, &#x2018;clinical depression&#x2019;, &#x2018;major depressive disorder&#x2019;, &#x2018;depression carers&#x2019;, &#x2018;support depression sufferers&#x2019; and &#x2018;help depression&#x2019;. These terms were the terms used in the original Delphi study [<xref ref-type="bibr" rid="CR20">20</xref>]. The following terms were also included:<list list-type="bullet"><list-item><p id="Par20">&#x2018;how to help someone with depression&#x2019; - generated because this is likely the phrasing a member of the public would use</p></list-item><list-item><p id="Par21">&#x2018;major depressive episode&#x2019; - generated because this is the term used in DSM 5 diagnostic criteria</p></list-item><list-item><p id="Par22">&#x2018;first aid for depression&#x2019; - generated because applying the concept of first aid for mental health problems is a more common concept than it was at the time of the first Delphi study.</p></list-item></list></p>
        <p id="Par23">Based on previous similar Delphi studies [<xref ref-type="bibr" rid="CR18">18</xref>], the first 50 websites, journal articles and books for each of the search terms were retrieved and reviewed for relevant information. The decision to only examine the first 50 websites, books and journal articles for each search term is based on previous Delphi studies that found that the quality of the resources declined rapidly after the first 50 [<xref ref-type="bibr" rid="CR21">21</xref>].</p>
        <p id="Par24">In order to minimise the influence of Google&#x2019;s searching algorithms the following steps were taken: signing out of any Google profiles, clearing the search history, disabling location features and deselecting &#x2018;any country&#x2019;. Links appearing in the websites were reviewed. Websites, articles and books were excluded if they were a duplicate, did not contain information about mental health first aid or were published before the date of the previous Delphi literature search (2007). The content from 137 websites, 19 books and one journal article were analysed to develop the survey with helping statements collated from these sources and reviewed by the research team to ensure that consistent, simple language was used. Figure&#xA0;<xref rid="Fig1" ref-type="fig">1</xref> summarises the literature search results.<fig id="Fig1"><label>Fig. 1</label><caption><p>Summary of Literature Search</p></caption><graphic xlink:href="40359_2019_310_Fig1_HTML" id="MO1"/></fig></p>
        <p id="Par25">The first author extracted the information from the articles, websites and books and drafted survey items. The research team reviewed the original extracted text and the drafted survey items to finalise them (see Fig.&#xA0;<xref rid="Fig2" ref-type="fig">2</xref> for examples). The survey was administered via SurveyMonkey. Participants rated the survey items, &#x201C;using a 5-point Likert scale (&#x2018;essential&#x2019;, &#x2018;important&#x2019;, &#x2018;don&#x2019;t know/depends&#x2019;, &#x2018;unimportant&#x2019; or &#x2018;should not be included&#x2019;), according to whether or not they should be included in the guidelines&#x201D; [<xref ref-type="bibr" rid="CR22">22</xref>].<fig id="Fig2"><label>Fig. 2</label><caption><p>Example of development of survey items</p></caption><graphic xlink:href="40359_2019_310_Fig2_HTML" id="MO2"/></fig></p>
      </sec>
      <sec id="Sec5">
        <title>Step 3: data collection and analysis</title>
        <p id="Par26">Between March 2017 and April 2018, data were collected over three rounds of a survey. The Round 1 survey included the survey items developed using the literature search described above and open-ended questions asking for participant comments or suggested new items. The Round 2 survey consisted of these new items and any items needing to be re-rated because they did not receive clear consensus (see point 2 below). The Round 3 survey consisted of items that were new in Round 2 that did not receive clear consensus. See Additional file <xref rid="MOESM1" ref-type="media">1</xref> for copies of the 3 survey rounds.</p>
        <p id="Par27">After participants completed a survey round, the survey items were categorised as follows:<list list-type="order"><list-item><p id="Par28">Endorsed. The item received an &#x2018;essential&#x2019; or &#x2018;important&#x2019; rating from at least 80% of participants from each of the panels.</p></list-item><list-item><p id="Par29">Re-rate. The item received an &#x2018;essential&#x2019; or &#x2018;important&#x2019; rating from 70 to 79% of participants from each of the panels or 80% or more from at least one panel and 70&#x2013;79% from the remaining panels.</p></list-item><list-item><p id="Par30">Rejected. Item did not meet the criteria to be endorsed or re-rated.</p></list-item></list></p>
        <p id="Par31">If a re-rated item did not receive an &#x2018;essential&#x2019; or &#x2018;important&#x2019; rating from 80% or more of participants in each of the panels, it was rejected.</p>
        <p id="Par32">The comments collected in Round 1 were analysed by the working group to develop new items that were not included in the Round 1 survey.</p>
        <p id="Par33">Participants were given a report of Round 1 and 2 responses that included the items that were endorsed, rejected, and the ones that needed to be re-rated in the next Round. For each item that needed to be re-rated, the report included each panel&#x2019;s percentages for each rating (i.e. &#x201C;essential&#x201D;, &#x201C;important&#x201D;, etc) and the participant&#x2019;s individual score. Participants could use this report to compare their ratings with each panel&#x2019;s ratings and decide if they wanted to change their rating score.</p>
      </sec>
      <sec id="Sec6">
        <title>Step 4: re-develop the 2008 guidelines</title>
        <p id="Par34">The first author wrote the endorsed items into a guidelines document, combining survey items and deleting repetition as needed. However, the original wording was retained as much as possible. Examples and explanatory notes were used for clarification of items. The working group reviewed this draft and it was given to participants for final comment and endorsement.</p>
      </sec>
      <sec id="Sec7">
        <title>Ethics, consent and permissions</title>
        <p id="Par35">This research was approved by the University of Melbourne Human Ethics Committee (ID#1648030). Informed consent, including permission to report individual participant&#x2019;s de-identified qualitative data, was obtained from all participants by clicking &#x2018;yes&#x2019; to a question about informed consent in the Round 1 survey.</p>
      </sec>
    </sec>
    <sec id="Sec8">
      <title>Results</title>
      <sec id="Sec9">
        <title>Participants</title>
        <p id="Par36">Eighty-six people were recruited and 53 completed all three survey rounds (see Table&#xA0;<xref rid="Tab1" ref-type="table">1</xref> for the retention rate for each of the panels). Of the 53 who completed all three rounds, 38 were females, 14 were males and one person did not wish to disclose their gender. The average age of participants was 46.5&#x2009;years (SD&#x2009;=&#x2009;11.61, range 21&#x2013;69). Participants were from Australia, UK, Ireland, Canada and the USA. The professional panel included educators, researchers, nurses, social workers and psychologists.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Retention rate</p></caption><table frame="hsides" rules="groups"><thead><tr><th/><th>Round 1</th><th>Round 2</th><th>Round 3</th><th>Retention</th></tr></thead><tbody><tr><td>Lived Experience</td><td>60</td><td>38</td><td>36</td><td>60%</td></tr><tr><td>Professional</td><td>26</td><td>22</td><td>17</td><td>65%</td></tr><tr><td>Total</td><td>86</td><td>60</td><td>53</td><td>62%</td></tr></tbody></table></table-wrap></p>
        <p id="Par37">It was difficult to recruit enough professional and carer experts to allow for stable results. Many of the carers also had professional experience so, with their permission, they were re-allocated to the professional panel. The one carer with no secondary experience was combined with the consumer panel to form a &#x2018;lived experience&#x2019; panel. This was deemed reasonable given the high correlations across items between the panels (see Table&#xA0;<xref rid="Tab2" ref-type="table">2</xref>) and is in line with other similar Delphi studies [<xref ref-type="bibr" rid="CR12">12</xref>].<table-wrap id="Tab2"><label>Table 2</label><caption><p>Pearson&#x2019;s correlations across items between panels</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Panels</th><th>Pearson&#x2019;s correlation</th></tr></thead><tbody><tr><td>Consumer and Carer</td><td>0.91</td></tr><tr><td>Consumer and prof</td><td>0.93</td></tr><tr><td>Carer and prof</td><td>0.90</td></tr></tbody></table></table-wrap></p>
        <p id="Par38">The lived experience panel included consumers and carers who were members of advocacy groups (e.g. National Alliance of Mental Illness), formal peer support programs (e.g. Flourish Australia) or who had professional experience (e.g. Mental Health First Aid Instructors). Given that Mental Health First Aid Instructors may be very familiar with the contents of the 2008 Guidelines, the number of Instructors allowed to participate was limited to no more than 50%. Forty-two per cent of the Lived Experience and 53% of the Professional panel were Instructors, for a total of 45%.</p>
      </sec>
      <sec id="Sec10">
        <title>Item rating</title>
        <p id="Par39">Three hundred and fifty-two items were rated over the three rounds and a total of 183 were endorsed and 169 rejected. See Fig.&#xA0;<xref rid="Fig3" ref-type="fig">3</xref> for information about the number of items rated, endorsed and rejected. See Additional&#xA0;file&#xA0;<xref rid="MOESM2" ref-type="media">2</xref> for a list of the endorsed and rejected items.<fig id="Fig3"><label>Fig. 3</label><caption><p>Summary of Item Rating</p></caption><graphic xlink:href="40359_2019_310_Fig3_HTML" id="MO3"/></fig></p>
        <p id="Par40">The endorsed items formed the basis of the guidelines document entitled <italic>Depression: Mental Health First Aid Guidelines (Revised 2018)</italic> [<xref ref-type="bibr" rid="CR23">23</xref>]<italic>,</italic> which will be&#xA0;available from the Mental Health First Aid Australia website (<ext-link ext-link-type="uri" xlink:href="http://mhfa.com.au">mhfa.com.au</ext-link>). The main topics covered in the guidelines are:<list list-type="bullet"><list-item><p id="Par41">How do I know if someone is experiencing depression?</p></list-item><list-item><p id="Par42">How should I approach someone who may be experiencing depression?</p></list-item><list-item><p id="Par43">How can I be supportive?<list list-type="bullet"><list-item><p id="Par44">&#xB0; Treat the person with respect and dignity</p></list-item><list-item><p id="Par45">&#xB0; Offer consistent emotional support and understanding</p></list-item><list-item><p id="Par46">&#xB0; Encourage the person to talk to you</p></list-item><list-item><p id="Par47">&#xB0; Be a good listener</p></list-item><list-item><p id="Par48">&#xB0; Have realistic expectations for the person</p></list-item><list-item><p id="Par49">&#xB0; Acknowledge the person&#x2019;s strengths</p></list-item><list-item><p id="Par50">&#xB0; Give the person hope for recovery</p></list-item><list-item><p id="Par51">&#xB0; Providing ongoing support</p></list-item><list-item><p id="Par52">&#xB0; What does not help?</p></list-item></list></p></list-item><list-item><p id="Par53">What if I experience difficulties when talking to the person?<list list-type="bullet"><list-item><p id="Par54">&#xB0; Self-care</p></list-item></list></p></list-item><list-item><p id="Par55">Should I encourage the person to seek professional help?</p></list-item><list-item><p id="Par56">What about self-help strategies?</p></list-item><list-item><p id="Par57">What if the person doesn&#x2019;t want help?</p></list-item><list-item><p id="Par58">What if there is risk of harm to the person or others?</p></list-item></list></p>
        <p id="Par59">The final draft of the guidelines was provided to participants who completed all three Rounds of the survey for final comments and endorsement. A few minor changes relating to structural composition of the guidelines were made as a result of participant comments.</p>
      </sec>
      <sec id="Sec11">
        <title>Difference between panels</title>
        <p id="Par60">The percentage endorsements for items were strongly positively correlated across the two panels, (<italic>r</italic>&#xA0;=&#x2009;0.95; t(254)&#x2009;=&#x2009;48.49; <italic>p</italic>&#xA0;=&#x2009;&lt;.001). However, there were also some differences. As per previous studies (e.g. [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR24">24</xref>]), items that were endorsed by one panel but rejected by the other, and that received a notably lower rating (&#xB1;10%) are presented below.</p>
        <sec id="Sec12">
          <title>
            <italic>Items rejected by the lived experience panel with a difference of&#x2009;&#x2265;&#x2009;10%</italic>
          </title>
          <p id="Par61">Eighteen items were endorsed by the professional panel but received a lower rating from the lived experience panel:<list list-type="bullet"><list-item><p id="Par62">Use of diagnostic terms<list list-type="bullet"><list-item><p id="Par63">&#xB0; The first aider should tell the person that depression is common.</p></list-item><list-item><p id="Par64">&#xB0; The first aider should tell the person that depression is an illness.</p></list-item><list-item><p id="Par65">&#xB0; If the first aider thinks someone may be depressed, they should approach the person about their concerns.</p></list-item></list></p></list-item><list-item><p id="Par66">Evidence base<list list-type="bullet"><list-item><p id="Par67">&#xB0; The first aider should tell the person about options for getting evidence-based online or telephone mental health services.</p></list-item><list-item><p id="Par68">&#xB0; If the person is interested in self-help strategies, the first aider should provide them with a range of information about evidence-based self-help strategies.</p></list-item><list-item><p id="Par69">&#xB0; If the person is interested in self-help strategies, the first aider should encourage the person to use evidence-based strategies.</p></list-item></list></p></list-item><list-item><p id="Par70">Recovery/getting help<list list-type="bullet"><list-item><p id="Par71">&#xB0; The first aider should let the person know that getting better takes time, but that it will happen.</p></list-item><list-item><p id="Par72">&#xB0; The first aider should encourage the person to participate in some activities that once gave them pleasure, e.g. hobbies, sport, religious or cultural activities</p></list-item><list-item><p id="Par73">&#xB0; The first aider should continue to involve the person in any activities that they have shared previously.</p></list-item><list-item><p id="Par74">&#xB0; The first aider should offer to assist the person to investigate available sources of help.</p></list-item><list-item><p id="Par75">&#xB0; The first aider should ask the person if they have tried to get help.</p></list-item><list-item><p id="Par76">&#xB0; The first aider should ask the person how much involvement they want the first aider to have with planning for and attending their appointment.</p></list-item></list></p></list-item><list-item><p id="Par77">Distorted thinking<list list-type="bullet"><list-item><p id="Par78">&#xB0; If the person appears irrational, the first aider should not try to talk the person out of their thoughts or feelings.</p></list-item><list-item><p id="Par79">&#xB0; The first aider should not agree with distorted negative thoughts, as these are a symptom of depression.</p></list-item></list></p></list-item><list-item><p id="Par80">Other<list list-type="bullet"><list-item><p id="Par81">&#xB0; The first aider should ask the person if anyone else knows how they are feeling.</p></list-item><list-item><p id="Par82">&#xB0; The first aider should tell the person that they are not to blame for feeling &#x2018;down&#x2019;.</p></list-item><list-item><p id="Par83">&#xB0; The first aider should learn about depression by seeking advice from a mental health professional.</p></list-item><list-item><p id="Par84">&#xB0; If the first aider does not feel that they are able to help the person, they should ask someone else to take on the first aider role.</p></list-item></list></p></list-item></list></p>
        </sec>
        <sec id="Sec13">
          <title>
            <italic>Items rejected by the professional panel with a difference of&#x2009;&#x2265;&#x2009;10%</italic>
          </title>
          <p id="Par85">There were five items that were endorsed by the lived experience panel and received a notably lower rating from the professional panel:<list list-type="bullet"><list-item><p id="Par86">The first aider should not use a &#x2018;tough-love&#x2019; approach to try and make the person better, e.g. the first aider telling the person they will not spend time with them until they get better or get professional help.</p></list-item><list-item><p id="Par87">The first aider should offer emotional support and hope of a more positive future in whatever form the depressed person will accept.</p></list-item><list-item><p id="Par88">If assisting someone from a cultural background that is different from the first aider&#x2019;s, the first aider should learn about how depression symptoms may manifest in people from the person&#x2019;s cultural background.</p></list-item><list-item><p id="Par89">If the person does not have the energy or is not able to think clearly enough to investigate available sources of help, the first aider should offer to assist with this.</p></list-item><list-item><p id="Par90">If the person refuses to seek or accept professional help, the first aider should ask the person whether they would like the first aider to check in on them.</p></list-item></list></p>
        </sec>
      </sec>
      <sec id="Sec14">
        <title>Differences between the 2008 and 2018 guidelines</title>
        <p id="Par91">A total of 64 items were endorsed and included in the 2008 guidelines. These endorsed items were included in the 2018 Delphi survey in addition to new items gleaned from the literature search. One hundred and eighty-three items were endorsed and included in the 2018 guidelines. There were 58 items that were endorsed in both the 2008 and 2018 Delphi studies. There were 125 additional items endorsed in the 2018 study. See Additional file <xref rid="MOESM2" ref-type="media">2</xref> for a comparison of item ratings from the 2008 and 2018 studies.</p>
        <p id="Par92">There were some similarities and differences noted between the 2008 and 2018 guidelines. For the 64 survey items that appeared in both the current and the 2008 Delphi, the endorsement ratings were similar. The endorsement rates for survey items in the 2018 study were found to correlate with those in the 2008 study as follows:<list list-type="bullet"><list-item><p id="Par93">Professional panels - Pearson&#x2019;s correlation of r&#x2009;=&#x2009;.43 (<italic>t(45)</italic>&#xA0;=&#x2009;3.20, <italic>p</italic>&#xA0;=&#x2009;.003)</p></list-item><list-item><p id="Par94">Lived experience panels &#x2013; Pearson&#x2019;s correlation of r&#x2009;=&#x2009;.43 (t(45)&#x2009;=&#x2009;3.21, <italic>p</italic>&#xA0;=&#x2009;.002).</p></list-item></list></p>
        <p id="Par95">Note that only endorsed items from the 2008 study were included in the 2018 study, which reduced the range of ratings and is likely to have reduced the correlations.</p>
      </sec>
    </sec>
    <sec id="Sec15">
      <title>Discussion</title>
      <p id="Par96">This research aimed to redevelop guidelines published in 2008 that give advice on how to provide mental health first aid to someone who may be experiencing depression. One hundred and eighty-three items were endorsed by both expert panels and were included in the guidelines. The guidelines will be&#xA0;available to the public on the MHFA Australia website (<ext-link ext-link-type="uri" xlink:href="http://mhfa.com.au">mhfa.com.au</ext-link>) and they will inform future editions of MHFA Australia courses. They will also be used to develop user-friendly infographics that will be available to the public on the MHFA Australia website.</p>
      <p id="Par97">These guidelines address a variety of topics or situations that a person may encounter when providing mental health first aid to someone who may be experiencing depression. These include recognising the signs of depression in a person, talking with the person about their concerns, how to support the person, what to do if difficulties such as communication problems are encountered, how to encourage help-seeking and what to do if there is risk of harm to the person or others.</p>
      <sec id="Sec16">
        <title>Differences between the two 2018 expert panels</title>
        <p id="Par98">There were a number of items that received a notably different rating score between the two panels. These were categorised into groups &#x2013; Use of diagnostic terms, Evidence base, Recovery/getting help, Distorted thinking, and Other. Using the qualitative data collected in the Round 1 survey, the reason for the differences between the rating scores of the two panels could be hypothesised. First, there were four items about how the first aider should approach distorted thinking. None of these items reached consensus to be included in the guidelines. However, two items were endorsed by the professional panel, but not by the lived experience panel. The two items were actions that the first aider should <bold>not</bold> do (<italic>The first aider should not agree with distorted negative thoughts, as these are a symptom of depression</italic> and <italic>If the person appears irrational, the first aider should not try to talk the person out of their thoughts or feelings</italic>). The comments suggest that the lived experience panel thought it was appropriate to acknowledge the person&#x2019;s distorted thinking. Lived experience panel members commented that the first aider needed to have sufficient experience or skills to talk about distorted thoughts in a constructive way. One lived-experience panel member said, &#x201C;Negative thoughts can be discussed within a conversation but should not become the focus of a conversation.&#x201D; And another said, &#x201C;This highly depends on the experience of the first aider, if they do not feel equipped to safely discuss the irrational thoughts then they shouldn&#x2019;t take it upon themselves to delve deeper as it may reveal/trigger other issues.&#x201D;</p>
        <p id="Par99">A number of items that implied that the first aider may be labelling or diagnosing the person as having depression were not endorsed by the lived-experience panel, e.g. <italic>The first aider should tell the person that depression is an illness</italic><italic>.</italic> The lived experience panel thought that it was important to not label the person as having depression, but rather &#x201C;&#x2026;highlight [the] symptoms the [person is] showing&#x2026;&#x201D;. Another lived-experience participant said, &#x201C;[It is] better to discuss symptoms and that they are often associated with depression, and that this might be something to explore, rather than providing a diagnosis.&#x201D;</p>
      </sec>
      <sec id="Sec17">
        <title>Differences between the 2008 and 2018 guidelines</title>
        <p id="Par100">There were a number of differences noted between the 2008 and 2018 guidelines. The 2018 guidelines included 125 additional items, allowing them to be more nuanced. The complexity of depression is better represented in the re-developed guidelines, for example the item <italic>The first aider should not ignore any signs or symptoms of depression that they have noticed or assume that they will just go away</italic> was endorsed in both 2008 and 2018, but <italic>The first aider should not assume that the person&#x2019;s symptoms are due to depression</italic> was an additional item in the 2018 re-development, illustrating the complexity in attributing symptoms of mental illness. The re-developed guidelines also allow for a more considered approach to the person when offering help, for example two new items to the 2018 guidelines are:<disp-quote><p id="Par101">
<italic>The first aider should consider whether they are the best person to approach the person or whether somebody else might be more appropriate.</italic>
</p></disp-quote><disp-quote><p id="Par102">
<italic>If the first aider thinks someone may be depressed, they should try to spend time with the person and gently bring up their concerns with them, e.g. mention that the person seems down today.</italic>
</p></disp-quote>The mental health first aider role is better defined in the re-developed guidelines. For example, one item that was endorsed in 2008, but not in 2018, was <italic>The first aider needs to let the person with depression know that they will not be abandoned</italic>. The rejection of this item in the 2018 study recognises the limitations and needs of the first aider. One lived-experience participant said, &#x201C;The first aider may find themselves unable to offer ongoing support due to personal or professional circumstances&#x2026;The first aider should not feel trapped in a caregiving role.&#x201D;</p>
        <p id="Par103">The first aid guidance is also more detailed in the 2018 guidelines. For example, the sections on &#x2018;self-help&#x2019; and &#x2018;what to do if the person does not want help&#x2019; have an additional six and five items, respectively. The additional items encourage the first aider to know more about self-help and help-seeking and respect the person&#x2019;s ideas about what might be helpful. Although the additional detail may be in some respects helpful, it may also add complexity to the training and this will need careful consideration when updating the course.</p>
        <p id="Par104">Items about first aiders&#x2019; knowledge of evidence-based treatments, services or self-help strategies were generally not endorsed. The qualitative data suggested that knowing evidence-based information was outside the role of the first aider. A lived-experience participant said, &#x201C;Whether treatment is evidence based or how treatment might help or even be undertaken is really beyond the scope of first aid.&#x201D; Finally, the 2018 guidelines introduced a first aider self-care section.</p>
      </sec>
      <sec id="Sec18">
        <title>Strengths and limitations</title>
        <p id="Par105">Delphi method studies typically use one expert panel, usually professionals with expertise in the area of study [<xref ref-type="bibr" rid="CR25">25</xref>]. However, multiple expert panels, including consumer and carer participants were used for this Delphi study, mirroring similar recent work in the mental health field [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR24">24</xref>]. This allows the voice of lived experience to contribute equally to the development of guidelines, which is a strength of this study.</p>
        <p id="Par106">There are a few limitations to this study. Because participants may have been asked to rate survey items that were outside their area of expertise, key actions may have been omitted. Also, participants were not able to discuss their responses with others, which may have led to biases or incorrect assumptions influencing their responses. However, this limitation was ameliorated in that, by eliminating &#x2018;consensus by discussion&#x2019;, all voices (including quiet or less confident, but equally valid voices) influence the endorsement process just as powerfully. Another limitation is that the professional panel did not include some types of clinicians, such as psychiatrists and primary care physicians. However, as these are not clinical practice guidelines, these experts would have had less relevant expertise than some other professional groups. Finally, by only reviewing the first 50 websites, books and journal articles some first aid actions may have been missed. However, this limitation was minimised because participants could write in missing first aid actions.</p>
      </sec>
    </sec>
    <sec id="Sec19">
      <title>Conclusion</title>
      <p id="Par107">This project used the consensus of consumers, carers and professionals to re-develop the mental health first aid guidelines for depression. This Delphi study ensures that the guidelines that inform the Mental Health First Aid Australia courses and the courses delivered by their international counterparts are current and include the most appropriate helping actions. These updated guidelines are now more detailed, allowing for a more nuanced approach to providing first aid to someone with depression. These guidelines (and the associated infographic) are available on the Mental Health First Aid website, and will be used to update future versions of the Mental Health First Aid Australia course.</p>
    </sec>
    <sec sec-type="supplementary-material">
      <title>Additional files</title>
      <sec id="Sec20">
        <p>
<supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="40359_2019_310_MOESM1_ESM.pdf"><label>Additional file 1:</label><caption><p>Survey Questionnaire. (PDF 1582 kb)</p></caption></media></supplementary-material>
<supplementary-material content-type="local-data" id="MOESM2"><media xlink:href="40359_2019_310_MOESM2_ESM.xlsx"><label>Additional file 2:</label><caption><p>Results of Item Rating. (XLSX 51 kb)</p></caption></media></supplementary-material>
</p>
      </sec>
    </sec>
  </body>
  <back>
    <glossary>
      <title>Abbreviation</title>
      <def-list>
        <def-item>
          <term>MHFA</term>
          <def>
            <p id="Par5">Mental Health First Aid</p>
          </def>
        </def-item>
      </def-list>
    </glossary>
    <fn-group>
      <fn>
        <p>
          <bold>Publisher&#x2019;s Note</bold>
        </p>
        <p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p>
      </fn>
    </fn-group>
    <ack>
      <title>Acknowledgements</title>
      <p>We wish to acknowledge the participants who gave their time and shared their expertise with us.</p>
      <sec id="FPar1">
        <title>Ethics and consent to participate</title>
        <p id="Par108">This research was approved by the University of Melbourne Human Ethics Committee (ID#1648030). Informed consent, including permission to report individual participant&#x2019;s de-identified qualitative data, was obtained from all participants by clicking &#x2018;yes&#x2019; to a question about informed consent in the Round 1 survey.</p>
      </sec>
    </ack>
    <notes notes-type="author-contribution">
      <title>Authors&#x2019; contributions</title>
      <p>KSB conducted the literature search, developed the surveys, collected and analysed the data, wrote the first draft of and finalised the guidelines, and wrote the first draft and edited this article. FAC developed the surveys, analysed the data, edited and finalised the guidelines and edited this article. FLB developed the surveys, analysed the data, edited and finalised the guidelines and edited this article. CMK developed the surveys, analysed the data, edited and finalised the guidelines and edited this article. BAK developed the surveys, analysed the data, edited and finalised the guidelines and edited this article. AFJ was the responsible researcher and developed the surveys, analysed the data, edited and finalised the guidelines and edited this article. All authors read and approved the final manuscript.</p>
    </notes>
    <notes notes-type="funding-information">
      <title>Funding</title>
      <p>This was an unfunded project.</p>
    </notes>
    <notes notes-type="data-availability">
      <title>Availability of data and materials</title>
      <p>All data generated or analysed during this study are included in this published article as a supplementary file. The datasets analysed during the current study are available from the corresponding author on reasonable request.</p>
    </notes>
    <notes>
      <title>Consent for publication</title>
      <p id="Par109">Participants were informed of the possibility of having the results published in a peer reviewed article and that their unidentified data may be published in this article. Consent was obtained in the Round 1 survey.</p>
    </notes>
    <notes notes-type="COI-statement">
      <title>Competing interests</title>
      <p id="Par110">The authors declare they have no competing interests.</p>
    </notes>
    <ref-list id="Bib1">
      <title>References</title>
      <ref id="CR1">
        <label>1.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>World Health Organisation</collab>
          </person-group>
          <source>Depression and other common mental disorders: Global Health estimates</source>
          <year>2017</year>
          <publisher-loc>Geneva</publisher-loc>
          <publisher-name>World Health Organisation</publisher-name>
        </element-citation>
      </ref>
      <ref id="CR2">
        <label>2.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Post</surname>
              <given-names>RM</given-names>
            </name>
          </person-group>
          <article-title>Duration of untreated illness and outcomes in unipolar depression: a systematic review and meta-analysis</article-title>
          <source>J Affect Disord</source>
          <year>2010</year>
          <volume>18</volume>
          <fpage>256</fpage>
          <lpage>271</lpage>
        </element-citation>
      </ref>
      <ref id="CR3">
        <label>3.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Cutler</surname>
              <given-names>TL</given-names>
            </name>
            <name>
              <surname>Reavley</surname>
              <given-names>NJ</given-names>
            </name>
            <name>
              <surname>Jorm</surname>
              <given-names>AF</given-names>
            </name>
          </person-group>
          <article-title>How &#x2018;mental health smart&#x2019; are you? Analysis of responses to an Australian broadcasting corporation news webstie quiz</article-title>
          <source>Adv Ment Health</source>
          <year>2018</year>
          <volume>16</volume>
          <fpage>5</fpage>
          <lpage>18</lpage>
          <pub-id pub-id-type="doi">10.1080/18387357.2017.1317581</pub-id>
        </element-citation>
      </ref>
      <ref id="CR4">
        <label>4.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Rossetto</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Jorm</surname>
              <given-names>AF</given-names>
            </name>
            <name>
              <surname>Reavley</surname>
              <given-names>NJ</given-names>
            </name>
          </person-group>
          <article-title>Quality of helping behaviours of members of the public towards a person with a mental illness: a descriptive analysis of data from an Australian national survey</article-title>
          <source>Ann General Psychiatry</source>
          <year>2014</year>
          <volume>13</volume>
          <fpage>2</fpage>
          <pub-id pub-id-type="doi">10.1186/1744-859X-13-2</pub-id>
        </element-citation>
      </ref>
      <ref id="CR5">
        <label>5.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Kitchener</surname>
              <given-names>BA</given-names>
            </name>
            <name>
              <surname>Jorm</surname>
              <given-names>AF</given-names>
            </name>
            <name>
              <surname>Kelly</surname>
              <given-names>CM</given-names>
            </name>
          </person-group>
          <source>Mental health first aid manual</source>
          <year>2017</year>
          <edition>4</edition>
          <publisher-loc>Melbourne</publisher-loc>
          <publisher-name>Mental Health First Aid Australia</publisher-name>
        </element-citation>
      </ref>
      <ref id="CR6">
        <label>6.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Kitchener</surname>
              <given-names>BA</given-names>
            </name>
            <name>
              <surname>Jorm</surname>
              <given-names>AF</given-names>
            </name>
            <name>
              <surname>Kelly</surname>
              <given-names>CM</given-names>
            </name>
          </person-group>
          <source>Mental Health First Aid International Manual</source>
          <year>2015</year>
          <publisher-loc>Melbourne</publisher-loc>
          <publisher-name>Mental health first aid Australia</publisher-name>
        </element-citation>
      </ref>
      <ref id="CR7">
        <label>7.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Morgan</surname>
              <given-names>Amy J.</given-names>
            </name>
            <name>
              <surname>Ross</surname>
              <given-names>Anna</given-names>
            </name>
            <name>
              <surname>Reavley</surname>
              <given-names>Nicola J.</given-names>
            </name>
          </person-group>
          <article-title>Systematic review and meta-analysis of Mental Health First Aid training: Effects on knowledge, stigma, and helping behaviour</article-title>
          <source>PLOS ONE</source>
          <year>2018</year>
          <volume>13</volume>
          <issue>5</issue>
          <fpage>e0197102</fpage>
          <pub-id pub-id-type="doi">10.1371/journal.pone.0197102</pub-id>
          <pub-id pub-id-type="pmid">29851974</pub-id>
        </element-citation>
      </ref>
      <ref id="CR8">
        <label>8.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>Mental Health First Aid Australia</collab>
          </person-group>
          <source>Non-suicidal self-injury: first aid guidelines (revised)</source>
          <year>2014</year>
          <publisher-loc>Melbourne</publisher-loc>
          <publisher-name>Mental Health First Aid</publisher-name>
        </element-citation>
      </ref>
      <ref id="CR9">
        <label>9.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>Mental Health First Aid Australia</collab>
          </person-group>
          <source>Psychosis: first aid guidelines</source>
          <year>2008</year>
          <publisher-loc>Melbourne</publisher-loc>
          <publisher-name>Mental Health First Aid Australia</publisher-name>
        </element-citation>
      </ref>
      <ref id="CR10">
        <label>10.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>Mental Health First Aid Australia</collab>
          </person-group>
          <source>Depression: first aid guidelines</source>
          <year>2008</year>
          <publisher-loc>Melbourne</publisher-loc>
          <publisher-name>Mental Health First Aid Australia</publisher-name>
        </element-citation>
      </ref>
      <ref id="CR11">
        <label>11.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Kitchener</surname>
              <given-names>BA</given-names>
            </name>
            <name>
              <surname>Jorm</surname>
              <given-names>AF</given-names>
            </name>
            <name>
              <surname>Kelly</surname>
              <given-names>CM</given-names>
            </name>
          </person-group>
          <source>Mental health first aid manual</source>
          <year>2013</year>
          <edition>3</edition>
          <publisher-loc>Melbourne</publisher-loc>
          <publisher-name>Mental Health First Aid Australia</publisher-name>
        </element-citation>
      </ref>
      <ref id="CR12">
        <label>12.</label>
        <mixed-citation publication-type="other">Bond KS, Jorm AF, Miller HE, Rodda SN, Reavley NJ, Kelly CM, Kitchener BA. How a concerned family member, friend or member of the public can help someone with gambling problems: a Delphi consensus study. BMC Psychol. 2016;4(1):6.</mixed-citation>
      </ref>
      <ref id="CR13">
        <label>13.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hart</surname>
              <given-names>Laura M.</given-names>
            </name>
            <name>
              <surname>Jorm</surname>
              <given-names>Anthony F.</given-names>
            </name>
            <name>
              <surname>Paxton</surname>
              <given-names>Susan J.</given-names>
            </name>
            <name>
              <surname>Cvetkovski</surname>
              <given-names>Stefan</given-names>
            </name>
          </person-group>
          <article-title>Mental health first aid guidelines: an evaluation of impact following download from the World Wide Web</article-title>
          <source>Early Intervention in Psychiatry</source>
          <year>2012</year>
          <volume>6</volume>
          <issue>4</issue>
          <fpage>399</fpage>
          <lpage>406</lpage>
          <pub-id pub-id-type="doi">10.1111/j.1751-7893.2012.00345.x</pub-id>
          <pub-id pub-id-type="pmid">22379952</pub-id>
        </element-citation>
      </ref>
      <ref id="CR14">
        <label>14.</label>
        <mixed-citation publication-type="other">Australian Clinical Practice Guidelines [<ext-link ext-link-type="uri" xlink:href="https://www.clinicalguidelines.gov.au/faq-page#t317162n3615">https://www.clinicalguidelines.gov.au/faq-page#t317162n3615</ext-link>].</mixed-citation>
      </ref>
      <ref id="CR15">
        <label>15.</label>
        <mixed-citation publication-type="other">Ross A, Kelly C, Jorm A. Re-development of mental health first aid guidelines for suicidal ideation and behaviour: a Delphi study. BioMed Central Psychiatry. 2014;14(1):241.</mixed-citation>
      </ref>
      <ref id="CR16">
        <label>16.</label>
        <mixed-citation publication-type="other">Ross A, Kelly C, Jorm A. Re-development of mental health first aid guidelines for non-suicidal self-injury: a Delphi study. BMC Psychiatry. 2014;14(1):236.</mixed-citation>
      </ref>
      <ref id="CR17">
        <label>17.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Jorm</surname>
              <given-names>Anthony F</given-names>
            </name>
          </person-group>
          <article-title>Using the Delphi expert consensus method in mental health research</article-title>
          <source>Australian &amp; New Zealand Journal of Psychiatry</source>
          <year>2015</year>
          <volume>49</volume>
          <issue>10</issue>
          <fpage>887</fpage>
          <lpage>897</lpage>
          <pub-id pub-id-type="doi">10.1177/0004867415600891</pub-id>
          <pub-id pub-id-type="pmid">26296368</pub-id>
        </element-citation>
      </ref>
      <ref id="CR18">
        <label>18.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Jorm</surname>
              <given-names>Anthony F.</given-names>
            </name>
            <name>
              <surname>Ross</surname>
              <given-names>Anna M.</given-names>
            </name>
          </person-group>
          <article-title>Guidelines for the public on how to provide mental health first aid: narrative review</article-title>
          <source>BJPsych Open</source>
          <year>2018</year>
          <volume>4</volume>
          <issue>6</issue>
          <fpage>427</fpage>
          <lpage>440</lpage>
          <pub-id pub-id-type="doi">10.1192/bjo.2018.58</pub-id>
          <pub-id pub-id-type="pmid">30450221</pub-id>
        </element-citation>
      </ref>
      <ref id="CR19">
        <label>19.</label>
        <mixed-citation publication-type="other">Bond KS, Jorm AF, Miller HE, Rodda SN, Reavley NJ, Kelly CM, Kitchener BA. How a concerned family member, friend or member of the public can help someone with gambling problems: a Delphi consensus study. BioMed Central Psychology. 2016;4(1):6.</mixed-citation>
      </ref>
      <ref id="CR20">
        <label>20.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Langlands</surname>
              <given-names>RL</given-names>
            </name>
            <name>
              <surname>Jorm</surname>
              <given-names>AF</given-names>
            </name>
            <name>
              <surname>Kelly</surname>
              <given-names>CM</given-names>
            </name>
            <name>
              <surname>Kitchener</surname>
              <given-names>BA</given-names>
            </name>
          </person-group>
          <article-title>First aid for depression: a Delphi consensus study with consumers, carers and clinicians</article-title>
          <source>J Affect Disord</source>
          <year>2008</year>
          <volume>105</volume>
          <fpage>157</fpage>
          <lpage>166</lpage>
          <pub-id pub-id-type="doi">10.1016/j.jad.2007.05.004</pub-id>
          <pub-id pub-id-type="pmid">17574684</pub-id>
        </element-citation>
      </ref>
      <ref id="CR21">
        <label>21.</label>
        <mixed-citation publication-type="other">Kelly CM, Jorm AF, Kitchener BA, Langlands RL. Development of mental health first aid guidelines for suicidal ideation and behaviour: a Delphi study. BioMed Central Psychiatry. 2008;8(1):17.</mixed-citation>
      </ref>
      <ref id="CR22">
        <label>22.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bond</surname>
              <given-names>K. S.</given-names>
            </name>
            <name>
              <surname>Jorm</surname>
              <given-names>A. F.</given-names>
            </name>
            <name>
              <surname>Kelly</surname>
              <given-names>C. M.</given-names>
            </name>
            <name>
              <surname>Kitchener</surname>
              <given-names>B. A.</given-names>
            </name>
            <name>
              <surname>Morris</surname>
              <given-names>S. L.</given-names>
            </name>
            <name>
              <surname>Mason</surname>
              <given-names>R. J.</given-names>
            </name>
          </person-group>
          <article-title>Considerations when providing mental health first aid to an LGBTIQ person: a Delphi study</article-title>
          <source>Advances in Mental Health</source>
          <year>2017</year>
          <volume>15</volume>
          <issue>2</issue>
          <fpage>183</fpage>
          <lpage>197</lpage>
          <pub-id pub-id-type="doi">10.1080/18387357.2017.1279017</pub-id>
        </element-citation>
      </ref>
      <ref id="CR23">
        <label>23.</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>Mental Health First Aid Australia</collab>
          </person-group>
          <source>Depression: mental health first aid guidelines (revised 2018)</source>
          <year>2018</year>
          <publisher-loc>Melbourne</publisher-loc>
          <publisher-name>Mental Health First Aid Australia</publisher-name>
        </element-citation>
      </ref>
      <ref id="CR24">
        <label>24.</label>
        <mixed-citation publication-type="other">Bond KS, Chalmers KJ, Jorm AF, Kitchener BA, Reavley NJ. Assisting Australians with mental health problems and financial difficulties: a Delphi study to develop guidelines for financial counsellors, financial institutionstaff, mental health professionals and carers. BMC Health Serv Res. 2015;15(1):218.</mixed-citation>
      </ref>
      <ref id="CR25">
        <label>25.</label>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hasson</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Keeney</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>McKenna</surname>
              <given-names>H</given-names>
            </name>
          </person-group>
          <article-title>Research guidelines for the Delphi survey technique</article-title>
          <source>J Adv Nurs</source>
          <year>2000</year>
          <volume>32</volume>
          <fpage>1008</fpage>
          <lpage>1015</lpage>
          <pub-id pub-id-type="pmid">11095242</pub-id>
        </element-citation>
      </ref>
    </ref-list>
  </back>
</article>
</pmc-articleset>