Can Gazefinder® detect specific symptoms of neurodevelopmental disorders in children? – a preliminary study of clinical application to neurodevelopmental screening

Can Gazefinder® detect specific symptoms of neurodevelopmental disorders in children? – a preliminary study of clinical application to neurodevelopmental screening | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Can Gazefinder ® detect specific symptoms of neurodevelopmental disorders in children? – a preliminary study of clinical application to neurodevelopmental screening Masatsugu Orui, Mami Ishikuro, Taku Obara, Aoi Noda, Genki Shinoda, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5362638/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Gazefinder ® , an eye-tracking system, was developed to capture atypical gaze patterns of diagnostic value (e.g., limited duration of eye gaze fixation on social information) in people with autism spectrum disorder (ASD). However, whether it can detect specific symptoms of neurodevelopmental disorders other than ASD is unclear. Therefore, indicating associations between neurodevelopmental symptoms and gaze data measured by Gazefinder ® is essential for its application in screening neurodevelopmental disorders other than ASD. This large-scale longitudinal study analyzed data from 2,101 subjects to examine associations between the duration of gaze fixation on social information as measured by Gazefinder ® at age 4 and subscale scores of the Strength and Difficulties Questionnaire (SDQ) at ages 6–7. Results of analysis of covariance (ANCOVA) revealed a significant association between the duration of gaze fixation on social information and SDQ’s peer problems (core feature of ASD). Notably, SDQ’s hyperactivity/inattention (core feature of attention deficit hyperactivity disorder (ADHD)) was also associated with the duration of eye gaze fixation. In conclusion, Gazefinder ® ’s gaze data at age 4 can detect symptoms of not only ASD but also ADHD at ages 6–7 longitudinally and have potential as a primary screening tool for neurodevelopmental disorders other than ASD. Biological sciences/Psychology Health sciences/Health care Health sciences/Health care/Paediatrics Health sciences/Health care/Public health Gazefinder eye-tracking neurodevelopmental disorder ASD ADHD primary screening Figures Figure 1 Figure 2 Background Early intervention is important for children with neurodevelopmental disorders, and appropriate support from an early stage has a large impact on their subsequent development 1 – 3 . However, with an increasing awareness of neurodevelopmental disorders in recent years, excessive seeking of an early diagnosis has become problematic, leading to warnings that neurodevelopmental disorders may be over-diagnosed 4 – 5 . Assessments by neurodevelopmental scales alone may include bias because parents who are concerned about developmental delays in their children tend to give biased answers in the scale questionnaires. Therefore, there is a need to develop more reliable or accurate screening to avoid over- or misdiagnosing of neurodevelopmental disorders while using digital biomarkers such as gaze patterns. Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by a “lack of social communication and social interaction” and “restricted repetitive patterns of behavior, interests, and actions,” with atypical gaze patterns being one of its diagnostic criteria 6 . Eye-tracking systems such as Tobii® (Tobii Technology, Stockholm, Sweden) and iSCAN® (ISCAN Inc., Woburn, Massachusetts, USA) have been used to detect atypical gaze patterns in children and adolescents with ASD 7 – 11 . Gazefinder®, an eye-tracking system that measures unique gaze patterns of people with ASD, was developed as an evaluation method that does not require any special skills. Moreover, it can be performed in a shorter amount of time compared with Tobii® and iSCAN® and has advantages such as posing less psychological burden on subjects and not requiring verbal responses 12 – 19 . Three studies have used Gazefinder® to distinguish between psychiatrist-diagnosed ASD and typical development 12 – 14 based on atypical gaze patterns, but to the best of our knowledge, no study has examined specific symptoms of neurodevelopmental disorders other than ASD using the device. Although it is reasonable that Gazefinder® can detect specific symptoms and characteristic features of ASD, features of other neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) might also be detected by Gazefinder® since there are not a small number of children who are diagnosed with ASD and are comorbid with ADHD 20 – 22 . This could potentially lead to the use of Gazefinder® as a screening tool to detect specific symptoms and characteristic features of ADHD. Longitudinal evaluation and analysis of relationships between subscales of the Strength and Difficulties Questionnaire (SDQ) 23 , an effective screening scale for detecting neurodevelopmental disorders, and eye gaze data measured by Gazefinder® (hereinafter, “gaze data”) will provide essential insight into accurate screening of children with neurodevelopmental characteristics. Therefore, we focused on the potential ability of Gazefinder® to allow for screening of neurodevelopmental disorders other than ASD. In the present study, we compared gaze data collected at age 4 in the Birth and Three-Generation Cohort Study (BirThree Cohort Study) of the Tohoku Medical Megabank Project (TMM) with data from the SDQ to examine which neurodevelopmental subscales are associated with gaze data at age 4, and whether gaze data at age 4 can detect subsequent neurodevelopmental problems at ages 6–7. We hypothesized that (1) gaze data are specifically associated with SDQ subscales characteristic of both ASD and ADHD, and (2) gaze data at age 4 can detect longitudinally the presence of symptoms of not only ASD but also ADHD at ages 6–7. Results Basic characteristics of subjects Basic characteristics of subjects are shown in Table 1. There were about equal numbers of men and women. Associations between gaze data and neurod evelopmental subscales at age 4 In the first analysis, we performed analysis of covariance (ANCOVA) to examine associations between gaze data and SDQ subscales at age 4. Higher scores of SDQ subscales indicate greater problems in corresponding neurodevelopmental aspects. Among five human face stimuli (“blinking,” “mouth moving,” “silence,” “still face,” and “talking”), the duration of eye gaze fixation on the person’s eye was no significant associated with higher scores. On the other hand, for people and geometry stimuli (“same size” and “small window”), a shorter duration of eye gaze fixation on people in “same size” was significantly associated with higher scores of “hyperactivity/inattention” and “peer problems.” Moreover, a shorter duration of eye gaze fixation on people in “small window” showed an associational trend with higher scores of “hyperactivity/inattention” but no significance. We also performed tests for linear trend to evaluate the dose-response relationship between the duration of eye gaze fixation on social information and SDQ’s subscale scores. In tests for linear trend, “same size” and “small window” showed dose-response relationships with “hyperactivity/inattention.” “Same size” and “small window” also showed a significant trend of dose-response relationships with “peer problems” (Table 2-1 to 2-4). Associations between gaze data at age 4 and neurodevelopmental subscales at ages 6–7 In the second analysis of associations between SDQ subscales at ages 6–7 and gaze data collected at age 4, a shorter duration of eye gaze fixation on “same size” was significantly associated with “peer problems,” and “small window” had a significant association with “hyperactivity/inattention.” Furthermore, a significant trend of dose-response relationship was observed in “talking”, “same size” and “small window” stimuli and “peer problems,” and “same size” and “small window” stimuli and “hyperactivity/inattention.” In cases of “peer problems” in “same size” stimulus and “hyperactivity/inattention” in “small window,” there were significant associations between gaze data measured by Gazefinder ® ’s and SDQ’s subscales at ages 6–7, which these has a significant dose-response relationship (Table 3-1 to 3-4). Discussion This is the first study to examine associations between gaze data of Gazefinder ® and SDQ subscales. The results revealed significant associations between a shorter duration of eye gaze fixation on social information at age 4 and the SDQ subscales “peer problems” (core feature of ASD) and “hyperactivity/inattention” (core feature of ADHD) at ages 6–7, which these has a significant dose-response relationship. Since Gazefinder ® was developed as a screening tool for ASD based on atypical gaze patterns of people with ASD, “same size” stimulus of Gazefinder ® was expected to detect “peer problems,” core features of ASD. This finding is consistent with a previous study reporting the validity of people and geometry stimuli measured by Gazefinder ® for predicting autistic features 19 . Notably, hyperactivity/inattention can also be detected by Gazefinder ® based on atypical gaze patterns. The reason why Gazefinder ® can detect “hyperactivity/inattention”, core features of ADHD is unclear in this study. However, previous studies examining the duration of eye gaze fixation on social information measured by eye-tracking devices other than Gazefinder ® have reported that people with ASD alone and those with the comorbidity of ASD and ADHD were detected 24,25 . Moreover, some individuals with ASD are likely to have ADHD symptoms, especially hyperactivity/inattention. Indeed, among newly diagnosed patients with ASD in two U.S. healthcare databases, ADHD was the most common comorbidity (Medicaid: 50.09%; Optum: 44.16%) 21 . Against these backdrops, we analyzed the additional analysis (see Supplementary Table 1) that examined the duration of eye gaze fixation on social information among subjects with high scores (more than 95th percentile) for 1) “hyperactivity/inattention” alone, 2) “peer problems” alone, and 3) both “hyperactivity/inattention” and “peer problems.” As a result, subjects having symptoms of both “hyperactivity/inattention” and “peer problems” had a shorter duration of eye gaze fixation on “small window,” but no significance. Therefore, the significant association that observed between gaze data and “hyperactivity/inattention” at both ages 4 and 6–7 might have been affected by features of the comorbidity of ASD and ADHD. However, this additional analysis is not sufficient, a future study will be necessary to evaluate the association between gaze data measured by Gazefinder ® and children with diagnosis of ADHD as well as ASD in detail. In terms of application in primary screening for neurodevelopmental disorders, Gazefinder ® has the advantage of being a simple screening tool 12-19 , with no respondent bias unlike other conventional neurodevelopmental scales that are answered by parents/guardians. All eye gaze fixation tests for the various stimuli in Gazefinder ® can be completed in about two minutes, and no special testing skills are required 12-19 . In Japan, health screening systems that were implemented nationwide in accordance with the Maternal and Child Health Act of 1965 include screening of neurodevelopmental disorders for the early detection of delays in growth and development 26,27 . Although these health screening systems for children are based on the standards of child welfare specified by the Ministry of Health, Labour and Welfare in Japan, some concerns have been raised regarding respondent bias when screening of neurodevelopmental disorders is based on semi-structured interviews with public health nurses or guardians. Our findings suggest that children with a shorter duration of eye gaze fixation on social information as measured by Gazefinder ® at age 4 may have peer problems, a core feature of ASD, as well as hyperactivity/inattention, a core feature of ADHD. Notably, these associations persisted even after two to three years. Therefore, the advantage of Gazefinder ® to potentially capture the features of both ASD and ADHD may promote early detection and intervention of these disorders. This study has several limitations worth noting. First, the subjects of this study included some children with neurodevelopmental disabilities which were not diagnosed. Since this was a cohort study targeting the general population, there were a certain number of subjects who were not diagnosed or did not provide answers about their past medical history. Second, there is respondent bias inherent to neurodevelopmental scales such as SDQ. Some parents who are concerned about developmental delays in their children tend to give biased answers in these questionnaires. Third, given that as many as 4,311 parents or guardians did not respond to the neurodevelopmental scale questionnaire, there is a possibility that our findings might have been under- or over-estimated. Finally, solid discrimination methods of neurodevelopmental problems in childhood have not been established. By using Gazefinder ® , which stimuli should be selected and how stimuli should be utilized for screening are still ongoing topics of discussion. Despite these limitations, strengths of the present study are that the sample size was larger than those of previous studies, and that the longitudinal design helped reveal the importance of the duration of eye gaze fixation on social information using Gazefinder ® at ages 4 and 6–7. In conclusion, our findings show that a shorter duration of eye gaze fixation on social information at age 4 is significantly associated with “peer problems,” a core feature of ASD at both age 4 and ages 6–7. Moreover, it showed a significant association and dose-response relationship even in longitudinal analysis between gaze data and “hyperactivity/inattention”, a core feature of ADHD, suggesting that Gazefinder ® may be a useful tool for primary screening of not only ASD but also ADHD. This is a preliminary study of clinical application to neurodevelopmental screening; therefore, further study will be performed for the accuracy of screening. Methods TMM BirThree Cohort Study and subjects The TMM aims to provide medical care to overcome damage from the Great East Japan Earthquake in 2011 and support health services by conducting personalized medical care and supporting disaster victims. The BirThree Cohort Study, a part of the TMM, recruited pregnant women and their children, partners, and parents in certain regions of Miyagi and Iwate Prefectures of Japan from July 2013 to March 2017. Details regarding the recruitment procedure have been described previously 28,29 . From among 23,143 children and 9,459 siblings recruited for the BirThree Cohort Study, subjects aged 4 years included 26,572 children, and of these, 20,001 subjects who did not participate in measurements with Gazefinder ® were excluded. Subsequently, we selected subjects who completed the neurodevelopmental scale questionnaire at both ages 4 and 6–7 and for whom gaze data at age 4 were available. Four subjects who had been diagnosed with mental retardation and developmental disabilities were excluded. The final study population consisted of 2,101 subjects (Figure 1). Incidentally, we excluded four subjects who had been diagnosed with intellectual disability, given potential bias in gaze data measured by Gazefinder ® . The reason for targeting children at age 4 was that all children undergo a health checkup at 3 years and 6 months of age in Japan, and considering the possibility of adopting it for health checkups at 3 years and 6 months of age in the future. Gazefinder ® measurements Subjects were asked to sit in front of the monitor to undergo gaze measurements for about two minutes under the supervision of the research coordinator. Eye position was measured using a camera equipped with an infrared light source below a 19” transistor (1280 × 1024 pixels). Using corneal reflection, eye position was recorded at a frequency of 50 Hz as X and Y coordinates. Eye position calibration was performed before showing a series of videos using a 5-point method, in which each subject followed the position of a ball around the screen. It is simple to set up with no difficult preparations needed, and measurements are easily performed as subjects are required only to watch stimuli on the monitor for about two minutes. After calibration, eight short videos were shown for the following stimuli: five showing human faces, one showing biological motion, and two showing people and geometric patterns. Human face stimuli consisted of the following five facial expressions: “blinking” (opening and closing the eyes repeatedly; five seconds), “mouth moving” (opening and closing the mouth repeatedly; five seconds), “silence” (closing the mouth; five seconds), “still face” (four seconds), and “talking” (talking to subjects; “hello,” “what is your name,” and “let’s play together”; seven seconds). People and geometry stimuli consisted of the following two patterns: 1) “same size” (at the same size for 10 seconds) and 2) “small window” (stimuli of geometry depicted in small-frame images in a small window on an image of people for 16 seconds) (Figure 2). For human face stimuli, the proportion of time spent gazing at specific objects was categorized as follows: Group A, eyes; Group B, mouth; Other: other parts of the image; and Off screen/not detected. For people and geometry stimuli, categories were Group A, people; Group B, geometric patterns; Other, other parts of the image; and Off screen/not detected. Among these patterns of stimuli, 1) “a person’s eyes” under various conditions provided in the images of five human faces (“blinking,” “mouth moving,” “silence,” “still face,” and “talking”) and 2) “people” in the case of “same size” and “small window” of people and geometry stimuli were considered to represent social information. Accordingly, we defined social information as gaze patterns towards under these various conditions that are “persons’ eye” in the case of the human face stimuli, and “people” in the case of people and geometry stimuli 12 . Therefore, we measured the proportion of time spent gazing at specific objects, i.e., “person’s eye” in the case of human face stimuli and “people” in the case of people and geometry stimuli. 3. Measurement of symptoms of ASD and ADHD using the Strengths and Difficulty Questionnaire (SDQ) at ages 4 and 6 – 7 The SDQ is a neurodevelopmental scale answered by parents or schoolteachers and includes 25 questions reflecting four domains of difficulties including “emotional problems” (feeling depressed or anxious in new situations and being scared), “conduct problems” (fights, lying and cheating, stealing things, and not obeying adults), “hyperactivity/inattention” (restlessness, fidgety, being easily distracted, and difficulties concentrating and thinking carefully before acting), and “peer problems” (prefer being alone, have no good friends, disliked by other friends, and bullied by others), and one subscale relating to strength –prosocial behavior–. The SDQ scale is not specific to ASD, but rather is used to screen the overall mental health status of children 30,31 . Its reliability and validity have been demonstrated in various studies, and it is widely used worldwide, including in Japan, for clinical evaluations and screening such as at school health check-ups and for various types of research 33 . Each of the 25 questions is evaluated on a 3-point scale of “not true” (0 points), “somewhat true” (1 point), and “certainly true” (2 points), with scores ranging from 0 to 10 points for each subscale. A higher score corresponds to more difficulties. In this study, we adopted the “emotional problems,” “conduct problems,” “hyperactivity/inattention,” and “peer problems” subscales as outcomes 32,33 . 4. Statistical analysis 4-1. Categorized gaze data at age 4 In this study, we analyzed the duration of eye gaze fixation on the monitor for each stimulus (i.e., “blinking,” “mouth moving,” “silence,” “still face,” and “talking” of human face stimuli, and “same size” and “small window” of people and geometry stimuli) by referring to a previous study 12 . First, we confirmed the distribution of the duration of eye gaze fixation on the monitor for each stimulus. There were concerns about the reliability of gaze data from children who were gazing off-screen most of the time. Therefore, children with a duration of eye gaze fixation on the monitor below the 5th percentile of the whole cohort were excluded from the analysis. Next, we categorized the duration of eye gaze fixation for each stimulus into four categories based on the three quartile points (the first quartile, median, and the third quartile). Incidentally, the number of excluded subjects were as follows: blinking: n = 112, mouth moving: n = 109, silence: n = 113, still face: n = 109, talking: n = 112, same size: n = 203, and small window: n = 213. 4-2. Associations between gaze data and neurodevelopmental subscales at age 4 (First Analysis) In the first analysis, we examined the association between the duration of eye gaze fixation on Group A of each stimulus and SDQ subscale scores (“emotional problems,” “conduct problems,” “hyperactivity/inattention,” and “peer problems”) at age 4 after categorizing into four groups. We performed ANCOVA adjusted for sex, and then compared the scores of each developmental subscale of the SDQ across quartile groups. Tests for linear trends were also performed. 4-3. Associations between gaze data and neurodevelopmental subscales at ages 6–7 (Second Analysis) In the second analysis, to examine whether Gazefinder ® gaze data at age 4 can detect specific subsequent symptoms of neurodevelopmental disorders at ages 6–7, we analyzed the associations between the duration of eye gaze fixation on Group A of each stimulus at age 4 and SDQ subscale scores at ages 6–7. We performed ANCOVA adjusted for age and sex, and then compared the scores of each developmental subscale across quartile groups. Tests for linear trends were also performed. 4-4. Overall statistical analysis To avoid the problem of multiple comparisons, we performed Bonferroni’s correction. Therefore, statistical significance was evaluated using two-sided, design-based tests with a 0.714% level of significance (significance level: 5%/7-time of testing). All analysis were performed with Stata 18 (StataCorp, 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LLC). 5. Ethical considerations The present study was approved by the ethics committee of Tohoku University School of Medicine (approval: 2013-4-103; date: May 10, 2013; latest revision: 2023-4-040; approval date: June 21, 2023). The TMM BirThree Cohort Study has been carried out in compliance with the research criteria approved by the Tohoku University School of Medicine ethical committee. All participants in the TMM BirThree Cohort Study gave their informed consent. Because every participant in this study was a minor, all guardians gave their proxy consent. Lastly, this study was carried out in compliance with the Declaration of Helsinki since it involved human research subjects. Declarations Conflicts of interest The authors declare no conflict of interest with respect to this research study and paper. Author Contribution Masatsugu Orui conceptualized and designed this study, conducted the initial analyses, and drafted the initial manuscript. Also, managed the implementation of the BirThree Cohort Study.Kenji J Tsuchiya supervised this study's analysis and drafting initial manuscript. Shinichi Kuriyama and Taku Obara conceptualized, designed, and organized the BirThree Cohort Study and reviewed the manuscript.Mami Ishikuro, Keiko Murakami, Aoi Noda, and Genki Shinoda managed the implementation of the BirThree Cohort Study and reviewed the manuscript.Atsushi Hozawa, Naoki Nakaya, Hirohito Metoki, Masahiro Kikuya, Tomoko Nishimura, Keiko Tanaka, and Yoshihiro Miyake reviewed the manuscript critically. Acknowledgement We thank the members of ToMMo including GMRC (Genome Medical Research Coordinators), administrative personnel, and software engineers for their assistance in the projects. The full list of members is available at: https://www.megabank.tohoku.ac.jp/english/a230901/. Data Availability All data used to support the findings may be released upon request to the corresponding author in the Tohoku Medical Megabank Organization. First of all, please contact the corresponding author in this paper. References Shimomura, H. et al. 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Vugteveen, J., De Bildt, A., Hartman, C.A. & Timmerman, M.E. Using the Dutch multi-informant Strengths and Difficulties Questionnaire (SDQ) to predict adolescent psychiatric diagnoses. Eur Child Adolesc Psychiatry. 27 , 1347-1359. https://doi.10.1007/s00787-018-1127-y (2018). Grasso, M., Lazzaro, G., Demaria, F., Menghini, D., & Vicari, S. The Strengths and Difficulties Questionnaire as a Valuable Screening Tool for Identifying Core Symptoms and Behavioural and Emotional Problems in Children with Neuropsychiatric Disorders. Int J Environ Res Public Health. 19 , 7731. https;//doi.10.3390/ijerph19137731 (2022). Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.xlsx Table120241029.xlsx Table220241029.xlsx Table320241029.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Orui","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABKUlEQVRIie3Rv0rDQBzA8V85SJfTrBdEfQLh5CBalOZVEg7SJUPHbB4I6SK4KvUhOjpeOLBLpGvExRCwS0Cli0MGU7UYSDK4Cd4XjsBxH+5PAHS6vx8FcCYCEID7NUE6Fso6oVj9iqwV4TXS0sFknq1eSzWcSXS3wmPYO7Je4nwc+p7oqycY3DaInQSMxJHiM2nwKabABlOO2FUSeAL7FKykSWQAJBaKU4kZqognHrmxsxWFnoAAwIqaZLHM32X5Q87Eg/omZtFOUtcm0lDDDXFpitakOhjp2CUt7OP7aORayuC9G0oOry84YzjxWUSeqWy7y2KUp2F54mzPzxUU5em+2Y+zHId899LkWW41X2yTJ9Dnt/brjGooS3QSp32699ZNdDqd7t/0AaWdaTLw9ym7AAAAAElFTkSuQmCC","orcid":"","institution":"Tohoku University","correspondingAuthor":true,"prefix":"","firstName":"Masatsugu","middleName":"","lastName":"Orui","suffix":""},{"id":376655964,"identity":"667692fc-48c2-4fdc-800d-4443e0046e2d","order_by":1,"name":"Mami Ishikuro","email":"","orcid":"","institution":"Tohoku 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University","correspondingAuthor":false,"prefix":"","firstName":"Genki","middleName":"","lastName":"Shinoda","suffix":""},{"id":376655968,"identity":"dd82d684-8c87-4e40-9be3-7889c7f8d4e6","order_by":5,"name":"Keiko Murakami","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Keiko","middleName":"","lastName":"Murakami","suffix":""},{"id":376655969,"identity":"758018c1-ed5e-44d3-a83e-fa344426f528","order_by":6,"name":"Hirohito Metoki","email":"","orcid":"","institution":"Tohoku Medical and Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Hirohito","middleName":"","lastName":"Metoki","suffix":""},{"id":376655970,"identity":"a88e1c52-7995-4c01-93e0-7e6d7f1348f3","order_by":7,"name":"Masahiro Kikuya","email":"","orcid":"","institution":"Teikyo University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Kikuya","suffix":""},{"id":376655971,"identity":"c8027c0c-824a-4db4-bc41-71fb239c4fdd","order_by":8,"name":"Naoki Nakaya","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Naoki","middleName":"","lastName":"Nakaya","suffix":""},{"id":376655972,"identity":"13b55ded-e5be-4dec-8410-134319638bed","order_by":9,"name":"Tomoko Nishimura","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Nishimura","suffix":""},{"id":376655973,"identity":"638df53f-0744-4f19-8001-93747fc45f22","order_by":10,"name":"Keiko Tanaka","email":"","orcid":"","institution":"Ehime University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Keiko","middleName":"","lastName":"Tanaka","suffix":""},{"id":376655974,"identity":"22c2d29b-d92d-48fc-a069-ab060b50c5a9","order_by":11,"name":"Yoshihiro Miyake","email":"","orcid":"","institution":"Ehime University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yoshihiro","middleName":"","lastName":"Miyake","suffix":""},{"id":376655975,"identity":"08c3a02f-7a5e-4c3f-ae3a-4f6c33dbfcdd","order_by":12,"name":"Atsushi Hozawa","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Hozawa","suffix":""},{"id":376655976,"identity":"11586231-c01d-4b64-ba8c-1fbcfe5af40b","order_by":13,"name":"Kenji J Tsuchiya","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"J","lastName":"Tsuchiya","suffix":""},{"id":376655977,"identity":"a7ca3da2-7b37-4cbd-b261-6ab36c5b8f56","order_by":14,"name":"Shinichi Kuriyama","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Shinichi","middleName":"","lastName":"Kuriyama","suffix":""}],"badges":[],"createdAt":"2024-10-30 17:08:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5362638/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5362638/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70391375,"identity":"e157acae-2fbd-41db-9b98-9dd69cb9c988","added_by":"auto","created_at":"2024-12-02 17:30:47","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":116991,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure 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10:39:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1035975,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5362638/v1/15cf019a-727e-4c3f-b199-c866eea222ce.pdf"},{"id":70391351,"identity":"b6482b3e-760e-4ede-9003-0e8bacd22a62","added_by":"auto","created_at":"2024-12-02 17:30:45","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13530,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5362638/v1/08e385b1e500a74943b10da6.xlsx"},{"id":70391450,"identity":"b4922f2a-2617-4f1b-b2a6-f70645d743a5","added_by":"auto","created_at":"2024-12-02 17:30:52","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12286,"visible":true,"origin":"","legend":"","description":"","filename":"Table120241029.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5362638/v1/f6a93ad96f84540936c97a1d.xlsx"},{"id":70391377,"identity":"7d138e42-281d-4a83-8fca-4a858785f4ab","added_by":"auto","created_at":"2024-12-02 17:30:47","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":16386,"visible":true,"origin":"","legend":"","description":"","filename":"Table220241029.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5362638/v1/ef23966f3d17faa5d98a22a2.xlsx"},{"id":70391605,"identity":"36fcebe4-55ab-48a3-8a7a-e569aedc9985","added_by":"auto","created_at":"2024-12-02 17:31:04","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":16812,"visible":true,"origin":"","legend":"","description":"","filename":"Table320241029.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5362638/v1/3665507d7ff22ad0aa4d59c3.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eCan Gazefinder\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e®\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e detect specific symptoms of neurodevelopmental disorders in children? – a preliminary study of clinical application to neurodevelopmental screening\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eEarly intervention is important for children with neurodevelopmental disorders, and appropriate support from an early stage has a large impact on their subsequent development\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. However, with an increasing awareness of neurodevelopmental disorders in recent years, excessive seeking of an early diagnosis has become problematic, leading to warnings that neurodevelopmental disorders may be over-diagnosed\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Assessments by neurodevelopmental scales alone may include bias because parents who are concerned about developmental delays in their children tend to give biased answers in the scale questionnaires. Therefore, there is a need to develop more reliable or accurate screening to avoid over- or misdiagnosing of neurodevelopmental disorders while using digital biomarkers such as gaze patterns.\u003c/p\u003e \u003cp\u003eAutism spectrum disorder (ASD) is a neurodevelopmental condition characterized by a \u0026ldquo;lack of social communication and social interaction\u0026rdquo; and \u0026ldquo;restricted repetitive patterns of behavior, interests, and actions,\u0026rdquo; with atypical gaze patterns being one of its diagnostic criteria\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Eye-tracking systems such as Tobii\u0026reg; (Tobii Technology, Stockholm, Sweden) and iSCAN\u0026reg; (ISCAN Inc., Woburn, Massachusetts, USA) have been used to detect atypical gaze patterns in children and adolescents with ASD\u003csup\u003e\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Gazefinder\u0026reg;, an eye-tracking system that measures unique gaze patterns of people with ASD, was developed as an evaluation method that does not require any special skills. Moreover, it can be performed in a shorter amount of time compared with Tobii\u0026reg; and iSCAN\u0026reg; and has advantages such as posing less psychological burden on subjects and not requiring verbal responses\u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThree studies have used Gazefinder\u0026reg; to distinguish between psychiatrist-diagnosed ASD and typical development\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e based on atypical gaze patterns, but to the best of our knowledge, no study has examined specific symptoms of neurodevelopmental disorders other than ASD using the device. Although it is reasonable that Gazefinder\u0026reg; can detect specific symptoms and characteristic features of ASD, features of other neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) might also be detected by Gazefinder\u0026reg; since there are not a small number of children who are diagnosed with ASD and are comorbid with ADHD\u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. This could potentially lead to the use of Gazefinder\u0026reg; as a screening tool to detect specific symptoms and characteristic features of ADHD. Longitudinal evaluation and analysis of relationships between subscales of the Strength and Difficulties Questionnaire (SDQ)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, an effective screening scale for detecting neurodevelopmental disorders, and eye gaze data measured by Gazefinder\u0026reg; (hereinafter, \u0026ldquo;gaze data\u0026rdquo;) will provide essential insight into accurate screening of children with neurodevelopmental characteristics. Therefore, we focused on the potential ability of Gazefinder\u0026reg; to allow for screening of neurodevelopmental disorders other than ASD.\u003c/p\u003e \u003cp\u003eIn the present study, we compared gaze data collected at age 4 in the Birth and Three-Generation Cohort Study (BirThree Cohort Study) of the Tohoku Medical Megabank Project (TMM) with data from the SDQ to examine which neurodevelopmental subscales are associated with gaze data at age 4, and whether gaze data at age 4 can detect subsequent neurodevelopmental problems at ages 6\u0026ndash;7. We hypothesized that (1) gaze data are specifically associated with SDQ subscales characteristic of both ASD and ADHD, and (2) gaze data at age 4 can detect longitudinally the presence of symptoms of not only ASD but also ADHD at ages 6\u0026ndash;7.\u003c/p\u003e"},{"header":"Results","content":"\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eBasic characteristics of subjects\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eBasic characteristics of subjects are shown in Table 1. There were about equal numbers of men and women.\u003c/p\u003e\n\u003col start=\"2\"\u003e\n \u003cli\u003e\u003cstrong\u003eAssociations between gaze data and neurod\u003c/strong\u003e\u003cstrong\u003eevelopmental subscales at age 4\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eIn the first analysis, we performed analysis of covariance (ANCOVA) to examine associations between gaze data and SDQ subscales at age 4. Higher scores of SDQ subscales indicate greater problems in corresponding neurodevelopmental aspects. Among five human face stimuli (\u0026ldquo;blinking,\u0026rdquo; \u0026ldquo;mouth moving,\u0026rdquo; \u0026ldquo;silence,\u0026rdquo; \u0026ldquo;still face,\u0026rdquo; and \u0026ldquo;talking\u0026rdquo;), the duration of eye gaze fixation on the person\u0026rsquo;s eye was no significant associated with higher scores. On the other hand, for people and geometry stimuli (\u0026ldquo;same size\u0026rdquo; and \u0026ldquo;small window\u0026rdquo;), a shorter duration of eye gaze fixation on people in \u0026ldquo;same size\u0026rdquo; was significantly associated with higher scores of \u0026ldquo;hyperactivity/inattention\u0026rdquo; and \u0026ldquo;peer problems.\u0026rdquo; Moreover, a shorter duration of eye gaze fixation on people in \u0026ldquo;small window\u0026rdquo; showed an associational trend with higher scores of \u0026ldquo;hyperactivity/inattention\u0026rdquo; but no significance.\u003c/p\u003e\n\u003cp\u003eWe also performed tests for linear trend to evaluate the dose-response relationship between the duration of eye gaze fixation on social information and SDQ\u0026rsquo;s subscale scores. In tests for linear trend, \u0026ldquo;same size\u0026rdquo; and \u0026ldquo;small window\u0026rdquo; showed dose-response relationships with \u0026ldquo;hyperactivity/inattention.\u0026rdquo; \u0026ldquo;Same size\u0026rdquo; and \u0026ldquo;small window\u0026rdquo; also showed a significant trend of dose-response relationships with \u0026ldquo;peer problems\u0026rdquo; (Table 2-1 to 2-4).\u003c/p\u003e\n\u003col start=\"3\"\u003e\n \u003cli\u003e\u003cstrong\u003eAssociations between gaze data at age 4 and neurodevelopmental subscales at ages 6\u0026ndash;7\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eIn the second analysis of associations between SDQ subscales at ages 6\u0026ndash;7 and gaze data collected at age 4, a shorter duration of eye gaze fixation on \u0026ldquo;same size\u0026rdquo; was significantly associated with \u0026ldquo;peer problems,\u0026rdquo; and \u0026ldquo;small window\u0026rdquo; had a significant association with \u0026ldquo;hyperactivity/inattention.\u0026rdquo; Furthermore, a significant trend of dose-response relationship was observed in \u0026ldquo;talking\u0026rdquo;, \u0026ldquo;same size\u0026rdquo; and \u0026ldquo;small window\u0026rdquo; stimuli and \u0026ldquo;peer problems,\u0026rdquo; and \u0026ldquo;same size\u0026rdquo; and \u0026ldquo;small window\u0026rdquo; stimuli and \u0026ldquo;hyperactivity/inattention.\u0026rdquo;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn cases of \u0026ldquo;peer problems\u0026rdquo; in \u0026ldquo;same size\u0026rdquo; stimulus and \u0026ldquo;hyperactivity/inattention\u0026rdquo; in \u0026ldquo;small window,\u0026rdquo; there were significant associations between gaze data measured by Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e\u0026rsquo;s and SDQ\u0026rsquo;s subscales at ages 6\u0026ndash;7, which these has a significant dose-response relationship (Table 3-1 to 3-4).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first study to examine associations between gaze data of Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e and SDQ subscales. The results revealed significant associations between a shorter duration of eye gaze fixation on social information at age 4 and the SDQ subscales \u0026ldquo;peer problems\u0026rdquo; (core feature of ASD) and \u0026ldquo;hyperactivity/inattention\u0026rdquo; (core feature of ADHD) at ages 6\u0026ndash;7, which these has a significant dose-response relationship.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSince Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e was developed as a screening tool for ASD based on atypical gaze patterns of people with ASD, \u0026ldquo;same size\u0026rdquo; stimulus of Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e was expected to detect \u0026ldquo;peer problems,\u0026rdquo; core features of ASD. This finding is consistent with a previous study reporting the validity of people and geometry stimuli measured by Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e for predicting autistic features\u003csup\u003e19\u003c/sup\u003e. Notably, hyperactivity/inattention can also be detected by Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e based on atypical gaze patterns. The reason why Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e can detect \u0026ldquo;hyperactivity/inattention\u0026rdquo;, core features of ADHD is unclear in this study. However, previous studies examining the duration of eye gaze fixation on social information measured by eye-tracking devices other than Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e have reported that people with ASD alone and those with the comorbidity of ASD and ADHD were detected\u003csup\u003e24,25\u003c/sup\u003e. Moreover, some individuals with ASD are likely to have ADHD symptoms, especially hyperactivity/inattention. Indeed, among newly diagnosed patients with ASD in two U.S. healthcare databases, ADHD was the most common comorbidity (Medicaid: 50.09%; Optum: 44.16%)\u003csup\u003e21\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAgainst these backdrops, we analyzed the additional analysis (see Supplementary Table 1) that examined the duration of eye gaze fixation on social information among subjects with high scores (more than 95th percentile) for 1) \u0026ldquo;hyperactivity/inattention\u0026rdquo; alone, 2) \u0026ldquo;peer problems\u0026rdquo; alone, and 3) both \u0026ldquo;hyperactivity/inattention\u0026rdquo; and \u0026ldquo;peer problems.\u0026rdquo; As a result, subjects having symptoms of both \u0026ldquo;hyperactivity/inattention\u0026rdquo; and \u0026ldquo;peer problems\u0026rdquo; had a shorter duration of eye gaze fixation on \u0026ldquo;small window,\u0026rdquo; but no significance. Therefore, the significant association that observed between gaze data and \u0026ldquo;hyperactivity/inattention\u0026rdquo; at both ages 4 and 6\u0026ndash;7 might have been affected by features of the comorbidity of ASD and ADHD. However, this additional analysis is not sufficient, a future study will be necessary to evaluate the association between gaze data measured by Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e and children with diagnosis of ADHD as well as ASD in detail.\u003c/p\u003e\n\u003cp\u003eIn terms of application in primary screening for neurodevelopmental disorders, Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e has the advantage of being a simple screening tool\u003csup\u003e12-19\u003c/sup\u003e, with no respondent bias unlike other conventional neurodevelopmental scales that are answered by parents/guardians. All eye gaze fixation tests for the various stimuli in Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e can be completed in about two minutes, and no special testing skills are required\u003csup\u003e12-19\u003c/sup\u003e. In Japan, health screening systems that were implemented nationwide in accordance with the Maternal and Child Health Act of 1965 include screening of neurodevelopmental disorders for the early detection of delays in growth and development\u003csup\u003e26,27\u003c/sup\u003e. Although these health screening systems for children are based on the standards of child welfare specified by the Ministry of Health, Labour and Welfare in Japan, some concerns have been raised regarding respondent bias when screening of neurodevelopmental disorders is based on semi-structured interviews with public health nurses or guardians. Our findings suggest that children with a shorter duration of eye gaze fixation on social information as measured by Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e at age 4 may have peer problems, a core feature of ASD, as well as hyperactivity/inattention, a core feature of ADHD. Notably, these associations persisted even after two to three years. Therefore, the advantage of Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e to potentially capture the features of both ASD and ADHD may promote early detection and intervention of these disorders.\u003cs\u003e\u0026nbsp;\u003c/s\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several limitations worth noting. First, the subjects of this study included some children with neurodevelopmental disabilities which were not diagnosed. Since this was a cohort study targeting the general population, there were a certain number of subjects who were not diagnosed or did not provide answers about their past medical history. Second, there is respondent bias inherent to neurodevelopmental scales such as SDQ. Some parents who are concerned about developmental delays in their children tend to give biased answers in these questionnaires. Third, given that as many as 4,311 parents or guardians did not respond to the neurodevelopmental scale questionnaire, there is a possibility that our findings might have been under- or over-estimated. Finally, solid discrimination methods of neurodevelopmental problems in childhood have not been established. By using Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e, which stimuli should be selected and how stimuli should be utilized for screening are still ongoing topics of discussion. Despite these limitations, strengths of the present study are that the sample size was larger than those of previous studies, and that the longitudinal design helped reveal the importance of the duration of eye gaze fixation on social information using Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e at ages 4 and 6\u0026ndash;7.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eour findings show that a shorter duration of eye gaze fixation on social information at age 4 is significantly associated with \u0026ldquo;peer problems,\u0026rdquo; a core feature of ASD at both age 4 and ages 6\u0026ndash;7. Moreover, it showed a significant association and dose-response relationship even in longitudinal analysis between gaze data and \u0026ldquo;hyperactivity/inattention\u0026rdquo;, a core feature of ADHD, suggesting that Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e may be a useful tool for primary screening of not only ASD but also ADHD. This is a preliminary study of clinical application to neurodevelopmental screening; therefore, further study will be performed for the accuracy of screening.\u003c/p\u003e"},{"header":"Methods","content":"\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eTMM BirThree Cohort Study and subjects\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe TMM aims to provide medical care to overcome damage from the Great East Japan Earthquake in 2011 and support health services by conducting personalized medical care and supporting disaster victims. The BirThree Cohort Study, a part of the TMM, recruited pregnant women and their children, partners, and parents in certain regions of Miyagi and Iwate Prefectures of Japan from July 2013 to March 2017. Details regarding the recruitment procedure have been described previously\u003csup\u003e28,29\u003c/sup\u003e. From among 23,143 children and 9,459 siblings recruited for the BirThree Cohort Study, subjects aged 4 years included 26,572 children, and of these, 20,001 subjects who did not participate in measurements with Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e were excluded. Subsequently, we selected subjects who completed the neurodevelopmental scale questionnaire at both ages 4 and 6\u0026ndash;7 and for whom gaze data at age 4 were available. Four subjects who had been diagnosed with mental retardation and developmental disabilities were excluded. The final study population consisted of 2,101 subjects (Figure 1). Incidentally, we excluded four subjects \u0026nbsp;who had been diagnosed with intellectual disability, given potential bias in gaze data measured by\u0026nbsp;Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe reason for targeting children at age 4 was that all children undergo a health checkup at 3 years and 6 months of age in Japan, and considering the possibility of adopting it for health checkups at 3 years and 6 months of age in the future.\u0026nbsp;\u003c/p\u003e\n\u003col start=\"2\"\u003e\n \u003cli\u003e\u003cstrong\u003eGazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e measurements\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eSubjects were asked to sit in front of the monitor to undergo gaze measurements for about two minutes under the supervision of the research coordinator. Eye position was measured using a camera equipped with an infrared light source below a 19\u0026rdquo; transistor (1280 \u0026times; 1024 pixels). Using corneal reflection, eye position was recorded at a frequency of 50 Hz as X and Y coordinates. Eye position calibration was performed before showing a series of videos using a 5-point method, in which each subject followed the position of a ball around the screen. It is simple to set up with no difficult preparations needed, and measurements are easily performed as subjects are required only to watch stimuli on the monitor for about two minutes.\u003c/p\u003e\n\u003cp\u003eAfter calibration, eight short videos were shown for the following stimuli: five showing human faces, one showing biological motion, and two showing people and geometric patterns. Human face stimuli consisted of the following five facial expressions: \u0026ldquo;blinking\u0026rdquo; (opening and closing the eyes repeatedly; five seconds), \u0026ldquo;mouth moving\u0026rdquo; (opening and closing the mouth repeatedly; five seconds), \u0026ldquo;silence\u0026rdquo; (closing the mouth; five seconds), \u0026ldquo;still face\u0026rdquo; (four seconds), and \u0026ldquo;talking\u0026rdquo; (talking to subjects; \u0026ldquo;hello,\u0026rdquo; \u0026ldquo;what is your name,\u0026rdquo; and \u0026ldquo;let\u0026rsquo;s play together\u0026rdquo;; seven seconds). People and geometry stimuli consisted of the following two patterns: 1) \u0026ldquo;same size\u0026rdquo; (at the same size for 10 seconds) and 2) \u0026ldquo;small window\u0026rdquo; (stimuli of geometry depicted in small-frame images in a small window on an image of people for 16 seconds) (Figure 2).\u003c/p\u003e\n\u003cp\u003eFor human face stimuli, the proportion of time spent gazing at specific objects was categorized as follows: Group A, eyes; Group B, mouth; Other: other parts of the image; and Off screen/not detected. For people and geometry stimuli, categories were Group A, people; Group B, geometric patterns; Other, other parts of the image; and Off screen/not detected.\u003c/p\u003e\n\u003cp\u003eAmong these patterns of stimuli, 1) \u0026ldquo;a person\u0026rsquo;s eyes\u0026rdquo; under various conditions provided in the images of five human faces (\u0026ldquo;blinking,\u0026rdquo; \u0026ldquo;mouth moving,\u0026rdquo; \u0026ldquo;silence,\u0026rdquo; \u0026ldquo;still face,\u0026rdquo; and \u0026ldquo;talking\u0026rdquo;) and 2) \u0026ldquo;people\u0026rdquo; in the case of \u0026nbsp;\u0026ldquo;same size\u0026rdquo; and \u0026ldquo;small window\u0026rdquo; of people and geometry stimuli were considered to represent social information. Accordingly, we defined social information as gaze patterns towards under these various conditions that are \u0026ldquo;persons\u0026rsquo; eye\u0026rdquo; in the case of the human face stimuli, and \u0026ldquo;people\u0026rdquo; in the case of people and geometry stimuli\u003csup\u003e12\u003c/sup\u003e. Therefore, we measured the proportion of time spent gazing at specific objects, i.e., \u0026ldquo;person\u0026rsquo;s eye\u0026rdquo; in the case of human face stimuli and \u0026ldquo;people\u0026rdquo; in the case of people and geometry stimuli.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Measurement of symptoms of ASD and ADHD using the Strengths and Difficulty Questionnaire (SDQ) at ages 4 and 6\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe SDQ is a neurodevelopmental scale answered by parents or schoolteachers and includes 25 questions reflecting four domains of difficulties including \u0026ldquo;emotional problems\u0026rdquo; (feeling depressed or anxious in new situations and being scared), \u0026ldquo;conduct problems\u0026rdquo; (fights, lying and cheating, stealing things, and not obeying adults), \u0026ldquo;hyperactivity/inattention\u0026rdquo; (restlessness, fidgety, being easily distracted, and difficulties concentrating and thinking carefully before acting), and \u0026ldquo;peer problems\u0026rdquo; (prefer being alone, have no good friends, disliked by other friends, and bullied by others), and one subscale relating to strength \u0026ndash;prosocial behavior\u0026ndash;. The SDQ scale is not specific to ASD, but rather is used to screen the overall mental health status of children\u003csup\u003e30,31\u003c/sup\u003e. Its reliability and validity have been demonstrated in various studies, and it is widely used worldwide, including in Japan, for clinical evaluations and screening such as at school health check-ups and for various types of research\u003csup\u003e33\u003c/sup\u003e. Each of the 25 questions is evaluated on a 3-point scale of \u0026ldquo;not true\u0026rdquo; (0 points), \u0026ldquo;somewhat true\u0026rdquo; (1 point), and \u0026ldquo;certainly true\u0026rdquo; (2 points), with scores ranging from 0 to 10 points for each subscale. A higher score corresponds to more difficulties. In this study, we adopted the \u0026ldquo;emotional problems,\u0026rdquo; \u0026ldquo;conduct problems,\u0026rdquo; \u0026ldquo;hyperactivity/inattention,\u0026rdquo; and \u0026ldquo;peer problems\u0026rdquo; subscales as outcomes\u003csup\u003e32,33\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4-1. Categorized gaze data at age 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, we analyzed the duration of eye gaze fixation on the monitor for each stimulus (i.e., \u0026ldquo;blinking,\u0026rdquo; \u0026ldquo;mouth moving,\u0026rdquo; \u0026ldquo;silence,\u0026rdquo; \u0026ldquo;still face,\u0026rdquo; and \u0026ldquo;talking\u0026rdquo; of human face stimuli, and \u0026ldquo;same size\u0026rdquo; and \u0026ldquo;small window\u0026rdquo; of people and geometry stimuli) by referring to a previous study\u003csup\u003e12\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eFirst, we confirmed the distribution of the duration of eye gaze fixation on the monitor for each stimulus. There were concerns about the reliability of gaze data from children who were gazing off-screen most of the time. Therefore, children with a duration of eye gaze fixation on the monitor below the 5th percentile of the whole cohort were excluded from the analysis. Next, we categorized the duration of eye gaze fixation for each stimulus into four categories based on the three quartile points (the first quartile, median, and the third quartile). Incidentally, the number of excluded subjects were as follows: blinking: n = 112, mouth moving: n = 109, silence: n = 113, still face: n = 109, talking: n = 112, same size: n = 203, and small window: n = 213.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4-2. Associations between gaze data and neurodevelopmental subscales at age 4 (First Analysis)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the first analysis, we examined the association between the duration of eye gaze fixation on Group A of each stimulus and SDQ subscale scores (\u0026ldquo;emotional problems,\u0026rdquo; \u0026ldquo;conduct problems,\u0026rdquo; \u0026ldquo;hyperactivity/inattention,\u0026rdquo; and \u0026ldquo;peer problems\u0026rdquo;) at age 4 after categorizing into four groups. We performed ANCOVA adjusted for sex, and then compared the scores of each developmental subscale of the SDQ across quartile groups. Tests for linear trends were also performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4-3. Associations between gaze data and neurodevelopmental subscales at ages 6\u0026ndash;7 (Second Analysis)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the second analysis, to examine whether Gazefinder\u003csup\u003e\u0026reg;\u003c/sup\u003e gaze data at age 4 can detect specific subsequent symptoms of neurodevelopmental disorders at ages 6\u0026ndash;7, we analyzed the associations between the duration of eye gaze fixation on Group A of each stimulus at age 4 and SDQ subscale scores at ages 6\u0026ndash;7. We performed ANCOVA adjusted for age and sex, and then compared the scores of each developmental subscale across quartile groups. Tests for linear trends were also performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4-4. Overall statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo avoid the problem of multiple comparisons, we performed Bonferroni\u0026rsquo;s correction. Therefore, statistical significance was evaluated using two-sided, design-based tests with a 0.714% level of significance (significance level: 5%/7-time of testing). All analysis were performed with Stata 18 (StataCorp, 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LLC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. Ethical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study was approved by the ethics committee of Tohoku University School of Medicine (approval: 2013-4-103; date: May 10, 2013; latest revision: 2023-4-040; approval date: June 21, 2023). The TMM BirThree Cohort Study has been carried out in compliance with the research criteria approved by the Tohoku University School of Medicine ethical committee. All participants in the TMM BirThree Cohort Study gave their informed consent. Because every participant in this study was a minor, all guardians gave their proxy consent. Lastly, this study was carried out in compliance with the Declaration of Helsinki since it involved human research subjects.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of interest\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest with respect to this research study and paper.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMasatsugu Orui conceptualized and designed this study, conducted the initial analyses, and drafted the initial manuscript. Also, managed the implementation of the BirThree Cohort Study.Kenji J Tsuchiya supervised this study's analysis and drafting initial manuscript. Shinichi Kuriyama and Taku Obara conceptualized, designed, and organized the BirThree Cohort Study and reviewed the manuscript.Mami Ishikuro, Keiko Murakami, Aoi Noda, and Genki Shinoda managed the implementation of the BirThree Cohort Study and reviewed the manuscript.Atsushi Hozawa, Naoki Nakaya, Hirohito Metoki, Masahiro Kikuya, Tomoko Nishimura, Keiko Tanaka, and Yoshihiro Miyake reviewed the manuscript critically.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank the members of ToMMo including GMRC (Genome Medical Research Coordinators), administrative personnel, and software engineers for their assistance in the projects. The full list of members is available at: https://www.megabank.tohoku.ac.jp/english/a230901/.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data used to support the findings may be released upon request to the corresponding author in the Tohoku Medical Megabank Organization. First of all, please contact the corresponding author in this paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eShimomura, H. et al. Early Developmental Signs in Children with Autism Spectrum Disorder: Results from the Japan Environment and Children\u0026apos;s Study. \u003cem\u003eChildren.\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 90. https://doi.10.3390/children9010090 (2022).\u003c/li\u003e\n \u003cli\u003eAoki, A. et al. Trajectories of Healthcare Utilization Among Children and Adolescents With Autism Spectrum Disorder and/or Attention-Deficit/Hyperactivity Disorder in Japan. \u003cem\u003eFront Psychiatry.\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 812347. https://doi.10.3389/fpsyt.2021.812347 (2022).\u003c/li\u003e\n \u003cli\u003eTachibana, Y. et al. 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Using the Strengths and Difficulties Questionnaire (SDQ) to screen for child psychiatric disorders. \u003cem\u003eBr J Psychiatry.\u0026nbsp;\u003c/em\u003e\u003cstrong\u003e177\u003c/strong\u003e, 534-539. https://doi.10.1192/bjp.177.6.534 (2000).\u003c/li\u003e\n \u003cli\u003eVugteveen, J., De Bildt, A., Hartman, C.A. \u0026amp; Timmerman, M.E. Using the Dutch multi-informant Strengths and Difficulties Questionnaire (SDQ) to predict adolescent psychiatric diagnoses. \u003cem\u003eEur Child Adolesc Psychiatry.\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 1347-1359. https://doi.10.1007/s00787-018-1127-y (2018).\u003c/li\u003e\n \u003cli\u003eGrasso, M., Lazzaro, G., Demaria, F., Menghini, D., \u0026amp; Vicari, S. The Strengths and Difficulties Questionnaire as a Valuable Screening Tool for Identifying Core Symptoms and Behavioural and Emotional Problems in Children with Neuropsychiatric Disorders. \u003cem\u003eInt J Environ Res Public Health.\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 7731. https;//doi.10.3390/ijerph19137731 (2022).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gazefinder, eye-tracking, neurodevelopmental disorder, ASD, ADHD, primary screening","lastPublishedDoi":"10.21203/rs.3.rs-5362638/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5362638/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGazefinder\u003csup\u003e®\u003c/sup\u003e, an eye-tracking system, was developed to capture atypical gaze patterns of diagnostic value (e.g., limited duration of eye gaze fixation on social information) in people with autism spectrum disorder (ASD). However, whether it can detect specific symptoms of neurodevelopmental disorders other than ASD is unclear. Therefore, indicating associations between neurodevelopmental symptoms and gaze data measured by Gazefinder\u003csup\u003e®\u003c/sup\u003e is essential for its application in screening neurodevelopmental disorders other than ASD. This large-scale longitudinal study analyzed data from 2,101 subjects to examine associations between the duration of gaze fixation on social information as measured by Gazefinder\u003csup\u003e®\u003c/sup\u003e at age 4 and subscale scores of the Strength and Difficulties Questionnaire (SDQ) at ages 6–7. Results of analysis of covariance (ANCOVA) revealed a significant association between the duration of gaze fixation on social information and SDQ’s peer problems (core feature of ASD). Notably, SDQ’s hyperactivity/inattention (core feature of attention deficit hyperactivity disorder (ADHD)) was also associated with the duration of eye gaze fixation. In conclusion, Gazefinder\u003csup\u003e®\u003c/sup\u003e’s gaze data at age 4 can detect symptoms of not only ASD but also ADHD at ages 6–7 longitudinally and have potential as a primary screening tool for neurodevelopmental disorders other than ASD.\u003c/p\u003e","manuscriptTitle":"Can Gazefinder® detect specific symptoms of neurodevelopmental disorders in children? – a preliminary study of clinical application to neurodevelopmental screening","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-02 17:25:49","doi":"10.21203/rs.3.rs-5362638/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bee98fc5-b5dd-4ca7-b589-4317f08699d4","owner":[],"postedDate":"December 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":40186722,"name":"Biological sciences/Psychology"},{"id":40186723,"name":"Health sciences/Health care"},{"id":40186724,"name":"Health sciences/Health care/Paediatrics"},{"id":40186725,"name":"Health sciences/Health care/Public health"}],"tags":[],"updatedAt":"2025-01-16T10:38:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-02 17:25:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5362638","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5362638","identity":"rs-5362638","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}