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Participants with autism spectrum disorder (ASD) (n = 121, mean [SD] age: 14.6 [8.0] years) and typically developing (TD) controls (n = 40, 16.4 [13.3] years) were presented with a series of videos representing biological motion on one side of a computer monitor screen and non-biological motion on the other, while their eye movements were recorded. As predicted, participants with ASD spent less overall time looking at presented stimuli than TD participants (P < 10-3) and showed less preference for biological motion (P < 10-5). Participants with ASD also had greater average latencies than TD participants of the first fixation on both biological (P < 0.01) and non-biological motion (P < 0.02). Findings suggest that individuals with ASD differ from TD individuals on multiple properties of eye movements and biological motion preference.
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Atenção/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Movimentos Oculares , Percepção de Movimento , Adolescente , Adulto , Criança , Tecnologia de Rastreamento Ocular , Feminino , Fixação Ocular , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Estudos Prospectivos , Análise e Desempenho de Tarefas , Gravação de Videoteipe , Adulto JovemRESUMO
BACKGROUND: Diminished visual monitoring of faces and activities of others is an early feature of autism spectrum disorder (ASD). It is uncertain whether deficits in activity monitoring, identified using a homogeneous set of stimuli, persist throughout the lifespan in ASD, and thus, whether they could serve as a biological indicator ("biomarker") of ASD. We investigated differences in visual attention during activity monitoring in children and adult participants with autism compared to a control group of participants without autism. METHODS: Eye movements of participants with autism (n = 122; mean age [SD] = 14.5 [8.0] years) and typically developing (TD) controls (n = 40, age = 16.4 [13.3] years) were recorded while they viewed a series of videos depicting two female actors conversing while interacting with their hands over a shared task. Actors either continuously focused their gaze on each other's face (mutual gaze) or on the shared activity area (shared focus). Mean percentage looking time was computed for the activity area, actors' heads, and their bodies. RESULTS: Compared to TD participants, participants with ASD looked longer at the activity area (mean % looking time: 58.5% vs. 53.8%, p < 0.005) but less at the heads (15.2% vs. 23.7%, p < 0.0001). Additionally, within-group differences in looking time were observed between the mutual gaze and shared focus conditions in both participants without ASD (activity: Δ = - 6.4%, p < 0.004; heads: Δ = + 3.5%, p < 0.02) and participants with ASD (bodies: Δ = + 1.6%, p < 0.002). LIMITATIONS: The TD participants were not as well characterized as the participants with ASD. Inclusion criteria regarding the cognitive ability [intelligence quotient (IQ) > 60] limited the ability to include individuals with substantial intellectual disability. CONCLUSIONS: Differences in attention to faces could constitute a feature discriminative between individuals with and without ASD across the lifespan, whereas between-group differences in looking at activities may shift with development. These findings may have applications in the search for underlying biological indicators specific to ASD. Trial registration ClinicalTrials.gov identifier NCT02668991.
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Atenção/fisiologia , Transtorno do Espectro Autista/psicologia , Comportamento Social , Adolescente , Adulto , Fatores Etários , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
BACKGROUND: Reduction or differences in facial expression are a core diagnostic feature of autism spectrum disorder (ASD), yet evidence regarding the extent of this discrepancy is limited and inconsistent. Use of automated facial expression detection technology enables accurate and efficient tracking of facial expressions that has potential to identify individual response differences. METHODS: Children and adults with ASD (N = 124) and typically developing (TD, N = 41) were shown short clips of "funny videos." Using automated facial analysis software, we investigated differences between ASD and TD groups and within the ASD group in evidence of facial action unit (AU) activation related to the expression of positive facial expression, in particular, a smile. RESULTS: Individuals with ASD on average showed less evidence of facial AUs (AU12, AU6) relating to positive facial expression, compared to the TD group (p < .05, r = - 0.17). Using Gaussian mixture model for clustering, we identified two distinct distributions within the ASD group, which were then compared to the TD group. One subgroup (n = 35), termed "over-responsive," expressed more intense positive facial expressions in response to the videos than the TD group (p < .001, r = 0.31). The second subgroup (n = 89), ("under-responsive"), displayed fewer, less intense positive facial expressions in response to videos than the TD group (p < .001; r = - 0.36). The over-responsive subgroup differed from the under-responsive subgroup in age and caregiver-reported impulsivity (p < .05, r = 0.21). Reduced expression in the under-responsive, but not the over-responsive group, was related to caregiver-reported social withdrawal (p < .01, r = - 0.3). LIMITATIONS: This exploratory study does not account for multiple comparisons, and future work will have to ascertain the strength and reproducibility of all results. Reduced displays of positive facial expressions do not mean individuals with ASD do not experience positive emotions. CONCLUSIONS: Individuals with ASD differed from the TD group in their facial expressions of positive emotion in response to "funny videos." Identification of subgroups based on response may help in parsing heterogeneity in ASD and enable targeting of treatment based on subtypes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299700. Registration date: November 24, 2014.
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Transtorno do Espectro Autista/diagnóstico , Expressão Facial , Reconhecimento Psicológico , Adolescente , Adulto , Algoritmos , Estudos de Casos e Controles , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Emoções , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Estudos Multicêntricos como Assunto , Estimulação Luminosa , Tempo de Reação , Adulto JovemRESUMO
OBJECTIVE: The relationship between sleep (caregiver-reported and actigraphy-measured) and other caregiver-reported behaviors in children and adults with autism spectrum disorder (ASD) was examined, including the use of machine learning to identify sleep variables important in predicting anxiety in ASD. METHODS: Caregivers of ASD (n = 144) and typically developing (TD) (n = 41) participants reported on sleep and other behaviors. ASD participants wore an actigraphy device at nighttime during an 8 or 10-week non-interventional study. Mean and variability of actigraphy measures for ASD participants in the week preceding midpoint and endpoint were calculated and compared with caregiver-reported and clinician-reported symptoms using a mixed effects model. An elastic-net model was developed to examine which sleep measures may drive prediction of anxiety. RESULTS: Prevalence of caregiver-reported sleep difficulties in ASD was approximately 70% and correlated significantly (p < 0.05) with sleep efficiency measured by actigraphy. Mean and variability of actigraphy measures like sleep efficiency and number of awakenings were related significantly (p < 0.05) to ASD symptom severity, hyperactivity and anxiety. In the elastic net model, caregiver-reported sleep, and variability of sleep efficiency and awakenings were amongst the important predictors of anxiety. CONCLUSION: Caregivers report problems with sleep in the majority of children and adults with ASD. Reported problems and actigraphy measures of sleep, particularly variability, are related to parent reported behaviors. Measuring variability in sleep may prove useful in understanding the relationship between sleep problems and behavior in individuals with ASD. These findings may have implications for both intervention and monitoring outcomes in ASD.
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BACKGROUND: Currently, no medications are approved to treat core symptoms of autism spectrum disorder (ASD). One barrier to ASD medication development is the lack of validated outcome measures able to detect symptom change. Current ASD interventions are often evaluated using retrospective caregiver reports that describe general clinical presentation but often require recall of specific behaviors weeks after they occur, potentially reducing accuracy of the ratings. My JAKE, a mobile and Web-based mobile health (mHealth) app that is part of the Janssen Autism Knowledge Engine-a dynamically updated clinical research system-was designed to help caregivers of individuals with ASD to continuously log symptoms, record treatments, and track progress, to mitigate difficulties associated with retrospective reporting. OBJECTIVE: My JAKE was deployed in an exploratory, noninterventional clinical trial to evaluate its utility and acceptability to monitor clinical outcomes in ASD. Hypotheses regarding relationships among daily tracking of symptoms, behavior, and retrospective caregiver reports were tested. METHODS: Caregivers of individuals with ASD aged 6 years to adults (N=144) used the My JAKE app to make daily reports on their child's sleep quality, affect, and other self-selected specific behaviors across the 8- to 10-week observational study. The results were compared with commonly used paper-and-pencil scales acquired over a concurrent period at regular 4-week intervals. RESULTS: Caregiver reporting of behaviors in real time was successfully captured by My JAKE. On average, caregivers made reports 2-3 days per week across the study period. Caregivers were positive about their use of the system, with over 50% indicating that they would like to use My JAKE to track behavior outside of a clinical trial. More positive average daily reporting of overall type of day was correlated with 4 weekly reports of lower caregiver burden made at 4-week intervals (r=-0.27, P=.006, n=88) and with ASD symptoms (r=-0.42, P<.001, n=112). CONCLUSIONS: My JAKE reporting aligned with retrospective Web-based or paper-and-pencil scales. Use of mHealth apps, such as My JAKE, has the potential to increase the validity and accuracy of caregiver-reported outcomes and could be a useful way of identifying early changes in response to intervention. Such systems may also assist caregivers in tracking symptoms and behavior outside of a clinical trial, help with personalized goal setting, and monitoring of progress, which could collectively improve understanding of and quality of life for individuals with ASD and their families. TRIAL REGISTRATION: ClinicalTrials.gov NCT02668991; https://clinicaltrials.gov/ct2/show/NCT02668991.
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Objective: The Janssen Autism Knowledge Engine (JAKE®) is a clinical research outcomes assessment system developed to more sensitively measure treatment outcomes and identify subpopulations in autism spectrum disorder (ASD). Here we describe JAKE and present results from its digital phenotyping (My JAKE) and biosensor (JAKE Sense) components. Methods: An observational, non-interventional, prospective study of JAKE in children and adults with ASD was conducted at nine sites in the United States. Feedback on JAKE usability was obtained from caregivers. JAKE Sense included electroencephalography, eye tracking, electrocardiography, electrodermal activity, facial affect analysis, and actigraphy. Caregivers of individuals with ASD reported behaviors using My JAKE. Results from My JAKE and JAKE Sense were compared to traditional ASD symptom measures. Results: Individuals with ASD (N = 144) and a cohort of typically developing (TD) individuals (N = 41) participated in JAKE Sense. Most caregivers reported that overall use and utility of My JAKE was "easy" (69%, 74/108) or "very easy" (74%, 80/108). My JAKE could detect differences in ASD symptoms as measured by traditional methods. The majority of biosensors included in JAKE Sense captured sizable amounts of quality data (i.e., 93-100% of eye tracker, facial affect analysis, and electrocardiogram data was of good quality), demonstrated differences between TD and ASD individuals, and correlated with ASD symptom scales. No significant safety events were reported. Conclusions: My JAKE was viewed as easy or very easy to use by caregivers participating in research outside of a clinical study. My JAKE sensitively measured a broad range of ASD symptoms. JAKE Sense biosensors were well-tolerated. JAKE functioned well when used at clinical sites previously inexperienced with some of the technologies. Lessons from the study will optimize JAKE for use in clinical trials to assess ASD interventions. Additionally, because biosensors were able to detect features differentiating TD and ASD individuals, and also were correlated with standardized symptom scales, these measures could be explored as potential biomarkers for ASD and as endpoints in future clinical studies. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02668991 identifier: NCT02668991.
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Facial expression is impaired in autism spectrum disorder (ASD), but rarely systematically studied. We focus on the ability of individuals with ASD to produce facial expressions of emotions in response to a verbal prompt. We used the Janssen Autism Knowledge Engine (JAKE®), including automated facial expression analysis software (FACET) to measure facial expressions in individuals with ASD (n = 144) and a typically developing (TD) comparison group (n = 41). Differences in ability to produce facial expressions were observed between ASD and TD groups, demonstrated by activation of facial action units (happy, scared, surprised, disgusted, but not angry or sad). Activation of facial action units correlated with parent-reported social communication skills. This approach has potential for diagnostic and response to intervention measures.Trial Registration NCT02299700.
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Transtorno do Espectro Autista/psicologia , Emoções , Expressão Facial , Adolescente , Adulto , Transtorno do Espectro Autista/fisiopatologia , Identificação Biométrica , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Eye-tracking studies have demonstrated that individuals with autism spectrum disorder sometimes show differences in attention and gaze patterns. This includes preference for certain nonsocial objects, heightened attention to detail, and more difficulty with attention shifting and disengagement, which may be associated with restricted and repetitive behaviors. This study utilized a visual exploration task and replicates findings of reduced number of objects explored and increased fixation duration on high autism interest objects in a large sample of individuals with autism spectrum disorder (n = 129, age 6-54 years) in comparison with a typically developing group. These findings correlated with parent-reported repetitive behaviors. Additionally, we applied recurrent quantification analysis to enable identification of new eye-tracking features, which accounted for temporal and spatial differences in viewing patterns. These new features were found to discriminate between autism spectrum disorder and typically developing groups and were correlated with parent-reported repetitive behaviors. Original and novel eye-tracking features identified by recurrent quantification analysis differed in their relationships to reported behaviors and were dependent on age. Trial Registration: NCT02299700. Autism Research 2018, 11: 1554-1566. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using eye-tracking technology and a visual exploration task, we showed that people with autism spectrum disorder (ASD) spend more time looking at particular kinds of objects, like trains and clocks, and look at fewer objects overall than people without ASD. Where people look and the order in which they look at objects were related to the restricted and repetitive behaviors reported by parents. Eye-tracking may be a useful addition to parent reports for measuring changes in behavior in individuals with ASD.
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Atenção/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Movimentos Oculares/fisiologia , Adolescente , Adulto , Fatores Etários , Transtorno do Espectro Autista/complicações , Criança , Transtornos Traumáticos Cumulativos/complicações , Transtornos Traumáticos Cumulativos/fisiopatologia , Feminino , Fixação Ocular/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Estimulação Luminosa/métodos , Fatores de Tempo , Adulto JovemRESUMO
Objective: To test usability and optimize the Janssen Autism Knowledge Engine (JAKE®) system's components, biosensors, and procedures used for objective measurement of core and associated symptoms of autism spectrum disorder (ASD) in clinical trials. Methods: A prospective, observational study of 29 children and adolescents with ASD using the JAKE system was conducted at three sites in the United States. This study was designed to establish the feasibility of the JAKE system and to learn practical aspects of its implementation. In addition to information collected by web and mobile components, wearable biosensor data were collected both continuously in natural settings and periodically during a battery of experimental tasks administered in laboratory settings. This study is registered at clinicaltrials.gov, NCT02299700. Results: Feedback collected throughout the study allowed future refinements to be planned for all components of the system. The Autism Behavior Inventory (ABI), a parent-reported measure of ASD core and associated symptoms, performed well. Among biosensors studied, the eye-tracker, sleep monitor, and electrocardiogram were shown to capture high quality data, whereas wireless electroencephalography was difficult to use due to its form factor. On an exit survey, the majority of parents rated their overall reaction to JAKE as positive/very positive. No significant device-related events were reported in the study. Conclusion: The results of this study, with the described changes, demonstrate that the JAKE system is a viable, useful, and safe platform for use in clinical trials of ASD, justifying larger validation and deployment studies of the optimized system.
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A number of recent studies using accelerometer features as input to machine learning classifiers show promising results for automatically detecting stereotypical motor movements (SMM) in individuals with Autism Spectrum Disorder (ASD). However, replicating these results across different types of accelerometers and their position on the body still remains a challenge. We introduce a new set of features in this domain based on recurrence plot and quantification analyses that are orientation invariant and able to capture non-linear dynamics of SMM. Applying these features to an existing published data set containing acceleration data, we achieve up to 9% average increase in accuracy compared to current state-of-the-art published results. Furthermore, we provide evidence that a single torso sensor can automatically detect multiple types of SMM in ASD, and that our approach allows recognition of SMM with high accuracy in individuals when using a person-independent classifier.
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We present a novel approach for enhancing the diversity of a chemical library rooted on the theory of the wisdom of crowds. Our approach was motivated by a desire to tap into the collective experience of our global medicinal chemistry community and involved four basic steps: (1) Candidate compounds for acquisition were screened using various structural and property filters in order to eliminate clearly nondrug-like matter. (2) The remaining compounds were clustered together with our in-house collection using a novel fingerprint-based clustering algorithm that emphasizes common substructures and works with millions of molecules. (3) Clusters populated exclusively by external compounds were identified as "diversity holes," and representative members of these clusters were presented to our global medicinal chemistry community, who were asked to specify which ones they liked, disliked, or were indifferent to using a simple point-and-click interface. (4) The resulting votes were used to rank the clusters from most to least desirable, and to prioritize which ones should be targeted for acquisition. Analysis of the voting results reveals interesting voter behaviors and distinct preferences for certain molecular property ranges that are fully consistent with lead-like profiles established through systematic analysis of large historical databases.
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Bibliotecas de Moléculas Pequenas/química , Química Farmacêutica/métodos , Análise por Conglomerados , Estrutura MolecularRESUMO
We introduce Single R-Group Polymorphisms (SRPs, pronounced 'sharps'), an intuitive framework for analyzing substituent effects and activity cliffs in a single congeneric series. A SRP is a pair of compounds that differ only in a single R-group position. Because the same substituent pair may occur in multiple SRPs in the series (i.e., with different combinations of substituents at the other R-group positions), SRP analysis makes it easy to identify systematic substituent effects and activity cliffs at each point of variation (R-cliffs). SRPs can be visualized as a symmetric heatmap where each cell represents a particular pair of substituents color-coded by the average difference in activity between the compounds that contain that particular SRP. SRP maps offer several advantages over existing techniques for visualizing activity cliffs: 1) the chemical structures of all the substituents are displayed simultaneously on a single map, thus directly engaging the pattern recognition abilities of the medicinal chemist; 2) it is based on R-group decomposition, a natural paradigm for generating and rationalizing SAR; 3) it uses a heatmap representation that makes it easy to identify systematic trends in the data; 4) it generalizes the concept of activity cliffs beyond similarity by allowing the analyst to sort the substituents according to any property of interest or place them manually in any desired order.
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Catepsinas/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteases/química , Software , Catepsinas/química , Gráficos por Computador , Ligantes , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We present ABCD, an integrated drug discovery informatics platform developed at Johnson & Johnson Pharmaceutical Research & Development, L.L.C. ABCD is an attempt to bridge multiple continents, data systems, and cultures using modern information technology and to provide scientists with tools that allow them to analyze multifactorial SAR and make informed, data-driven decisions. The system consists of three major components: (1) a data warehouse, which combines data from multiple chemical and pharmacological transactional databases, designed for supreme query performance; (2) a state-of-the-art application suite, which facilitates data upload, retrieval, mining, and reporting, and (3) a workspace, which facilitates collaboration and data sharing by allowing users to share queries, templates, results, and reports across project teams, campuses, and other organizational units. Chemical intelligence, performance, and analytical sophistication lie at the heart of the new system, which was developed entirely in-house. ABCD is used routinely by more than 1000 scientists around the world and is rapidly expanding into other functional areas within the J&J organization.