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  1. Article ; Online: Level of Attention to Motherese Speech as an Early Marker of Autism Spectrum Disorder.

    Pierce, Karen / Wen, Teresa H / Zahiri, Javad / Andreason, Charlene / Courchesne, Eric / Barnes, Cynthia C / Lopez, Linda / Arias, Steven J / Esquivel, Ahtziry / Cheng, Amanda

    JAMA network open

    2023  Volume 6, Issue 2, Page(s) e2255125

    Abstract: Importance: Caregivers have long captured the attention of their infants by speaking in motherese, a playful speech style characterized by heightened affect. Reduced attention to motherese in toddlers with autism spectrum disorder (ASD) may be a ... ...

    Abstract Importance: Caregivers have long captured the attention of their infants by speaking in motherese, a playful speech style characterized by heightened affect. Reduced attention to motherese in toddlers with autism spectrum disorder (ASD) may be a contributor to downstream language and social challenges and could be diagnostically revealing.
    Objective: To investigate whether attention toward motherese speech can be used as a diagnostic classifier of ASD and is associated with language and social ability.
    Design, setting, and participants: This diagnostic study included toddlers aged 12 to 48 months, spanning ASD and non-ASD diagnostic groups, at a research center. Data were collected from February 2018 to April 2021 and analyzed from April 2021 to March 2022.
    Exposures: Gaze-contingent eye-tracking test.
    Main outcomes and measures: Using gaze-contingent eye tracking wherein the location of a toddler's fixation triggered a specific movie file, toddlers participated in 1 or more 1-minute eye-tracking tests designed to quantify attention to motherese speech, including motherese vs traffic (ie, noisy vehicles on a highway) and motherese vs techno (ie, abstract shapes with music). Toddlers were also diagnostically and psychometrically evaluated by psychologists. Levels of fixation within motherese and nonmotherese movies and mean number of saccades per second were calculated. Receiver operating characteristic (ROC) curves were used to evaluate optimal fixation cutoff values and associated sensitivity, specificity, positive predictive value (PPV), and negative predictive value. Within the ASD group, toddlers were stratified based on low, middle, or high levels of interest in motherese speech, and associations with social and language abilities were examined.
    Results: A total of 653 toddlers were included (mean [SD] age, 26.45 [8.37] months; 480 males [73.51%]). Unlike toddlers without ASD, who almost uniformly attended to motherese speech with a median level of 82.25% and 80.75% across the 2 tests, among toddlers with ASD, there was a wide range, spanning 0% to 100%. Both the traffic and techno paradigms were effective diagnostic classifiers, with large between-group effect sizes (eg, ASD vs typical development: Cohen d, 1.0 in the techno paradigm). Across both paradigms, a cutoff value of 30% or less fixation on motherese resulted in an area under the ROC curve (AUC) of 0.733 (95% CI, 0.693-0.773) and 0.761 (95% CI, 0.717-0.804), respectively; specificity of 98% (95% CI, 95%-99%) and 96% (95% CI, 92%-98%), respectively; and PPV of 94% (95% CI, 86%-98%). Reflective of heterogeneity and expected subtypes in ASD, sensitivity was lower at 18% (95% CI, 14%-22%) and 29% (95% CI, 24%-34%), respectively. Combining metrics increased the AUC to 0.841 (95% CI, 0.805-0.877). Toddlers with ASD who showed the lowest levels of attention to motherese speech had weaker social and language abilities.
    Conclusions and relevance: In this diagnostic study, a subset of toddlers showed low levels of attention toward motherese speech. When a cutoff level of 30% or less fixation on motherese speech was used, toddlers in this range were diagnostically classified as having ASD with high accuracy. Insight into which toddlers show unusually low levels of attention to motherese may be beneficial not only for early ASD diagnosis and prognosis but also as a possible therapeutic target.
    MeSH term(s) Male ; Infant ; Humans ; Adult ; Autism Spectrum Disorder/diagnosis ; Speech ; Cognition ; ROC Curve ; Predictive Value of Tests
    Language English
    Publishing date 2023-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2574-3805
    ISSN (online) 2574-3805
    DOI 10.1001/jamanetworkopen.2022.55125
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Atypical functional connectivity of temporal cortex with precuneus and visual regions may be an early-age signature of ASD.

    Xiao, Yaqiong / Wen, Teresa H / Kupis, Lauren / Eyler, Lisa T / Taluja, Vani / Troxel, Jaden / Goel, Disha / Lombardo, Michael V / Pierce, Karen / Courchesne, Eric

    Molecular autism

    2023  Volume 14, Issue 1, Page(s) 11

    Abstract: Background: Social and language abilities are closely intertwined during early typical development. In autism spectrum disorder (ASD), however, deficits in social and language development are early-age core symptoms. We previously reported that superior ...

    Abstract Background: Social and language abilities are closely intertwined during early typical development. In autism spectrum disorder (ASD), however, deficits in social and language development are early-age core symptoms. We previously reported that superior temporal cortex, a well-established social and language region, shows reduced activation to social affective speech in ASD toddlers; however, the atypical cortical connectivity that accompanies this deviance remains unknown.
    Methods: We collected clinical, eye tracking, and resting-state fMRI data from 86 ASD and non-ASD subjects (mean age 2.3 ± 0.7 years). Functional connectivity of left and right superior temporal regions with other cortical regions and correlations between this connectivity and each child's social and language abilities were examined.
    Results: While there was no group difference in functional connectivity, the connectivity between superior temporal cortex and frontal and parietal regions was significantly correlated with language, communication, and social abilities in non-ASD subjects, but these effects were absent in ASD subjects. Instead, ASD subjects, regardless of different social or nonsocial visual preferences, showed atypical correlations between temporal-visual region connectivity and communication ability (r(49) = 0.55, p < 0.001) and between temporal-precuneus connectivity and expressive language ability (r(49) = 0.58, p < 0.001).
    Limitations: The distinct connectivity-behavior correlation patterns may be related to different developmental stages in ASD and non-ASD subjects. The use of a prior 2-year-old template for spatial normalization may not be optimal for a few subjects beyond this age range.
    Conclusions: Superior temporal cortex is known to have reduced activation to social affective speech in ASD at early ages, and here we find in ASD toddlers that it also has atypical connectivity with visual and precuneus cortices that is correlated with communication and language ability, a pattern not seen in non-ASD toddlers. This atypicality may be an early-age signature of ASD that also explains why the disorder has deviant early language and social development. Given that these atypical connectivity patterns are also present in older individuals with ASD, we conclude these atypical connectivity patterns persist across age and may explain why successful interventions targeting language and social skills at all ages in ASD are so difficult to achieve.
    MeSH term(s) Humans ; Aged ; Infant ; Child, Preschool ; Autism Spectrum Disorder ; Brain ; Brain Mapping ; Temporal Lobe ; Magnetic Resonance Imaging ; Parietal Lobe ; Neural Pathways
    Language English
    Publishing date 2023-03-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2540930-X
    ISSN 2040-2392 ; 2040-2392
    ISSN (online) 2040-2392
    ISSN 2040-2392
    DOI 10.1186/s13229-023-00543-8
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  3. Article: The Perineuronal 'Safety' Net? Perineuronal Net Abnormalities in Neurological Disorders.

    Wen, Teresa H / Binder, Devin K / Ethell, Iryna M / Razak, Khaleel A

    Frontiers in molecular neuroscience

    2018  Volume 11, Page(s) 270

    Abstract: Perineuronal nets (PNN) are extracellular matrix (ECM) assemblies that preferentially ensheath parvalbumin (PV) expressing interneurons. Converging evidence indicates that PV cells and PNN are impaired in a variety of neurological disorders. PNN ... ...

    Abstract Perineuronal nets (PNN) are extracellular matrix (ECM) assemblies that preferentially ensheath parvalbumin (PV) expressing interneurons. Converging evidence indicates that PV cells and PNN are impaired in a variety of neurological disorders. PNN development and maintenance is necessary for a number of processes within the CNS, including regulation of GABAergic cell function, protection of neurons from oxidative stress, and closure of developmental critical period plasticity windows. Understanding PNN functions may be essential for characterizing the mechanisms of altered cortical excitability observed in neurodegenerative and neurodevelopmental disorders. Indeed, PNN abnormalities have been observed in post-mortem brain tissues of patients with schizophrenia and Alzheimer's disease. There is impaired development of PNNs and enhanced activity of its key regulator matrix metalloproteinase-9 (MMP-9) in Fragile X Syndrome, a common genetic cause of autism. MMP-9, a protease that cleaves ECM, is differentially regulated in a number of these disorders. Despite this, few studies have addressed the interactions between PNN expression, MMP-9 activity and neuronal excitability. In this review, we highlight the current evidence for PNN abnormalities in CNS disorders associated with altered network function and MMP-9 levels, emphasizing the need for future work targeting PNNs in pathophysiology and therapeutic treatment of neurological disorders.
    Language English
    Publishing date 2018-08-03
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2018.00270
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  4. Article ; Online: Vacuum exhausted isolation locker (VEIL) to reduce inpatient droplet/aerosol transmission during COVID-19 pandemic.

    Gopesh, Tilvawala / Grant, Alex M / Wen, Jessica H / Wen, Teresa H / Criado-Hidalgo, Ernesto / Connacher, William J / Friend, James R / Morris, Timothy A

    Infection control and hospital epidemiology

    2021  Volume 43, Issue 1, Page(s) 105–107

    Abstract: The vacuum-exhausted isolation locker (VEIL) provides a safety barrier during the care of COVID-19 patients. The VEIL is a 175-L enclosure with exhaust ports to continuously extract air through viral particle filters connected to hospital suction. Our ... ...

    Abstract The vacuum-exhausted isolation locker (VEIL) provides a safety barrier during the care of COVID-19 patients. The VEIL is a 175-L enclosure with exhaust ports to continuously extract air through viral particle filters connected to hospital suction. Our experiments show that the VEIL contains and exhausts exhaled aerosols and droplets.
    MeSH term(s) Aerosols ; COVID-19 ; Humans ; Inpatients ; Pandemics ; SARS-CoV-2 ; Vacuum
    Chemical Substances Aerosols
    Language English
    Publishing date 2021-01-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639378-0
    ISSN 1559-6834 ; 0195-9417 ; 0899-823X
    ISSN (online) 1559-6834
    ISSN 0195-9417 ; 0899-823X
    DOI 10.1017/ice.2020.1414
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  5. Article ; Online: Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9.

    Toledo, Maximiliano A / Wen, Teresa H / Binder, Devin K / Ethell, Iryna M / Razak, Khaleel A

    Behavioural brain research

    2019  Volume 372, Page(s) 112068

    Abstract: Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. The Fmr1 knockout (KO) mouse is a commonly studied pre-clinical model of FXS. Adult male Fmr1 KO mice produce fewer ultrasonic vocalizations (USVs) during mating, ...

    Abstract Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. The Fmr1 knockout (KO) mouse is a commonly studied pre-clinical model of FXS. Adult male Fmr1 KO mice produce fewer ultrasonic vocalizations (USVs) during mating, suggestive of abnormal social communication. Minocycline treatment for 2 months from birth alleviates a number of FXS phenotypes in mice, including USV call rate deficits. In the current study, we investigated if treatment initiated past the early developmental period would be effective, given that in many cases, individuals with FXS are treated during later developmental periods. Wildtype (WT) and Fmr1 KO mice were treated with minocycline between postnatal day (P) 30 and P58. Mating-related USVs were then recorded from these mice between P75 and P90 and analyzed for call rate, duration, bandwidth, and peak frequency. Untreated Fmr1 KO mice call at a significantly reduced rate compared to untreated WT mice. After minocycline treatment from 1 to 2 months of age, WT and Fmr1 KO mice exhibited similar call rates, due to an increase in calling in the latter group. Minocycline is thought to be effective in reducing FXS symptoms by lowering matrix-metalloproteinase-9 (MMP-9) levels. To determine whether abnormal MMP-9 levels underlie USV deficits, we characterized USVs in Fmr1 KO mice which were heterozygous for MMP-9 (MMP-9
    MeSH term(s) Animal Communication ; Animals ; Disease Models, Animal ; Fragile X Mental Retardation Protein/genetics ; Fragile X Mental Retardation Protein/metabolism ; Fragile X Syndrome/drug therapy ; Fragile X Syndrome/genetics ; Male ; Matrix Metalloproteinase 9/deficiency ; Matrix Metalloproteinase 9/genetics ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mice, Knockout ; Minocycline/pharmacology ; Ultrasonics ; Vocalization, Animal/drug effects
    Chemical Substances Fmr1 protein, mouse ; Fragile X Mental Retardation Protein (139135-51-6) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Mmp9 protein, mouse (EC 3.4.24.35) ; Minocycline (FYY3R43WGO)
    Language English
    Publishing date 2019-07-02
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 449927-x
    ISSN 1872-7549 ; 0166-4328
    ISSN (online) 1872-7549
    ISSN 0166-4328
    DOI 10.1016/j.bbr.2019.112068
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  6. Article ; Online: Large scale validation of an early-age eye-tracking biomarker of an autism spectrum disorder subtype.

    Wen, Teresa H / Cheng, Amanda / Andreason, Charlene / Zahiri, Javad / Xiao, Yaqiong / Xu, Ronghui / Bao, Bokan / Courchesne, Eric / Barnes, Cynthia Carter / Arias, Steven J / Pierce, Karen

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 4253

    Abstract: Few clinically validated biomarkers of ASD exist which can rapidly, accurately, and objectively identify autism during the first years of life and be used to support optimized treatment outcomes and advances in precision medicine. As such, the goal of ... ...

    Abstract Few clinically validated biomarkers of ASD exist which can rapidly, accurately, and objectively identify autism during the first years of life and be used to support optimized treatment outcomes and advances in precision medicine. As such, the goal of the present study was to leverage both simple and computationally-advanced approaches to validate an eye-tracking measure of social attention preference, the GeoPref Test, among 1,863 ASD, delayed, or typical toddlers (12-48 months) referred from the community or general population via a primary care universal screening program. Toddlers participated in diagnostic and psychometric evaluations and the GeoPref Test: a 1-min movie containing side-by-side dynamic social and geometric images. Following testing, diagnosis was denoted as ASD, ASD features, LD, GDD, Other, typical sibling of ASD proband, or typical. Relative to other diagnostic groups, ASD toddlers exhibited the highest levels of visual attention towards geometric images and those with especially high fixation levels exhibited poor clinical profiles. Using the 69% fixation threshold, the GeoPref Test had 98% specificity, 17% sensitivity, 81% PPV, and 65% NPV. Sensitivity increased to 33% when saccades were included, with comparable validity across sex, ethnicity, or race. The GeoPref Test was also highly reliable up to 24 months following the initial test. Finally, fixation levels among twins concordant for ASD were significantly correlated, indicating that GeoPref Test performance may be genetically driven. As the GeoPref Test yields few false positives (~ 2%) and is equally valid across demographic categories, the current findings highlight the ability of the GeoPref Test to rapidly and accurately detect autism before the 2nd birthday in a subset of children and serve as a biomarker for a unique ASD subtype in clinical trials.
    MeSH term(s) Autism Spectrum Disorder/diagnosis ; Autistic Disorder ; Biomarkers ; Eye-Tracking Technology ; Humans ; Saccades
    Chemical Substances Biomarkers
    Language English
    Publishing date 2022-03-11
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-08102-6
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  7. Article ; Online: Neural responses to affective speech, including motherese, map onto clinical and social eye tracking profiles in toddlers with ASD.

    Xiao, Yaqiong / Wen, Teresa H / Kupis, Lauren / Eyler, Lisa T / Goel, Disha / Vaux, Keith / Lombardo, Michael V / Lewis, Nathan E / Pierce, Karen / Courchesne, Eric

    Nature human behaviour

    2022  Volume 6, Issue 3, Page(s) 443–454

    Abstract: Affective speech, including motherese, captures an infant's attention and enhances social, language and emotional development. Decreased behavioural response to affective speech and reduced caregiver-child interactions are early signs of autism in ... ...

    Abstract Affective speech, including motherese, captures an infant's attention and enhances social, language and emotional development. Decreased behavioural response to affective speech and reduced caregiver-child interactions are early signs of autism in infants. To understand this, we measured neural responses to mild affect speech, moderate affect speech and motherese using natural sleep functional magnetic resonance imaging and behavioural preference for motherese using eye tracking in typically developing toddlers and those with autism. By combining diverse neural-clinical data using similarity network fusion, we discovered four distinct clusters of toddlers. The autism cluster with the weakest superior temporal responses to affective speech and very poor social and language abilities had reduced behavioural preference for motherese, while the typically developing cluster with the strongest superior temporal response to affective speech showed the opposite effect. We conclude that significantly reduced behavioural preference for motherese in autism is related to impaired development of temporal cortical systems that normally respond to parental affective speech.
    MeSH term(s) Attention ; Autism Spectrum Disorder/diagnostic imaging ; Eye-Tracking Technology ; Humans ; Infant ; Language Development ; Speech
    Language English
    Publishing date 2022-01-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2397-3374
    ISSN (online) 2397-3374
    DOI 10.1038/s41562-021-01237-y
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  8. Article ; Online: Magnesium-based biodegradable microelectrodes for neural recording.

    Zhang, Chaoxing / Wen, Teresa H / Razak, Khaleel A / Lin, Jiajia / Xu, Changlu / Seo, Catherine / Villafana, Edgar / Jimenez, Hector / Liu, Huinan

    Materials science & engineering. C, Materials for biological applications

    2020  Volume 110, Page(s) 110614

    Abstract: This article reports fabrication, characterization, degradation and electrical properties of biodegradable magnesium (Mg) microwires coated with two functional polymers, and the first in vivo evidence on the feasibility of Mg-based biodegradable ... ...

    Abstract This article reports fabrication, characterization, degradation and electrical properties of biodegradable magnesium (Mg) microwires coated with two functional polymers, and the first in vivo evidence on the feasibility of Mg-based biodegradable microelectrodes for neural recording. Conductive poly(3,4‑ethylenedioxythiophene) (PEDOT) coating was first electrochemically deposited onto Mg microwire surface, and insulating biodegradable poly(glycerol sebacate) (PGS) was then spray-coated onto PEDOT surface to improve the overall properties of microelectrode. The assembled PGS/PEDOT-coated Mg microelectrodes showed high homogeneity in coating thickness, surface morphology and composition before and after in vivo recording. The charge storage capacity (CSC) of PGS/PEDOT-coated Mg microwire (1.72 mC/cm
    MeSH term(s) Animals ; Bridged Bicyclo Compounds, Heterocyclic ; Coated Materials, Biocompatible ; Decanoates ; Electric Conductivity ; Electrodes, Implanted ; Glycerol/analogs & derivatives ; Magnesium ; Mice ; Microelectrodes ; Polymers
    Chemical Substances Bridged Bicyclo Compounds, Heterocyclic ; Coated Materials, Biocompatible ; Decanoates ; Polymers ; poly(3,4-ethylene dioxythiophene) ; poly(glycerol-sebacate) ; Magnesium (I38ZP9992A) ; Glycerol (PDC6A3C0OX)
    Language English
    Publishing date 2020-01-03
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2012160-X
    ISSN 1873-0191 ; 0928-4931
    ISSN (online) 1873-0191
    ISSN 0928-4931
    DOI 10.1016/j.msec.2019.110614
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  9. Article ; Online: Developmental Changes in EEG Phenotypes in a Mouse Model of Fragile X Syndrome.

    Wen, Teresa H / Lovelace, Jonathan W / Ethell, Iryna M / Binder, Devin K / Razak, Khaleel A

    Neuroscience

    2018  Volume 398, Page(s) 126–143

    Abstract: Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. Sensory-processing deficits are common in humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, manifesting in the auditory system as debilitating ... ...

    Abstract Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. Sensory-processing deficits are common in humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, manifesting in the auditory system as debilitating hypersensitivity and abnormal electroencephalographic (EEG) and event-related potential (ERP) phenotypes. FXS is a neurodevelopmental disorder, but how EEG/ERP phenotypes change during development is unclear. Therefore, we characterized baseline and stimulus-evoked EEG in auditory and frontal cortex of developing (postnatal day (P) 21 and P30) and adult (P60) wildtype (WT) and Fmr1 KO mice with the FVB genetic background. We found that baseline gamma-band power and N1 amplitude of auditory ERP were increased in frontal cortex of Fmr1 KO mice during development and in adults. Baseline gamma power was increased in auditory cortex at P30. Genotype differences in stimulus-evoked gamma power were present in both cortical regions, but the direction and strength of the changes were age-dependent. These findings suggest that cortical deficits are present during early development and may contribute to sensory-processing deficits in FXS, which in turn may lead to anxiety and delayed language. Developmental changes in EEG measures indicate that observations at a single time-point during development are not reflective of FXS disease progression and highlight the need to identify developmental trajectories and optimal windows for treatment.
    MeSH term(s) Animals ; Auditory Cortex/growth & development ; Auditory Cortex/physiopathology ; Brain Waves/physiology ; Cerebral Cortex/growth & development ; Cerebral Cortex/physiopathology ; Disease Models, Animal ; Evoked Potentials ; Fragile X Mental Retardation Protein/genetics ; Fragile X Syndrome/physiopathology ; Mice, Knockout ; Phenotype
    Chemical Substances Fmr1 protein, mouse ; Fragile X Mental Retardation Protein (139135-51-6)
    Language English
    Publishing date 2018-12-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 196739-3
    ISSN 1873-7544 ; 0306-4522
    ISSN (online) 1873-7544
    ISSN 0306-4522
    DOI 10.1016/j.neuroscience.2018.11.047
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  10. Article ; Online: A predictive ensemble classifier for the gene expression diagnosis of ASD at ages 1 to 4 years.

    Bao, Bokan / Zahiri, Javad / Gazestani, Vahid H / Lopez, Linda / Xiao, Yaqiong / Kim, Raphael / Wen, Teresa H / Chiang, Austin W T / Nalabolu, Srinivasa / Pierce, Karen / Robasky, Kimberly / Wang, Tianyun / Hoekzema, Kendra / Eichler, Evan E / Lewis, Nathan E / Courchesne, Eric

    Molecular psychiatry

    2022  Volume 28, Issue 2, Page(s) 822–833

    Abstract: Autism Spectrum Disorder (ASD) diagnosis remains behavior-based and the median age of diagnosis is ~52 months, nearly 5 years after its first-trimester origin. Accurate and clinically-translatable early-age diagnostics do not exist due to ASD genetic and ...

    Abstract Autism Spectrum Disorder (ASD) diagnosis remains behavior-based and the median age of diagnosis is ~52 months, nearly 5 years after its first-trimester origin. Accurate and clinically-translatable early-age diagnostics do not exist due to ASD genetic and clinical heterogeneity. Here we collected clinical, diagnostic, and leukocyte RNA data from 240 ASD and typically developing (TD) toddlers (175 toddlers for training and 65 for test). To identify gene expression ASD diagnostic classifiers, we developed 42,840 models composed of 3570 gene expression feature selection sets and 12 classification methods. We found that 742 models had AUC-ROC ≥ 0.8 on both Training and Test sets. Weighted Bayesian model averaging of these 742 models yielded an ensemble classifier model with accurate performance in Training and Test gene expression datasets with ASD diagnostic classification AUC-ROC scores of 85-89% and AUC-PR scores of 84-92%. ASD toddlers with ensemble scores above and below the overall ASD ensemble mean of 0.723 (on a scale of 0 to 1) had similar diagnostic and psychometric scores, but those below this ASD ensemble mean had more prenatal risk events than TD toddlers. Ensemble model feature genes were involved in cell cycle, inflammation/immune response, transcriptional gene regulation, cytokine response, and PI3K-AKT, RAS and Wnt signaling pathways. We additionally collected targeted DNA sequencing smMIPs data on a subset of ASD risk genes from 217 of the 240 ASD and TD toddlers. This DNA sequencing found about the same percentage of SFARI Level 1 and 2 ASD risk gene mutations in TD (12 of 105) as in ASD (13 of 112) toddlers, and classification based only on the presence of mutation in these risk genes performed at a chance level of 49%. By contrast, the leukocyte ensemble gene expression classifier correctly diagnostically classified 88% of TD and ASD toddlers with ASD risk gene mutations. Our ensemble ASD gene expression classifier is diagnostically predictive and replicable across different toddler ages, races, and ethnicities; out-performs a risk gene mutation classifier; and has potential for clinical translation.
    MeSH term(s) Humans ; Child, Preschool ; Infant ; Autism Spectrum Disorder/diagnosis ; Autism Spectrum Disorder/genetics ; Bayes Theorem ; Phosphatidylinositol 3-Kinases ; Immunity ; Gene Expression
    Chemical Substances Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
    Language English
    Publishing date 2022-10-20
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-022-01826-x
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