Pregnancy data enable identification of relevant biomarkers and a partial prognosis of autism at birth

Attempts to extract early biomarkers and expedite detection of Autism Spectrum Disorder (ASD) have been centered on postnatal measures of babies at familial risk. Here, we suggest that it might be possible to do these tasks already at birth relying on ultrasound and biological measurements routinely collected from pregnant mothers and fetuses during gestation and birth. We performed a gradient boosting decision tree classification analysis in parallel with statistical tests on a population of babies with typical development or later diagnosed with ASD. By focusing on minimization of the false positive rate, the cross-validated specificity of the classifier reached to 96% with a sensitivity of 41% and a positive predictive value of 77%. Extracted biomarkers included sex, maternal familial history of auto-immune diseases, maternal immunization to CMV, IgG CMV level, timing of fetal rotation on head, femoral length in the 3rd trimester, white cells in the 3rd trimester, fetal heart rate during labour, newborn feeding and newborn’s temperature difference between birth and one day after. Statistical models revealed that 38% of babies later diagnosed with ASD had significantly larger fetal cephalic perimeter than age matched neurotypical babies, suggesting an in-utero origin of the bigger brains of toddlers with ASD. Results pave the way to use pregnancy follow-up measurements to provide an early prognosis of ASD and implement pre-symptomatic behavioral interventions to attenuate efficiently ASD developmental sequels.

[1]  Alexander J. Casson,et al.  Applying Machine Learning to Kinematic and Eye Movement Features of a Movement Imitation Task to Predict Autism Diagnosis , 2020, Scientific Reports.

[2]  Taghi M. Khoshgoftaar,et al.  Survey on categorical data for neural networks , 2020, Journal of Big Data.

[3]  Jessica B. Girault,et al.  Quantitative trait variation in ASD probands and toddler sibling outcomes at 24 months , 2020, Journal of Neurodevelopmental Disorders.

[4]  N. Nikitha Diagnosis of Autism Spectrum Disorder , 2020 .

[5]  Xiao-Jiang Li,et al.  Maternal valproic acid exposure leads to neurogenesis defects and autism-like behaviors in non-human primates , 2019, Translational Psychiatry.

[6]  K. Kapur,et al.  Longitudinal EEG power in the first postnatal year differentiates autism outcomes , 2019, Nature Communications.

[7]  M. Kudo,et al.  Artificial intelligence predicts the progression of diabetic kidney disease using big data machine learning , 2019, Scientific Reports.

[8]  A. Carvalho,et al.  Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence. , 2019, The lancet. Psychiatry.

[9]  Y. Ben-Ari,et al.  Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth , 2019, Scientific Reports.

[10]  E. Chang,et al.  Immature excitatory neurons develop during adolescence in the human amygdala , 2019, Nature Communications.

[11]  Xiaolu Tian,et al.  Using Machine Learning Algorithms to Predict Hepatitis B Surface Antigen Seroclearance , 2019, Comput. Math. Methods Medicine.

[12]  Jessica L. Allen,et al.  Machine-learning to stratify diabetic patients using novel cardiac biomarkers and integrative genomics , 2019, Cardiovascular Diabetology.

[13]  Christopher Y. Park,et al.  Whole-genome deep-learning analysis identifies contribution of noncoding mutations to autism risk , 2019, Nature Genetics.

[14]  G. Corrado,et al.  End-to-end lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography , 2019, Nature Medicine.

[15]  G. Su,et al.  Machine learning models to predict disease progression among veterans with hepatitis C virus , 2019, PloS one.

[16]  Y. Ben-Ari,et al.  Pyramidal neuron growth and increased hippocampal volume during labor and birth in autism , 2019, Science Advances.

[17]  S. Roux,et al.  Autism is a prenatal disorder: Evidence from late gestation brain overgrowth , 2018, Autism research : official journal of the International Society for Autism Research.

[18]  Y. Ben-Ari,et al.  The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth. , 2018, Cerebral cortex.

[19]  I. Hertz-Picciotto,et al.  A Prospective Study of Environmental Exposures and Early Biomarkers in Autism Spectrum Disorder: Design, Protocols, and Preliminary Data from the MARBLES Study , 2018, Environmental health perspectives.

[20]  Scott M. Lundberg,et al.  Explainable machine-learning predictions for the prevention of hypoxaemia during surgery , 2018, Nature Biomedical Engineering.

[21]  Lubo Zhang,et al.  Gestational Hypoxia and Developmental Plasticity. , 2018, Physiological reviews.

[22]  Nathan E. Lewis,et al.  The ASD Living Biology: from cell proliferation to clinical phenotype , 2018, Molecular Psychiatry.

[23]  C. McDougle,et al.  Maternal and Early Postnatal Immune Activation Produce Dissociable Effects on Neurotransmission in mPFC–Amygdala Circuits , 2018, The Journal of Neuroscience.

[24]  Nicole Barger,et al.  Neuron numbers increase in the human amygdala from birth to adulthood, but not in autism , 2018, Proceedings of the National Academy of Sciences.

[25]  Tonya White,et al.  A prospective study of fetal head growth, autistic traits and autism spectrum disorder , 2018, Autism research : official journal of the International Society for Autism Research.

[26]  Y. Ben-Ari NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders , 2017, Trends in Neurosciences.

[27]  Guido Gerig,et al.  Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age , 2017, Science Translational Medicine.

[28]  Lauren E. Libero,et al.  In pursuit of neurophenotypes: The consequences of having autism and a big brain , 2017, Autism research : official journal of the International Society for Autism Research.

[29]  Y. Ben-Ari,et al.  Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders , 2017, Translational Psychiatry.

[30]  Alan C. Evans,et al.  Early brain development in infants at high risk for autism spectrum disorder , 2017, Nature.

[31]  D. Amaral,et al.  Selective lesion of the hippocampus increases the differentiation of immature neurons in the monkey amygdala , 2016, Proceedings of the National Academy of Sciences.

[32]  Chandra L. Theesfeld,et al.  Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder , 2016, Nature Neuroscience.

[33]  Tianqi Chen,et al.  XGBoost: A Scalable Tree Boosting System , 2016, KDD.

[34]  Tony Charman,et al.  Diagnosis of autism spectrum disorder: reconciling the syndrome, its diverse origins, and variation in expression , 2016, The Lancet Neurology.

[35]  Hyunju Kim,et al.  The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring , 2016, Science.

[36]  M. Maybery,et al.  A Prospective Ultrasound Study of Prenatal Growth in Infant Siblings of Children With Autism , 2016, Autism research : official journal of the International Society for Autism Research.

[37]  C. Arnaud,et al.  Prenasal thickness to nasal bone length ratio: effectiveness as a second or third trimester marker for Down syndrome. , 2015, European journal of obstetrics, gynecology, and reproductive biology.

[38]  A. McAllister,et al.  Immune mediators in the brain and peripheral tissues in autism spectrum disorder , 2015, Nature Reviews Neuroscience.

[39]  Karim Jerbi,et al.  Exceeding chance level by chance: The caveat of theoretical chance levels in brain signal classification and statistical assessment of decoding accuracy , 2015, Journal of Neuroscience Methods.

[40]  Brian K. Lee,et al.  Changes in Prevalence of Autism Spectrum Disorders in 2001–2011: Findings from the Stockholm Youth Cohort , 2014, Journal of Autism and Developmental Disorders.

[41]  Boris Yamrom,et al.  The contribution of de novo coding mutations to autism spectrum disorder , 2014, Nature.

[42]  Kathryn Roeder,et al.  Most genetic risk for autism resides with common variation , 2014, Nature Genetics.

[43]  Eric Courchesne,et al.  Patches of disorganization in the neocortex of children with autism. , 2014, The New England journal of medicine.

[44]  A. Iosif,et al.  Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring , 2014, Biological Psychiatry.

[45]  Mogens Vestergaard,et al.  Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. , 2013, JAMA.

[46]  M. Daly,et al.  Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis , 2013, The Lancet.

[47]  Peter C Austin,et al.  Using methods from the data-mining and machine-learning literature for disease classification and prediction: a case study examining classification of heart failure subtypes. , 2013, Journal of clinical epidemiology.

[48]  D. Schendel,et al.  Autism After Infection, Febrile Episodes, and Antibiotic Use During Pregnancy: An Exploratory Study , 2012, Pediatrics.

[49]  Kathryn Roeder,et al.  Common genetic variants, acting additively, are a major source of risk for autism , 2012, Molecular Autism.

[50]  P. Patterson,et al.  Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism , 2012, Brain, Behavior, and Immunity.

[51]  Irva Hertz-Picciotto,et al.  Tipping the Balance of Autism Risk: Potential Mechanisms Linking Pesticides and Autism , 2012, Environmental health perspectives.

[52]  Y. S. Kim,et al.  Global Prevalence of Autism and Other Pervasive Developmental Disorders , 2012, Autism research : official journal of the International Society for Autism Research.

[53]  Johnny L. Matson,et al.  The increasing prevalence of autism spectrum disorders , 2011 .

[54]  S. Rogers,et al.  Intervening in infancy: implications for autism spectrum disorders. , 2010, Journal of child psychology and psychiatry, and allied disciplines.

[55]  S. Sekulic,et al.  Probability of breech presentation and its significance , 2010, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[56]  P. Mortensen,et al.  Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders , 2009, Pediatrics.

[57]  S. Rogers,et al.  What are infant siblings teaching us about autism in infancy? , 2009, Autism research : official journal of the International Society for Autism Research.

[58]  Y. Ben-Ari Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders , 2008, Trends in Neurosciences.

[59]  W. McMahon,et al.  A Retrospective Fetal Ultrasound Study of Brain Size in Autism , 2007, Biological Psychiatry.

[60]  R. Khazipov,et al.  GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. , 2007, Physiological reviews.

[61]  R. Khazipov,et al.  Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain During Delivery , 2006, Science.

[62]  T. Bourgeron,et al.  Searching for ways out of the autism maze: genetic, epigenetic and environmental clues , 2006, Trends in Neurosciences.

[63]  A. Ng Feature selection, L1 vs. L2 regularization, and rotational invariance , 2004, Twenty-first international conference on Machine learning - ICML '04.

[64]  J. Hallmayer,et al.  Perinatal factors and the development of autism: a population study. , 2004, Archives of general psychiatry.

[65]  Eric Fombonne,et al.  Autism Spectrum Disorders: Early Detection, Intervention, Education, and Psychopharmacological Management , 2003, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[66]  Ruth A. Carper,et al.  Evidence of brain overgrowth in the first year of life in autism. , 2003, JAMA.

[67]  P. Bundred,et al.  Finger and toe ratios in humans and mice: implications for the aetiology of diseases influenced by HOX genes. , 2003, Medical hypotheses.

[68]  J. Friedman Greedy function approximation: A gradient boosting machine. , 2001 .

[69]  L. Hansson,et al.  The birth process initiates an acute phase reaction in the fetus‐newborn infant , 2000, Acta paediatrica.

[70]  Y. Ben-Ari,et al.  Generation and Propagation of 4-ap-induced Epileptiform Activity in Neonatal Intact Limbic Structures in Vitro , 2022 .

[71]  I. Ingemarsson,et al.  Long term outcome after umbilical artery acidaemia at term birth: influence of gender and duration of fetal heart rate abnormalities , 1997, British journal of obstetrics and gynaecology.

[72]  Anil K. Jain,et al.  Small Sample Size Effects in Statistical Pattern Recognition: Recommendations for Practitioners , 1991, IEEE Trans. Pattern Anal. Mach. Intell..

[73]  L. Kouam,et al.  [Frequency of breech presentation during pregnancy and on full term (author's transl)]. , 1981, Zentralblatt fur Gynakologie.

[74]  M. Fujimura,et al.  Velocity of head growth during the perinatal period. , 1977, Archives of disease in childhood.

[75]  B. Chandrasekaran,et al.  On dimensionality and sample size in statistical pattern classification , 1971, Pattern Recognit..