464869 Multivariate Data Analysis of Markers of Oxidative Stress and DNA Methylation in Children with Autism Spectrum Disorder
Daniel Howsmon1, Uwe Kruger1, Stepan Melnyk2, Jill James2, and Juergen Hahn1 1Rensselaer Polytechnic Institute; 2Arkansas Children’s Hospital
Autism Spectrum Disorder (ASD) encompasses a large group of early-onset neurological diseases characterized by difficulties with social communication/interaction and expression of restricted repetitive behaviors and interests . In addition to these defining behavioral symptoms, individuals with ASD frequently have one or more co-occurring conditions, including intellectual disability, ADHD, speech and language delays, psychiatric diagnoses, epilepsy, sleep disorders, and gastrointestinal problems –. ASD affects approximately 2% of the population and affects males disproportionately , . It is often associated with an impaired quality of life  and the lifetime cost of supporting an individual with ASD amounts to $1.4 – 2.4MM, depending on co-existing intellectual disorders .
Abnormalities in folate-dependent one-carbon metabolism (FOCM) and transsulfuration (TS) pathways may contribute to ASD liability. Adenylosuccinate lyase and methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been shown to increase ASD liability. Limited evidence for the involvement of reduced folate carrier (RFC1) , , transcobalamin II (TCII) , serine hydroxymethyltransferase I (SHMT1) , 5- methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) , , and catechol-O- methyltransferase (COMT) ,  polymorphisms in ASD liability also suggests that the FOCM/TS pathways are involved in ASD etiology. Environmentally-derived evidence associates valproate ,  and traffic-related air pollution ,  exposure with increased ASD risk and prenatal folate supplementation with protective effects against ASD , .
Multivariable statistical techniques enable researchers to investigate simultaneously occurring changes in metabolites of an entire pathway rather than just single metabolites. Metabolite data from the IMAGE study at Arkansas Children’s Hospital Research Institute  was used to investigate differences in FOCM/TS metabolites between children with ASD and age-matched neurotypical controls (NEU). Dimensionality reduction via Fisher discriminant analysis (FDA) prior to classification allows multivariate relationships to influence the separation of the two groups. Additionally, Vineland scores, evaluating adaptive behavior, were regressed on the metabolite data for the ASD cases via kernel partial least squares (KPLS) to investigate the importance of metabolite combinations on ASD severity.
 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, D.C.: American Psychiatric Association, 2013.
 S. E. Levy, E. Giarelli, L.-C. Lee, L. A. Schieve, R. S. Kirby, C. Cunniff, J. Nicholas, J. Reaven, and C. E. Rice, “Autism spectrum disorder and co-occurring developmental, psychiatric, and medical conditions among children in multiple populations of the United States,” J. Dev. Behav. Pediatr., vol. 31, no. 4, pp. 267–275, 2010.
 J. M. Perrin, D. L. Coury, S. L. Hyman, L. Cole, A. M. Reynolds, and T. Clemons, “Complementary and Alternative Medicine Use in a Large Pediatric Autism Sample,” Pediatrics, vol. 130, no. Supplement 2, pp. S77–S82, Nov. 2012.
 C. D. Pulcini, J. M. Perrin, A. J. Houtrow, J. Sargent, A. Shui, and K. Kuhlthau, “Examining Trends and Coexisting Conditions Among Children Qualifying for SSI Under ADHD, ASD, and ID,” Acad. Pediatr., vol. 15, no. 4, pp. 439–443, Jul. 2015.
 A. Saunders, I. J. Kirk, and K. E. Waldie, “Autism Spectrum Disorder and Co-Existing Conditions: A Lexical Decision Erp Study,” Clin Exp Psychol, vol. 1, no. 001, 2015.
 B. Zablotsky, L.I. Black, M.J. Maenner, L.A. Schieve, S.J. Blumberg, “Estimated Prevalence of Autism and Other Developmental Disabilities Following Questionnaire Changes in the 2014 National Health Interview Survey”. National Health Statistics Reports, no 87, Nov. 2015.
 Maenner MJ, Rice CE, Arneson CL, and et al, “Potential impact of dsm-5 criteria on autism spectrum disorder prevalence estimates,” JAMA Psychiatry, vol. 71, no. 3, pp. 292–300, Mar. 2014.
 B. F. van Heijst and H. M. Geurts, “Quality of life in autism across the lifespan: A meta-analysis,” Autism, vol.
19, no. 2, pp. 158–167, Feb. 2015.
 Buescher AS, Cidav Z, Knapp M, and Mandell DS, “Costs of autism spectrum disorders in the united kingdom and the united states,” JAMA Pediatr., vol. 168, no. 8, pp. 721–728, Aug. 2014.
 S. J. James, S. Melnyk, S. Jernigan, M. A. Cleves, C. H. Halsted, D. H. Wong, P. Cutler, K. Bock, M. Boris, J.
J. Bradstreet, and others, “Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism,” Am. J. Med. Genet. B Neuropsychiatr. Genet., vol. 141, no. 8, pp. 947–956, 2006.
 S. J. James, S. Melnyk, S. Jernigan, O. Pavliv, T. Trusty, S. Lehman, L. Seidel, D. W. Gaylor, and M. A. Cleves, “A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism,” Am. J. Med. Genet. B Neuropsychiatr. Genet., vol. 153B, no. 6, pp. 1209–1220, Sep. 2010.
 N. S. Mohammad, J. M. N. Jain, K. P. Chintakindi, R. P. Singh, U. Naik, and R. R. D. Akella, “Aberrations in folate metabolic pathway and altered susceptibility to autism,” Psychiatr. Genet., vol. 19, no. 4, pp. 171–176, Aug. 2009.
 R. J. Schmidt, R. L. Hansen, J. Hartiala, H. Allayee, L. C. Schmidt, D. J. Tancredi, F. Tassone, and I. Hertz- Picciotto, “Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism,” Epidemiol. Camb. Mass, vol. 22, no. 4, pp. 476–485, Jul. 2011.
 R. L. Bromley, G. E. Mawer, M. Briggs, C. Cheyne, J. Clayton-Smith, M. García-Fiñana, R. Kneen, S. B. Lucas, R. Shallcross, G. A. Baker, O. B. of the L. and M. N. Group, G. Baker, M. Briggs, R. Bromley, J. Clayton-Smith, P. Dixon, A. Fryer, A. Gummery, R. Kneen, L. Kerr, S. Lucas, G. Mawer, and R. Shallcross, “The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs,” J. Neurol. Neurosurg. Psychiatry, vol. 84, no. 6, pp. 637–643, Jun. 2013.
 J. Christensen, T. K. Grønborg, M. J. Sørensen, D. Schendel, E. T. Parner, L. H. Pedersen, and M. Vestergaard, “Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism,” Jama, vol. 309, no. 16, pp. 1696–1703, 2013.
 W. Mandy and M.-C. Lai, “Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition,” J. Child Psychol. Psychiatry, vol. 57, no. 3, pp. 271–292, Mar. 2016.
 P. J. Landrigan, “What causes autism? Exploring the environmental contribution:,” Curr. Opin. Pediatr., vol.
22, no. 2, pp. 219–225, Apr. 2010.
 R. J. Schmidt, D. J. Tancredi, S. Ozonoff, R. L. Hansen, J. Hartiala, H. Allayee, L. C. Schmidt, F. Tassone, and
I. Hertz-Picciotto, “Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study,” Am. J. Clin. Nutr., vol. 96, no. 1, pp. 80–89, Jul. 2012.
 P. Surén, C. Roth, M. Bresnahan, M. Haugen, M. Hornig, D. Hirtz, K. K. Lie, I. Lipkin, P. Magnus, T. Reichborn-Kjennerud, S. Schjølberg, G. D. Smith, A.-S. Øyen, E. Susser, and C. Stoltenberg, “Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children,” JAMA, vol. 309, no. 6, pp. 570–577, Feb. 2013.
 S. Melnyk, G. J. Fuchs, E. Schulz, M. Lopez, S. G. Kahler, J. J. Fussell, J. Bellando, O. Pavliv, S. Rose, L. Seidel, D. W. Gaylor, and S. Jill James, “Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism,” J. Autism Dev. Disord., vol. 42, no. 3, pp. 367–377, Mar. 2012.