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Cited by 1,127Autism Spectrum Disorder ResearchChild Nutrition and Feeding IssuesGenetics and Neurodevelopmental Disorders

Autism spectrum disorder: Definition, epidemiology, causes, and clinical evaluation

Open access
Hodges, Holly, Fealko, Casey, Soares, Neelkamal·2020·Translational Pediatrics
DOI 10.21037/tp.2019.09.09PMC PMC7082249
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Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted interests and repetitive behaviors. There have been recent concerns about increased prevalence, and this article seeks to elaborate on factors that may influence prevalence rates, including recent changes to the diagnostic criteria. The authors review evidence that ASD is a neurobiological disorder influenced by both genetic and environmental factors affecting the developing brain, and enumerate factors that correlate with ASD risk. Finally, the article describes how clinical evaluation begins with developmental screening, followed by referral for a definitive diagnosis, and provides guidance on screening for comorbid conditions.

AI snapshot

Written from the paper’s full text.

TL;DR

ASD is a neurodevelopmental disorder defined by social communication deficits and restricted/repetitive behaviors, with DSM-5 criteria shifting to a dyad and likely affecting prevalence estimates. The review summarizes epidemiology, genetic/environmental risk correlates, and clinical evaluation, concluding no single causal pathway or biomarker exists.

Key findings

  • DSM-5 combined DSM-IV pervasive developmental disorder diagnoses into one ASD spectrum, moved from a triad to a dyad, added sensory symptoms and severity descriptors; a systematic review suggests only 50%–75% of individuals maintain diagnoses, though one study found 91% identified by parental report, and most studies suggest increased specificity with decreased sensitivity.
  • WHO estimates global ASD prevalence at 0.76%, but this accounts for only ~16% of the global child population; CDC estimates 1.68% of US 8-year-olds (1 in 59), US parent-reported diagnoses averaged 2.5% in 2016, and US prevalence more than doubled between 2000–2002 and 2010–2012 before appearing to stabilize from 2014 to 2016 with no statistically significant increase.
  • Male-to-female ratio is closer to 3:1 than 4:1 in a recent meta-analysis not using DSM-5 criteria; co-occurring conditions are common, including 83% with an additional developmental diagnosis, 10% at least one psychiatric diagnosis, 16% at least one neurologic diagnosis, intellectual disability at 31.0% (26.7%–39.4%), epilepsy ~20%, GI disorders 10–12%, sleep problems 50%–73%, overweight/obesity ~33%/18%, ADHD 25%–81%, and pooled adult anxiety/depression at 42%/37%.
  • ASD is neurobiological with genetic and environmental influences, but no single unifying cause has been elucidated; over 700 genes have been implicated, and there is no evidence that vaccines, thimerosal, or mercury is associated with ASD, with the largest Danish cohort finding no increased MMR risk. Prenatal valproic acid and thalidomide increase risk, folic acid may reduce risk in antiepileptic-exposed pregnancies, and advanced parental age and prematurity are risk factors.

Methods

  • Narrative review of ASD definition, epidemiology, causes, and clinical evaluation; no primary data collection or systematic search strategy is described.
  • Synthesizes published literature, meta-analyses, surveillance data, and professional guidelines (e.g., AAP, ACMGG) rather than conducting new analyses.
  • Main analysis is narrative synthesis of cited evidence; no formal meta-analysis or primary statistical modeling performed by the authors is reported.

Limitations

  • Stated: no single unifying cause or causal determinations; meta-analysis of pre/peri/postnatal risk factors showed significant heterogeneity preventing true determination; no clear ASD biomarkers or diagnostic measures exist.
  • Stated: WHO prevalence estimate covers only ~16% of the global child population; changing diagnostic criteria may impact prevalence and the full DSM-5 impact remains unknown.
  • Evident: as a narrative review without described systematic search or quality appraisal, conclusions depend on selected cited studies; some cited estimates predate DSM-5 or use non-DSM-5 criteria, and co-occurring condition rates vary by definition or measurement tool.

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Integrity signals

Registry

Crossref · 10.21037/tp.2019.09.09

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 122 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Studies estimating the potential impact of moving from the DSM-IV to the DSM-5 have predicted a decrease in ASD prevalence.

    “studies estimating the potential impact of moving from the DSM-IV to the DSM-5 have predicted a decrease in ASD prevalence (4,5)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Maenner MJ Rice CE Arneson CL Potential impact of DSM-5 criteria on autism spectrum disorder prevalence estimates. JAMA Psychiatry 2014; 71: 292- 300. 10.1001/jamapsychiatry.2013.3893 24452504 PMC4041577

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    • cites [5] Kulage KM Smaldone AM Cohn EG. How will DSM-5 affect autism diagnosis? A systematic literature review and meta-analysis. J Autism Dev Disord 2014; 44: 1918- 32. 10.1007/s10803-014-2065-2 24531932

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  • Interpretationcitation

    Children who previously met criteria for PDD-NOS under the DSM-IV might now be diagnosed with SPCD.

    “children who previously met criteria for PDD-NOS under the DSM-IV might now be diagnosed with SPCD.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    A systematic review suggests only 50% to 75% of individuals maintain diagnoses.

    “a systematic review suggests only 50% to 75% of individuals maintain diagnoses (9)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Sturmey P Dalfern S. The effects of DSM5 autism diagnostic criteria on number of individuals diagnosed with autism spectrum disorders: a systematic review. Rev J Autism Dev Disord 2014; 1: 249- 52. 10.1007/s40489-014-0016-7

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  • Premisecitation

    Often those who did not meet the requirements were previously classified as high functioning Asperger's syndrome and PDD-NOS.

    “Often those who did not meet the requirements were previously classified as high functioning Asperger’s syndrome and PDD-NOS (11,12).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] de Giambattista C Ventura P Trerotoli P Subtyping the autism spectrum disorder: comparison of children with high functioning autism and asperger syndrome. J Autism Dev Disord 2019; 49: 138- 50. 10.1007/s10803-018-3689-4 30043350 PMC6331497

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    • cites [12] Mazurek MO Lu F Symecko H A prospective study of the concordance of DSM-IV and DSM-5 diagnostic criteria for autism spectrum disorder. J Autism Dev Disord 2017; 47: 2783- 94. 10.1007/s10803-017-3200-7 28620892

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  • Premisecitation

    Caucasian children are consistently identified with ASD more often than black or Hispanic children.

    “Caucasian children are consistently identified with ASD more often than black or Hispanic children (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Baio J Wiggins L Christensen DL Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 2018; 67: 1- 23. 10.15585/mmwr.ss6706a1 29701730 PMC5919599

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  • Classified as probably not a substantial claim. 17
  • May combine two claims. 34

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 2013, the DSM-5 was published, updating the diagnostic criteria for ASD from the previous DSM-IV.

    “In 2013, the Diagnostic and Statistical Manual of Mental Disorders—5th edition (DSM-5) was published, updating the diagnostic criteria for ASD from the previous 4th edition (DSM-IV) (Table 1) (1,2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Publishing, 2013.

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    • cites [2] American Psychiatric Association. Diagnostic and statistcal manual of mental disorders. 4th ed. Washington: American Psychiatric Publishing, 1994.

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    Interpretationcitation

    While those diagnosed with ASD are more likely to have the condition, there is a higher number of children whose ASD diagnosis is missed, particularly older children, adolescents, adults, or those with a former diagnosis of Asperger's disorder or PDD-NOS.

    “while those diagnosed with ASD are more likely to have the condition, there is a higher number of children whose ASD diagnosis is missed, particularly older children, adolescents, adults, or those with a former diagnosis of Asperger’s disorder or PDD-NOS (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Lai MC Lombardo MV Chakrabarti B Subgrouping the autism "spectrum": reflections on DSM-5. PLoS Biol 2013; 11: e1001544. 10.1371/journal.pbio.1001544 23630456 PMC3635864

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    Premisecitation

    The CDC estimates about 1.68% of US children aged 8 years (or 1 in 59 children) are diagnosed with ASD.

    “The Centers for Disease Control and Prevention (CDC) estimates about 1.68% of United States (US) children aged 8 years (or 1 in 59 children) are diagnosed with ASD (6,17).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Baio J Wiggins L Christensen DL Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 2018; 67: 1- 23. 10.15585/mmwr.ss6706a1 29701730 PMC5919599

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    • cites [17] Palinkas LA Mendon SJ Hamilton AB. Annual review of public health innovations in mixed methods evaluations. Annu Rev Public Heal 2019; 40: 423- 42. 10.1146/annurev-publhealth-040218-044215 PMC6501787 30633710

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    Premisecitation

    In the US, parent-reported ASD diagnoses in 2016 averaged slightly higher at 2.5%.

    “In the US, parent-reported ASD diagnoses in 2016 averaged slightly higher at 2.5% (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Kogan MD Vladutiu CJ Schieve LA The prevalence of parent-reported autism spectrum disorder among US children. Pediatrics 2018; 142: e20174161. 10.1542/peds.2017-4161 30478241 PMC6317762

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    Premisecitation

    In the US, the prevalence of ASD has appeared to stabilize with no statistically significant increase from 2014 to 2016.

    “in the US, the prevalence of ASD has appeared to stabilize with no statistically significant increase from 2014 to 2016 (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Xu G Strathearn L Liu B Prevalence of autism spectrum disorder among US children and adolescents, 2014-2016. JAMA 2018; 319: 81. 10.1001/jama.2017.17812 29297068 PMC5833544

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    Interpretationcitation

    Insurance mandates requiring commercial plans to cover services for ASD along with improved awareness have likely contributed to the increase in ASD prevalence estimates as well as the increased diagnosis of milder cases of ASD in the US.

    “Insurance mandates requiring commercial plans to cover services for ASD along with improved awareness have likely contributed to the increase in ASD prevalence estimates as well as the increased diagnosis of milder cases of ASD in the US (6,20,21).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Baio J Wiggins L Christensen DL Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 2018; 67: 1- 23. 10.15585/mmwr.ss6706a1 29701730 PMC5919599

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    • cites [20] Mandell DS Barry CL Marcus SC Effects of autism spectrum disorder insurance mandates on the treated prevalence of autism spectrum disorder. JAMA Pediatr 2016; 170: 887- 93. 10.1001/jamapediatrics.2016.1049 27399053

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    • cites [21] Hansen SN Schendel DE Parner ET. Explaining the increase in the prevalence of autism spectrum disorders: the proportion attributable to changes in reporting practices. JAMA Pediatr 2015; 169: 56- 62. 10.1001/jamapediatrics.2014.1893 25365033

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    Interpretationcitation

    The number of people who would be diagnosed under the DSM-IV but not under the new DSM-5 appears to be declining over time, likely due to increased awareness and better documentation of behaviors.

    “the number of people who would be diagnosed under the DSM-IV, but not under the new DSM-5 appears to be declining over time, likely due to increased awareness and better documentation of behaviors (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Maenner MJ Rice CE Arneson CL Potential impact of DSM-5 criteria on autism spectrum disorder prevalence estimates. JAMA Psychiatry 2014; 71: 292- 300. 10.1001/jamapsychiatry.2013.3893 24452504 PMC4041577

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    Premisecitation

    Females are less likely to present with overt symptoms and are more likely to mask their social deficits through camouflaging, further hindering a timely diagnosis.

    “Not only are females less likely to present with overt symptoms, they are more likely to mask their social deficits through a process called “camouflaging”, further hindering a timely diagnosis (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Volkmar F Siegel M Woodbury-Smith M Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2014; 53: 237- 57. 10.1016/j.jaac.2013.10.013 24472258

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    Premisecitation

    The WHO estimates the international prevalence of ASD at 0.76%, but this only accounts for approximately 16% of the global child population.

    “The World Health Organization (WHO) estimates the international prevalence of ASD at 0.76%; however, this only accounts for approximately 16% of the global child population (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Baxter AJ Brugha TS Erskine HE The epidemiology and global burden of autism spectrum disorders. Psychol Med 2015; 45: 601- 13. 10.1017/S003329171400172X 25108395

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    Premisecitation

    Most studies suggest that the DSM-5 provides increased specificity and decreased sensitivity compared to the DSM-IV.

    “Overall, most studies suggest that the DSM-5 provides increased specificity and decreased sensitivity compared to the DSM-IV (5,13)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Kulage KM Smaldone AM Cohn EG. How will DSM-5 affect autism diagnosis? A systematic literature review and meta-analysis. J Autism Dev Disord 2014; 44: 1918- 32. 10.1007/s10803-014-2065-2 24531932

      Not checked in the free run.

    • cites [13] Gibbs V Aldridge F Chandler F Brief report: an exploratory study comparing diagnostic outcomes for autism spectrum disorders under DSM-IV-TR with the proposed DSM-5 revision. J Autism Dev Disord 2012; 42: 1750- 6. 10.1007/s10803-012-1560-6 22677932

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    Premisecitation

    In a recent meta-analysis, the true male-to-female ratio is closer to 3:1 than the previously reported 4:1, though this study was not done using the DSM-5 criteria.

    “in a recent meta-analysis (24), true male-to-female ratio is closer to 3:1 than the previously reported 4:1, though this study was not done using the DSM-5 criteria.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Loomes R Hull L Mandy WPL. What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry 2017; 56: 466- 74. 10.1016/j.jaac.2017.03.013 28545751

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    Premisecitation

    ASD occurs in all racial, ethnic, and socioeconomic groups, but its diagnosis is far from uniform across these groups.

    “ASD occurs in all racial, ethnic, and socioeconomic groups, but its diagnosis is far from uniform across these groups.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Baio J Wiggins L Christensen DL Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 2018; 67: 1- 23. 10.15585/mmwr.ss6706a1 29701730 PMC5919599

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    Premisecitation

    While genetics clearly play a role in ASD's etiology, phenotypic expression of genetic susceptibility remains extremely variable within ASD.

    “While genetics clearly play a role in ASD’s etiology, phenotypic expression of genetic susceptibility remains extremely variable within ASD (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Veenstra-Vanderweele J Christian SL Cook EH Jr. Autism as a paradigmatic complex genetic disorder. Annu Rev Genomics Hum Genet 2004; 5: 379- 405. 10.1146/annurev.genom.5.061903.180050 15485354

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    Premisecitation

    Advanced maternal and paternal age have both been shown to have an increased risk of having a child with ASD.

    “Advanced maternal and paternal age have both been shown to have an increased risk of having a child with ASD (59).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Croen LA Najjar DV Fireman B Maternal and paternal age and risk of autism spectrum disorders. Arch Pediatr Adolesc Med 2007; 161: 334- 40. 10.1001/archpedi.161.4.334 17404129

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    Premisecitation

    Neuropathologic studies have revealed differences in cerebellar architecture and connectivity, limbic system abnormalities, and frontal and temporal lobe cortical alterations, along with other subtle malformations.

    “Neuropathologic studies are limited, but have revealed differences in cerebellar architecture and connectivity, limbic system abnormalities, and frontal and temporal lobe cortical alterations, along with other subtle malformations (28,37,38).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28] Johnson CP Myers SM. Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007; 120: 1183- 215. 10.1542/peds.2007-2361 17967920

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    • cites [37] Skefos J Cummings C Enzer K Regional alterations in Purkinje cell density in patients with autism. PLoS One 2014; 9: e81255. 10.1371/journal.pone.0081255 24586223 PMC3933333

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    • cites [38] Stoodley CJ D’Mello AM Ellegood J Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat Neurosci 2017; 20: 1744- 51. 10.1038/s41593-017-0004-1 29184200 PMC5867894

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    Premisecitation

    Candidate genes in ASD include those that play a role in brain development or neurotransmitter function, or genes that affect neuronal excitability.

    “candidate genes in ASD include those that play a role in brain development or neurotransmitter function, or genes that affect neuronal excitability (46,47).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Rubenstein JL Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2003; 2: 255- 67. 10.1034/j.1601-183X.2003.00037.x 14606691 PMC6748642

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    • cites [47] McDougle CJ Erickson CA Stigler KA Neurochemistry in the pathophysiology of autism. J Clin Psychiatry 2005; 66 Suppl 10: 9- 18. 16401145

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    Premisecitation

    Prenatal exposure to thalidomide and valproic acid has been reported to increase ASD risk, while prenatal supplements of folic acid in patients exposed to antiepileptic drugs may reduce risk.

    “Prenatal exposure to thalidomide and valproic acid have been reported to increase risk, while studies suggest that prenatal supplements of folic acid in patients exposed to antiepileptic drugs may reduce risk (55-57).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [55] Surén P Roth C Bresnahan M Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA 2013; 309: 570- 7. 10.1001/jama.2012.155925 23403681 PMC3908544

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    • cites [56] Bjørk M Riedel B Spigset O Association of folic acid supplementation during pregnancy with the risk of autistic traits in children exposed to antiepileptic drugs in utero. JAMA Neurol 2018; 75: 160. 10.1001/jamaneurol.2017.3897 29279889 PMC5838632

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    • cites [57] Rasalam AD Hailey H Williams JHG Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol 2005; 47: 551- 5. 10.1017/S0012162205001076 16108456

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    Premisecitation

    Genetic factors play a role in ASD susceptibility, with siblings of patients with ASD carrying an increased risk of diagnosis compared to population norms, and a much higher, although not absolute, concordance of autism diagnosis in monozygotic twins.

    “Genetic factors play a role in ASD susceptibility, with siblings of patients with ASD carrying an increased risk of diagnosis when compared to population norms, and a much higher, although not absolute, concordance of autism diagnosis in monozygotic twins (42-44).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Kim H Keifer C Rodriguez-Seijas C Quantifying the optimal structure of the autism phenotype: a comprehensive comparison of dimensional, categorical, and hybrid models. J Am Acad Child Adolesc Psychiatry 2019; 58: 876- 86.e2. 10.1016/j.jaac.2018.09.431 30768420 PMC6488452

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    • cites [43] Sandin S Lichtenstein P Kuja-Halkola R The familial risk of autism. JAMA 2014; 311: 1770- 7. 10.1001/jama.2014.4144 24794370 PMC4381277

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    • cites [44] Risch N Hoffmann TJ Anderson M Familial recurrence of autism spectrum disorder: Evaluating genetic and environmental contributions. Am J Psychiatry 2014; 171: 1206- 13. 10.1176/appi.ajp.2014.13101359 24969362

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    Premisecitation

    A small explorative study of neocortical architecture from young children revealed focal disruption of cortical laminar architecture in the majority of subjects, suggesting problems with cortical layer formation and neuronal differentiation.

    “A small explorative study of neocortical architecture from young children revealed focal disruption of cortical laminar architecture in the majority of subjects, suggesting problems with cortical layer formation and neuronal differentiation (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] De Rubeis S He X Goldberg AP Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014; 515: 209- 15. 10.1038/nature13772 25363760 PMC4402723

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    Premisecitation

    Other risk factors for ASD include increased parental age and prematurity.

    “Other risk factors for ASD include increased parental age and prematurity (33-35).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Durkin MS Maenner MJ Newschaffer CJ Advanced parental age and the risk of autism spectrum disorder. Am J Epidemiol 2008; 168: 1268- 76. 10.1093/aje/kwn250 18945690 PMC2638544

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    • cites [34] Agrawal S Rao SC Bulsara MK Prevalence of autism spectrum disorder in preterm infants: a meta-analysis. Pediatrics 2018; 142: e20180134. 10.1542/peds.2018-0134 30076190

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    • cites [35] Wang C Geng H Liu W Prenatal, perinatal, and postnatal factors associated with autism: a meta-analysis. Medicine (Baltimore) 2017; 96: e6696. 10.1097/MD.0000000000006696 28471964 PMC5419910

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  • May combine two claims.

    Interpretationnone given

    ASD is a neurobiological disorder influenced by both genetic and environmental factors affecting the developing brain.

    “ASD is a neurobiological disorder influenced by both genetic and environmental factors affecting the developing brain.”
    • Also stated in: § Summary · plain
      “ASD is a neurobiological disorder influenced by both genetic and environmental factors affecting the developing brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Transcriptional and splicing dysregulation or alterations in epigenetic mechanisms such as DNA methylation or histone acetylation and modification may play a role in ASD.

    “Transcriptional and splicing dysregulation or alterations in epigenetic mechanisms such as DNA methylation or histone acetylation and modification may play a role (42,49-51).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [42] Kim H Keifer C Rodriguez-Seijas C Quantifying the optimal structure of the autism phenotype: a comprehensive comparison of dimensional, categorical, and hybrid models. J Am Acad Child Adolesc Psychiatry 2019; 58: 876- 86.e2. 10.1016/j.jaac.2018.09.431 30768420 PMC6488452

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    • cites [49] Voineagu I Wang X Johnston P Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 2011; 474: 380- 4. 10.1038/nature10110 21614001 PMC3607626

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    • cites [50] Ladd-Acosta C Hansen KD Briem E Common DNA methylation alterations in multiple brain regions in autism. Mol Psychiatry 2014; 19: 862- 71. 10.1038/mp.2013.114 23999529 PMC4184909

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    • cites [51] Sun W Poschmann J Cruz-Herrera Del Rosario R Histone acetylome-wide association study of autism spectrum disorder. Cell 2016; 167: 1385- 97.e11. 10.1016/j.cell.2016.10.031 27863250

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    Premisecitation

    Maternal history of autoimmune disease, such as diabetes, thyroid disease, or psoriasis, has been postulated, but study results remain mixed.

    “Maternal history of autoimmune disease, such as diabetes, thyroid disease, or psoriasis has been postulated, but study results remain mixed (60,61).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Xiang AH Wang X Martinez MP Maternal type 1 diabetes and risk of autism in offspring. JAMA 2018; 320: 89- 91. 10.1001/jama.2018.7614 29936530 PMC6134431

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    • cites [61] Croen LA Grether JK Yoshida CK Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Arch Pediatr Adolesc Med 2005; 159: 151- 7. 10.1001/archpedi.159.2.151 15699309

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    Premisecitation

    Genome wide association studies and whole exome sequencing methods have broadened understanding of ASD susceptibility genes, and learning more about the function of these genes can shed light on potential biologic mechanisms.

    “Genome wide association studies and whole exome sequencing methods have broadened our understanding of ASD susceptibility genes, and learning more regarding the function of these genes can shed light on potential biologic mechanisms (45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Walsh CA Morrow EM Rubenstein JLR. Autism and brain development. Cell 2008; 135: 396- 400. 10.1016/j.cell.2008.10.015 18984148 PMC2701104

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    Premisecitation

    A recent meta-analysis reported several pre, peri and postnatal risk factors that resulted in an elevated relative risk of ASD in offspring, but also revealed significant heterogeneity, resulting in an inability to make true determination regarding the importance of these factors.

    “A recent meta-analysis reported several pre, peri and postnatal risk factors that resulted in an elevated relative risk of ASD in offspring (35), but also revealed significant heterogeneity, resulting in an inability to make true determination regarding the importance of these factors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Wang C Geng H Liu W Prenatal, perinatal, and postnatal factors associated with autism: a meta-analysis. Medicine (Baltimore) 2017; 96: e6696. 10.1097/MD.0000000000006696 28471964 PMC5419910

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    Premisecitation

    Older gametes have a higher probability of carrying mutations which could result in additional obstetrical complications, including prematurity.

    “This could be due to the theory that older gametes have a higher probability of carrying mutations which could result in additional obstetrical complications, including prematurity (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Parner ET Baron-Cohen S Lauritsen MB Parental age and autism spectrum disorders. Ann Epidemiol 2012; 22: 143- 50. 10.1016/j.annepidem.2011.12.006 22277122 PMC4562461

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    Premisecitation

    Brain overgrowth in cortical size and increased extra-axial fluid have been described in children with ASD.

    “Brain overgrowth both in terms of cortical size and additionally in terms of increased extra-axial fluid have been described in children with ASD and are areas of ongoing study both in terms of furthering our understanding of its etiology, but also as a potential biomarker (40,41).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Shen MD Kim SH McKinstry RC Increased extra-axial cerebrospinal fluid in high-risk infants who later develop autism. Biol Psychiatry 2017; 82: 186- 93. 10.1016/j.biopsych.2017.02.1095 28392081 PMC5531051

      Not checked in the free run.

    • cites [41] Hazlett HC Gu H Munsell BC Early brain development in infants at high risk for autism spectrum disorder. Nature 2017; 542: 348- 51. 10.1038/nature21369 28202961 PMC5336143

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    No clear biomarkers or diagnostic measures for ASD exist.

    “While no clear biomarkers or diagnostic measures exist, clinical genetic testing is recommended as part of the initial medical evaluation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sleep problems have been reported to occur in anywhere from 50% to 73% of patients with ASD, with variation in prevalence dependent on the definition of sleep symptoms or the measurement tool used.

    “Sleep problems have been reported to occur in anywhere from 50% to 73% of patients with ASD with variation in prevalence dependent on the definition of sleep symptoms or the measurement tool used (90-92).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [90] Reynolds AM Soke GN Sabourin KR Sleep problems in 2- to 5-year-olds with autism spectrum disorder and other developmental delays. Pediatrics 2019; 143: e20180492. 10.1542/peds.2018-0492 30745433 PMC6398427

      Not checked in the free run.

    • cites [91] Krakowiak P Goodlin-Jones B Hertz-Picciotto I Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population-based study. J Sleep Res 2008; 17: 197- 206. 10.1111/j.1365-2869.2008.00650.x 18482108 PMC4041696

      Not checked in the free run.

    • cites [92] Polimeni MA Richdale AL Francis AJ. A survey of sleep problems in autism, Asperger's disorder and typically developing children. J Intellect Disabil Res 2005; 49: 260- 8. 10.1111/j.1365-2788.2005.00642.x 15816813

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Research continues to reveal factors that correlate with ASD risk, but no causal determinations have been made.

    “research continues to reveal factors that correlate with ASD risk, but no causal determinations have been made.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Ruzzo EK Pérez-Cano L Jung JY Inherited and de novo genetic risk for autism impacts shared networks. Cell 2019; 178: 850- 66.e26. 10.1016/j.cell.2019.07.015 31398340 PMC7102900

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Research continues to reveal factors that correlate with ASD risk.

    “Research continues to reveal factors that correlate with ASD risk and these findings may guide further etiologic investigation, but no final causal pathway has been elucidated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other behavioral or psychiatric co-occurring conditions in ASD include anxiety, ADHD, obsessive compulsive disorder, and mood disorders or other disruptive behavior disorders.

    “Other behavioral or psychiatric co-occurring conditions in ASD include anxiety, attention deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder, and mood disorders or other disruptive behavior disorders (81).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Soke GN Maenner MJ Christensen D Prevalence of co-occurring medical and behavioral conditions/symptoms among 4- and 8-year-old children with autism spectrum disorder in selected areas of the United States in 2010. J Autism Dev Disord 2018; 48: 2663- 76. 10.1007/s10803-018-3521-1 29524016 PMC6041136

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is no evidence that vaccines, thimerosal, or mercury is associated with ASD.

    “there is no evidence that vaccines, thimerosal, or mercury is associated with ASD (68-70).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [68] Taylor LE Swerdfeger AL Eslick GD. Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies. Vaccine 2014; 32: 3623- 9. 10.1016/j.vaccine.2014.04.085 24814559

      Not checked in the free run.

    • cites [69] Uno Y Uchiyama T Kurosawa M Early exposure to the combined measles-mumps-rubella vaccine and thimerosal-containing vaccines and risk of autism spectrum disorder. Vaccine 2015; 33: 2511- 6. 10.1016/j.vaccine.2014.12.036 25562790

      Not checked in the free run.

    • cites [70] Hviid A Hansen JV Frisch M Measles, mumps, rubella vaccination and autism a nationwide cohort study. Ann Intern Med 2019; 170: 513- 20. 10.7326/M18-2101 30831578

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Studies using electronic health record analysis revealed prevalence of epilepsy ~20% and GI disorders without inflammatory bowel disease at 10-12%.

    “Studies using electronic health record (EHR) analysis revealed prevalence of epilepsy ~20% and GI disorders [without inflammatory bowel disease (IBD)] at 10–12% (82).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Kohane IS McMurry A Weber G The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One 2012; 7: e33224. 10.1371/journal.pone.0033224 22511918 PMC3325235

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    These findings may guide further etiologic investigation.

    “Research continues to reveal factors that correlate with ASD risk and these findings may guide further etiologic investigation, but no final causal pathway has been elucidated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    At this time there is inadequate evidence to recommend routine testing for celiac disease, immunologic or neurochemical markers, mitochondrial disorders, allergy testing, hair analysis, intestinal permeability studies, erythrocyte glutathione peroxidase studies, stool analysis, urinary peptides, or vitamin and mineral deficiencies without a history of severe food selectivity.

    “At this time there is inadequate evidence to recommend routine testing for celiac disease, immunologic or neurochemical markers, mitochondrial disorders, allergy testing, hair analysis, intestinal permeability studies, erythrocyte glutathione peroxidase studies, stool analysis, urinary peptides or vitamin and mineral deficiencies without a history of severe food selectivity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other common co-occurring medical conditions include gastrointestinal disorders, including dietary restrictions and food selectivity, sleep disorders, obesity, and seizures.

    “Other common co-occurring medical conditions include gastrointestinal (GI) disorders, including dietary restrictions and food selectivity, sleep disorders, obesity, and seizures (81-84).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [81] Soke GN Maenner MJ Christensen D Prevalence of co-occurring medical and behavioral conditions/symptoms among 4- and 8-year-old children with autism spectrum disorder in selected areas of the United States in 2010. J Autism Dev Disord 2018; 48: 2663- 76. 10.1007/s10803-018-3521-1 29524016 PMC6041136

      Not checked in the free run.

    • cites [82] Kohane IS McMurry A Weber G The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One 2012; 7: e33224. 10.1371/journal.pone.0033224 22511918 PMC3325235

      Not checked in the free run.

    • cites [83] Kielinen M Rantala H Timonen E Associated medical disorders and disabilities in children with autistic disorder: A population-based study. Autism 2004; 8: 49- 60. 10.1177/1362361304040638 15070547

      Not checked in the free run.

    • cites [84] Curtin C Anderson SE Must A The prevalence of obesity in children with autism: a secondary data analysis using nationally representative data from the National Survey of Children’s Health. BMC Pediatr 2010; 10: 11. 10.1186/1471-2431-10-11 20178579 PMC2843677

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    According to a surveillance study of over 2,000 children with ASD, 83% had an additional developmental diagnosis, 10% had at least one psychiatric diagnosis, and 16% had at least one neurologic diagnosis.

    “According to a surveillance study of over 2,000 children with ASD, 83% had an additional developmental diagnosis, 10% had at least one psychiatric diagnosis, and 16% at least one neurologic diagnosis (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Levy SE Giarelli E Lee LC Autism spectrum disorder and co-occurring developmental, psychiatric, and medical conditions among children in multiple populations of the United States. J Dev Behav Pediatr 2010; 31: 267- 75. 10.1097/DBP.0b013e3181d5d03b 20431403

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent meta-analysis of 30 studies measuring rates of anxiety and 29 studies measuring rates of depression reported a high degree of heterogeneity, but stated pooled lifetime prevalence for adults with ASD to be 42% for any anxiety disorder and 37% for any depressive disorder, though self-report measures and ID could influence estimates.

    “A recent meta-analysis of 30 studies measuring rates of anxiety and 29 studies measuring rates of depression reported a high degree of heterogeneity from the current literature, but stated pooled lifetime prevalence for adults with ASD to be 42% for any anxiety disorder and 37% for any depressive disorder, though the use of self-report measures and the presence of ID could influence estimates (95)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Hollocks MJ Lerh JW Magiati I Anxiety and depression in adults with autism spectrum disorder: a systematic review and meta-analysis. Psychol Med 2019; 49: 559- 72. 10.1017/S0033291718002283 30178724

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rates of overweight and obesity in ASD are reported to be roughly 33% and 18% respectively, higher than rates in typically developing children.

    “Rates of overweight and obesity in ASD are reported to be roughly 33% and 18% respectively, higher than rates in typically developing children (81-84,93).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [81] Soke GN Maenner MJ Christensen D Prevalence of co-occurring medical and behavioral conditions/symptoms among 4- and 8-year-old children with autism spectrum disorder in selected areas of the United States in 2010. J Autism Dev Disord 2018; 48: 2663- 76. 10.1007/s10803-018-3521-1 29524016 PMC6041136

      Not checked in the free run.

    • cites [82] Kohane IS McMurry A Weber G The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One 2012; 7: e33224. 10.1371/journal.pone.0033224 22511918 PMC3325235

      Not checked in the free run.

    • cites [83] Kielinen M Rantala H Timonen E Associated medical disorders and disabilities in children with autistic disorder: A population-based study. Autism 2004; 8: 49- 60. 10.1177/1362361304040638 15070547

      Not checked in the free run.

    • cites [84] Curtin C Anderson SE Must A The prevalence of obesity in children with autism: a secondary data analysis using nationally representative data from the National Survey of Children’s Health. BMC Pediatr 2010; 10: 11. 10.1186/1471-2431-10-11 20178579 PMC2843677

      Not checked in the free run.

    • cites [93] Hill AP Zuckerman KE Fombonne E. Obesity and autism. Pediatrics 2015; 136: 1051- 61. 10.1542/peds.2015-1437 26527551 PMC4657601

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent publications suggest that whole exome sequencing may become the preferred method for clinical genetic testing in individuals with ASD.

    “of genetics continues to advance rapidly, recent publications suggest whole exome sequencing may become the preferred method for clinical genetic testing in individuals with ASD (100,101).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Srivastava S Love-Nichols JA Dies KA Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med 2019. [Epub ahead of print]. 10.1038/s41436-019-0554-6 31182824 PMC6831729

      Not checked in the free run.

    • cites [101] Feliciano P Zhou X Astrovskaya I Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes. NPJ Genom Med 2019; 4: 19. 10.1038/s41525-019-0093-8 31452935 PMC6707204

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    No final causal pathway for ASD has been elucidated.

    “Research continues to reveal factors that correlate with ASD risk and these findings may guide further etiologic investigation, but no final causal pathway has been elucidated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clinical genetic testing can provide information regarding medical interventions or work up that might be necessary and help with family planning.

    “clinical genetic testing is recommended and can provide information regarding medical interventions or work up that might be necessary and help with family planning (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Miller DT. Genetic testing for autism: recent advances and clinical implications. Expert Rev Mol Diagn 2010; 10: 837- 40. 10.1586/erm.10.82 20964600

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the past, rates of co-morbid intellectual disability in patients with ASD were reported from 50% to 70%, with the most recent CDC estimate reported at 31.0% (26.7% to 39.4%) with ID defined as IQ ≤70.

    “In the past, rates of co-morbid intellectual disability (ID) in patients with ASD were reported from 50% to 70%, with the most recent CDC estimate reported at 31.0% (26.7% to 39.4%) with ID defined as intelligence quotient (IQ) ≤70 (6,80).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Baio J Wiggins L Christensen DL Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 2018; 67: 1- 23. 10.15585/mmwr.ss6706a1 29701730 PMC5919599

      Not checked in the free run.

    • cites [80] Yeargin-Allsopp M Rice C Karapurkar T Prevalence of autism in a US metropolitan area. JAMA 2003; 289: 49- 55. 10.1001/jama.289.1.49 12503976

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In children with ASD seeking treatment, the rate of any anxiety disorder was found to be 42%, co-morbid oppositional defiant disorder at 46%, mood disorders at 8%, with 66% of the sample of over 600 patients having more than one co-occurring condition.

    “In children with ASD seeking treatment, the rate of any anxiety disorder was found to be similar at 42% and in addition this study reported co-morbid oppositional defiant disorder at a rate of 46% and mood disorders at 8%, with 66% of the sample of over 600 patients having more than one co-occurring condition (94).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Lecavalier L McCracken CE Aman MG An exploration of concomitant psychiatric disorders in children with autism spectrum disorder. Compr Psychiatry 2019; 88: 57- 64. 10.1016/j.comppsych.2018.10.012 30504071 PMC6295217

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Currently no clear ASD biomarkers or diagnostic measures exist, and the diagnosis is made based on fulfillment of descriptive criteria.

    “Currently no clear ASD biomarkers or diagnostic measures exist, and the diagnosis is made based on fulfillment of descriptive criteria.”
    Quote in the paperNot a substantial claim
46 of 46

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Authors
Hodges, H., Fealko, C., & Soares, N.
Affiliations
  • Baylor College of Medicine (US)
  • Western Michigan University (US)
Corresponding author
Soares, Neelkamal
ORCID
Venue
Translational Pediatrics
Publisher
AME Publishing Company
Published
2020-02
Volume
9
Issue
S1
Pages
S55-S65
ISSN
  • 2224-4336 (ISSN-L)
  • 2224-4344
DOI
10.21037/tp.2019.09.09
PMC
PMC7082249
OpenAlex
W2981275956
Cited by
1,127
References
120
Citations by year
2026: 223 · 2025: 283 · 2024: 235 · 2023: 201 · 2022: 114 · 2021: 55 · 2020: 14 · 2019: 1
FWCI
12.80
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Translational Pediatrics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
autism spectrum disorder, prevalence, diagnostic criteria, genetic factors, environmental risk factors, neurodevelopmental disorders, social communication deficits, restricted and repetitive behaviors, developmental screening, diagnosis, comorbidity screening

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