A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder

May combine two claims.

The 23 included studies were published between 2006 and 2015, included 174 to 4,057,712 participants born between the early 1990s through 2005, were based in 4 countries, and involved case-control, cohort, and ecological designs.

“The 23 included studies were all published between the years 2006 to 2015, included 174 to 4,057,712 participants born between the early 1990s through 2005, were based in 4 different countries, and involved case-control, cohort, and ecological study designs (Table 2).”

May combine two claims.

All included studies generally showed increased risk of ASD with increasing exposure to air pollution, although not consistently across all chemical components.

“All included studies generally showed increased risk of ASD with increasing exposure to air pollution, although not consistently across all chemical components.”

May combine two claims.

Sensitivity analysis for PM2.5 found an added study would need an effect estimate of OR = 1.02 to enlarge the confidence interval to overlap 1, and OR = 0.14 to shift the overall effect estimate to OR<1.

“Sensitivity analyses here (assuming the added hypothetical study would have a standard error of 0.04, equal to the smallest in our group of studies [39]) found that an added study would need an effect estimate of OR = 1.02 to enlarge the confidence interval to overlap 1, and an OR = 0.14 to shift the overall effect estimate to OR<1.”

• cites [39] TA Becerra, 2013, Ambient air pollution and autism in Los Angeles county, California, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

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

Study populations came from a variety of cohorts and regions, primarily in the U.S., such as Nurses' Health Study II, CHARGE, ADDM Network, CATSS, or identified through insurance claims or state departments tracking ASD diagnoses.

“Study populations came from a variety of cohorts and regions, primarily in the U.S., such as the Nurses’ Health Study II, U.C. Davis’ Childhood Autism Risks from Genetics and the Environment (CHARGE) study, the Center for Diseases Control and Prevention’s (CDC) Autism and Developmental Disabilities Monitoring (ADDM) Network, Child and Adolescent Twin Study in Sweden (CATSS), or identified through”

May combine two claims.

Sensitivity analysis found an additional new study would need an effect estimate of OR = 1.03 to enlarge the PM10 confidence interval to overlap 1, and OR = 0.44 to shift the overall effect estimate to OR<1.

“We found that an additional new study would need to have an effect estimate of OR = 1.03 to enlarge our confidence interval to overlap 1, and OR = 0.44 to shift our overall effect estimate to OR<1.”

May combine two claims.

One additional included study [53] reported effect estimates for both PM10 and PM2.5 but was not included in the meta-analysis because its study population was a subset of the population reported in a previous article [52] already included.

“One additional included study [53] also reported effect estimates for both PM10 and PM2.5 but ultimately was not included in the meta-analysis because upon personal communication with the study authors [64] it was determined that the study population was a subset of the population reported in a previous article [52] that was already included in the meta-analyses.”

• cites [53] HE Volk, 2014, Autism Spectrum Disorder: Interaction of Air Pollution with the MET Receptor Tyrosine Kinase Gene., EpidemiologyNot checked yet

  Not checked in the free run.

• cites [64] Volk HE. Email correspondence. 2014.Not checked yet

  Not checked in the free run.

• cites [52] HE Volk, 2013, Traffic-related air pollution, particulate matter, and autism, JAMA psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Across other air pollutants, there was generally a trend towards positive effects, increasing exposure associated with increased autism risk, although data were limited and confidence intervals commonly overlapped the null.

“We generally observed a trend towards positive effects (increasing exposure associated with increased autism risk), although there were limited data and confidence intervals commonly overlapped the null.”

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

We identified several findings from the grey literature through our comprehensive search, and two studies did find negative findings.

“We identified several findings from the grey literature through our comprehensive search, and two studies did find negative findings.”

May combine two claims.

All of the studies found null or minimal effects only, with OR<2.

“All of the studies found null or minimal effects only (i.e., OR<2).”

May combine two claims.

A positive relationship was observed between exposure and outcome where chance, bias, and confounding could not be ruled out with reasonable confidence.

“A positive relationship was observed between exposure and outcome where chance, bias, and confounding could not be ruled out with reasonable confidence.”

May combine two claims.

Leave-one-out analysis identified one study [39] as contributing to the majority of heterogeneity in the PM2.5 meta-analysis, and no particular methodological features driving heterogeneity could be identified.

“Again using a leave-one-out analysis, we identified one study in particular [39] that was contributing to the majority of the heterogeneity and we could not identify particular methodological features driving the heterogeneity so we classified it as unexplained.”

• cites [39] TA Becerra, 2013, Ambient air pollution and autism in Los Angeles county, California, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Effect estimates across studies were mostly positive, showing increased risk, and small (OR<2), and confidence intervals overlapped across studies for the majority of estimates.

“Effect estimates across studies were mostly positive (showing increased risk) and small (OR<2) and confidence intervals overlapped across studies for the majority of estimates.”

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

Coauthors felt there was some evidence of a dose-response relationship, but not enough to warrant upgrading of the evidence.

“Coauthors felt there was some evidence of a dose-response relationship, but not enough to warrant upgrading of the evidence.”

May combine two claims.

For PM2.5, the summary effect estimate was OR = 1.88 (95% CI: [1.11, 3.20]) with considerable statistical heterogeneity (I2 = 96%; p-value<0.0001).

“For PM2.5, the summary effect estimate was OR = 1.88 (95% CI: [1.11, 3.20]) but, similar to PM10 analyses, we found evidence of considerable statistical heterogeneity (I2 = 96%; p-value<0.0001).”

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

Study population sizes in the meta-analyses ranged from 524 to 83,229.

“Study population sizes ranged from 524–83,229.”

May combine two claims.

These studies reported effect estimates similar enough to be combined into a meta-analysis; we found statistically significant pooled effect estimates for both PM components, with a stronger effect demonstrated for PM2.5 than for PM10.

“These studies reported effect estimates similar enough to be combined into a meta-analysis we found statistically significant pooled effect estimates for both PM components, with a stronger effect demonstrated for PM2.5 than for PM10.”

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

Our systematic review results were generally in concert with previous expert-based narrative reviews that addressed the association of ASD and environmental chemical exposures more broadly.

“Our systematic review results were generally in concert with previous expert-based narrative reviews that addressed the association of ASD and environmental chemical exposures more broadly [18, 65–67].”

• cites [18] K Lyall, 2014, Maternal lifestyle and environmental risk factors for autism spectrum disorders, International Journal of Epidemiology sourceNot checked yet

  Not checked in the free run.

• cites [65] I Hertz-Picciotto, 2011, Autism Spectrum DisordersNot checked yet

  Not checked in the free run.

• cites [66] AE Kalkbrenner, 2014, Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence, Current Problems in Pediatric and Adolescent Health Care sourceNot checked yet

  Not checked in the free run.

• cites [67] DA Rossignol, 2014, Environmental toxicants and autism spectrum disorders: a systematic review, Translational Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Generally, the other air pollutants that could not be combined into a meta-analysis, such as some of the metal air pollutants, supported positive and statistically significant effects, although the effects were generally small and not consistent.

“Generally, the other air pollutants that could not be combined into a meta-analysis (such as some of the metal air pollutants) supported positive and statistically significant effects, although the effects were generally small and not consistent.”

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

Relatively few studies have been able to adequately power analyses of gene-environment interactions in ASD.

“relatively few studies have been able to adequately power such analyses.”

May combine two claims.

We identified statistical heterogeneity in our meta-analysis that could be minimized through incorporating a clustered data analysis structure, but not explained through differences in study design.

“We identified statistical heterogeneity in our meta-analysis that could be minimized through incorporating a clustered data analysis structure, but not explained through differences in study design.”

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

The observation that author cooperation was necessary to complete the meta-analysis is consistent with the authors' previous systematic reviews.

“This observation is consistent with our previous systematic reviews, [24, 27, 28, 30]”

• cites [24] E Koustas, 2014, The Navigation Guide—evidence-based medicine meets environmental health: systematic review of nonhuman evidence for PFOA effects on fetal growth, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

• cites [27] HM Vesterinen, 2014, Fetal growth and maternal glomerular filtration rate: a systematic review, Journal of Maternal-Fetal and Neonatal MedicineNot checked yet

  Not checked in the free run.

• cites [28] PI Johnson, 2016, Application of the Navigation Guide Methodology: Systematic review of the evidence for developmental and reproductive toxicity of triclosan, Environment InternationalNot checked yet

  Not checked in the free run.

• cites [30] PI Johnson, 2014, The Navigation Guide—evidence-based medicine meets environmental health: systematic review of human evidence for PFOA effects on fetal growth, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

May combine two claims.

We utilized six robust studies, five case-control and one cohort, with minimal risk of bias concerns that represented a total of 9,557 children with autism and 143,997 controls reporting on PM10 exposure, and a subset of these that also reported on PM2.5.

“We utilized six robust studies (five case-control and one cohort) with minimal risk of bias concerns that represented a total of 9,557 children with autism and 143,997 controls reporting on PM10 exposure, and a subset of these that also reported on PM2.5.”

May combine two claims.

The included studies varied in the adjusted confounders considered, the timing of exposure or outcome measurement, and the method used for assessing the ASD outcome.

“The included studies varied in the adjusted confounders considered, the timing of exposure or outcome measurement, and the method used for assessing the ASD outcome.”

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

The authors had completed their review but had not yet published their results when three new relevant studies were published.

“We had completed our review but had not yet published our results when three new relevant studies were published [69].”

• cites [69] M Guxens, 2016, Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The small number of studies in the meta-analysis and unexplained statistical heterogeneity across individual study estimates means the effect could be larger or smaller (including not significant) than these studies estimate.

“However, the small number of studies in the meta-analysis and unexplained statistical heterogeneity across the individual study estimates means that the effect could be larger or smaller (including not significant) than these studies estimate.”

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

Two of eight review authors independently recorded risk of bias determinations for each included study.

“Two of the eight review authors with subject-matter expertise (GW, AH, CN, AK, CL, TW, PS, EK) independently recorded risk of bias determinations for each included study.”

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

An additional reviewer screened 5% of titles/abstracts and full-texts for quality assurance.

“An additional reviewer (PS) screened five percent of the titles/abstracts and full-texts for quality assurance.”

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

References were screened in duplicate using structured forms.

“We screened references in duplicate for inclusion using structured forms in DRAGON (ICF International; available at: http://www.icfi.com/insights/products-and-tools/dragon-online-tool-systematic-review) and DistillerSR (Evidence Partners; available at: http://www.systematic-review.net).”

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

Title and abstract were independently reviewed by two of five reviewers.

“each reference from the literature search had the title and abstract independently reviewed by two of the five reviewers (ND, AH, AK, LD, GW) in a non-random assignment to ensure that the same two authors did not always screen the same references.”

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

Each review team member completed a conflict of interest statement at initiation.

“Each member of the review team also filled out a conflict of interest statement at the initiation of their involvement with the protocol to document any potential financial or other conflicts of interest, and these were appended to the protocol.”

Classified as probably not a substantial claim.

Review authors decided beforehand that different air pollutant chemicals or classes should be analyzed separately.

“In particular, review authors had decided beforehand that different air pollutant chemicals or classes of compounds (i.e., heavy metals, pesticides, and criteria air pollutants) should be analyzed separately in the absence of empirical evidence to suggest that we could combine these effect estimates.”

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

Two review authors subsequently reviewed ratings for all included studies to ensure consistency across studies with similar populations or designs.

“Based on this discussion, two review authors (JL, EK) subsequently reviewed ratings for all included studies to ensure consistency across studies with similar study populations or study design.”

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

Four authors and a research assistant independently extracted data from all included articles.

“Four authors (ND, LD, PS, EK) and a UCSF research assistant (HT) independently extracted data relating to study characteristics and outcome measures (S3 Table) from all included articles into a DRAGON database.”

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

An in-person meeting was held to review rationales and ratings for each study and come to consensus.

“We held an in-person meeting to review rationales and ratings for each study and come to consensus.”

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

The Navigation Guide systematic review methodology is based on Cochrane/GRADE methods and includes the same elements but accounts for differences in environmental health assessments.

“The Navigation Guide systematic review methodology is based on Cochrane/GRADE methods [21, 22] and includes all the same elements (protocol, development, risk of bias evaluation, evidence evaluation, etc.) but accounts for the differences in evidence and decision context inherent to environmental health assessments”

• cites [21] Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [Updated March 2011] 2011 [May 1, 2016]. Available from: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.cochrane-handbook.org" xlink:type="simple">www.cochrane-handbook.org</ext-link>.Not checked yet

  Not checked in the free run.

• cites [22] GH Guyatt, 2008, GRADE: an emerging consensus on rating quality of evidence and strength of recommendations, The BMJ sourceNot checked yet

  Not checked in the free run.

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

The protocol was developed prior to initiating the study and registered in PROSPERO (CRD # 42015017890).

“registered in PROSPERO, CRD # 42015017890”

• Also stated in: § The Navigation Guide Systematic Review Methodology · plain

  “We developed a protocol to outline the process for conducting the systematic review prior to initiating the study and registered the protocol with an international database for systematic reviews in March 2015.”

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

Full-text review was independently performed by two of five reviewers.

“Two of the five reviewers (ND, AH, AK, LD, GW) then independently performed a full-text review to evaluate inclusion criteria of each reference not excluded by title/abstract screening.”

Classified as probably not a substantial claim.

Review authors were instructed to separately rate exposure assessment risk of bias for each air pollutant chemical or class.

“Review authors were instructed to separately rate the exposure assessment risk of bias for each air pollutant chemical or classes of chemicals reported in the study under review.”

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

Review authors who were coauthors of a study recused themselves from rating risk of bias for that study.

“In the event that one of the review authors was a coauthor of the study in question, they recused themselves from rating the risk of bias for that particular study.”

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

To date, the Navigation Guide method has been used in 3 case studies.

“To date, the Navigation Guide method has been used in 3 case studies [25, 27, 28].”

• cites [25] J Lam, 2014, The Navigation Guide-evidence-based medicine meets environmental health: Integration of animal and human evidence for PFOA effects on fetal growth, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

• cites [27] HM Vesterinen, 2014, Fetal growth and maternal glomerular filtration rate: a systematic review, Journal of Maternal-Fetal and Neonatal MedicineNot checked yet

  Not checked in the free run.

• cites [28] PI Johnson, 2016, Application of the Navigation Guide Methodology: Systematic review of the evidence for developmental and reproductive toxicity of triclosan, Environment InternationalNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

A novel risk of bias instruction for exposure assessment was developed specifying considerations such as modeling, monitoring, and biomarkers.

“we ultimately developed a novel risk of bias instructions for exposure assessment that specified a list of important considerations, i.e., modeling, monitoring, biomarkers, etc.”

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

The search was not limited by language or start-date of publication.

“Our search was not limited by language or start-date of publication.”

Classified as probably not a substantial claim.

Risk of bias was assessed using a modified instrument based on the Cochrane Risk of Bias tool and AHRQ domains.

“We assessed risk of bias for each included study using a modified instrument we developed based on the Cochrane Collaboration’s “Risk of Bias” tool and the Agency for Healthcare Research and Quality’s (AHRQ) domains, i.e., selection bias, confounding, performance bias, attrition bias, detection bias, and reporting bias [21, 31].”

• cites [21] Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [Updated March 2011] 2011 [May 1, 2016]. Available from: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.cochrane-handbook.org" xlink:type="simple">www.cochrane-handbook.org</ext-link>.Not checked yet

  Not checked in the free run.

• cites [31] M Viswanathan, 2012, Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions, Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care InterventionsNot checked yet

  Not checked in the free run.

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

A third author performed QA/QC on all studies by reviewing the studies and extracted data to check for accuracy.

“A third author (JL) performed QA/QC on all of the studies by reviewing the studies and its extracted data to check for accuracy.”

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

Prenatal air pollution has been identified as having potentially greater impacts than adult exposures.

“prenatal air pollution has been identified as having potentially greater impacts than adult exposures [6].”

• cites [6] PJ Landrigan, 2005, Early environmental origins of neurodegenerative disease in later life, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Many studies rated probably high, with one high, for potential confounding were due to failure to adjust for many important confounders established beforehand in the protocol.

“Many of the studies rated as “probably high” (with one “high”) for potential confounding were due to the failure to adjust for many of the important confounders that we had established beforehand in our protocol.”

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

The majority of studies adjusted for maternal age, parental level of education, race/ethnicity, gender of child, household income, and some measure of socio-economic status.

“The majority of studies adjusted for maternal age, parental level of education, race/ethnicity, gender of child, household income, and some measure of socio-economic status.”

May combine two claims.

Exposures were not directly measured, lacking biomarkers or individual measurement of air pollutants, but this was accounted for in the risk-of-bias rating and no other areas of concern existed for indirectness.

“Exposures were not directly measured (lacking biomarkers or individual measurement of air pollutants); however this was accounted for in the ROB rating and no other areas of concern existed for indirectness.”

• AssumptionRests on an assumption: The risk-of-bias rating adequately accounts for the lack of direct exposure measurement, so no downgrade for indirectness is needed.

May combine two claims.

The OR = 1.03 needed to lose statistical significance for PM10 is reasonably within the range reported by existing studies, so a new study might easily shift interpretation of statistical significance; the OR = 0.44 needed to shift the overall effect to OR<1 seemed rather unlikely.

“The former OR estimate is reasonably within the range of that reported by existing studies (thus, it might be possibly for a new study to easily shift our interpretation of statistical significance of the overall effect estimate), but the OR required to shift the overall effect estimate to OR<1 seemed rather unlikely.”

May combine two claims.

With more information, the observed effect could change, and this change may be large enough to alter the conclusion.

“With more information, the observed effect could change, and this change may be large enough to alter the conclusion.”

May combine two claims.

Although there was concern regarding the risk of bias domain, we did not judge this sufficient to warrant downgrading the evidence and therefore remained at the initial moderate rating.

“Ultimately, although there was concern regarding the risk of bias domain, we did not judge this to be sufficient enough to warrant downgrading the evidence and therefore remained at the initial “moderate” rating.”

May combine two claims.

The OR = 1.02 needed to lose statistical significance for PM2.5 is outside the range reported by existing studies but not unreasonably so; the OR = 0.14 needed to shift the overall effect to OR<1 seems quite unlikely.

“The former OR estimate is outside the range of that reported by existing studies, but not unreasonably so; however, the OR required to shift the overall effect estimate to OR<1 seems quite unlikely.”

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

Initial exposure assessment risk of bias ratings for NATA data were assigned as probably low for higher confidence, probably high for medium confidence, and high for lower confidence.

““probably high” for those with “medium” confidence (i.e., coke oven emissions, vinyl chloride, chloroform, ethylene dibromide, etc.), and “high” for those with “lower” confidence (i.e., arsenic compounds, beryllium compounds, cadmium compounds, lead compounds, etc.).”

• cites [62] AS Rosenbaum, 1999, National estimates of outdoor air toxics concentrations, Journal of the Air & Waste Management Association sourceNot checked yet

  Not checked in the free run.

• cites [63] Environmental Protection Agency U.S. (US EPA). Limitations in the 1996 National-Scale Air Toxics Assessment 2015. Available: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://archive.epa.gov/airtoxics/nata/web/html/conf.html" xlink:type="simple">https://archive.epa.gov/airtoxics/nata/web/html/conf.html</ext-link>.Not checked yet

  Not checked in the free run.

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

The central nervous system was proposed as another organ negatively affected by air pollutants.

“More recently, the central nervous system was proposed as another organ negatively affected by air pollutants [5]”

• cites [5] G Oberdorster, 2002, Ultrafine particles in the urban air: to the respiratory tract—and beyond?, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The decision not to downgrade for publication bias was based on conducting a comprehensive search, finding grey literature, and finding studies of variable sizes, designs, and funding sources with similar findings.

“so we based our decision to not downgrade for publication bias on the fact that we conducted a comprehensive search, found studies from the grey literature, and found studies of variable sizes, designs, and funding sources that had similar findings.”

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

Systematic review methods have been used for decades in the clinical sciences.

“While systematic review methods have been used for decades in the clinical sciences [21, 22]”

• cites [21] Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [Updated March 2011] 2011 [May 1, 2016]. Available from: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.cochrane-handbook.org" xlink:type="simple">www.cochrane-handbook.org</ext-link>.Not checked yet

  Not checked in the free run.

• cites [22] GH Guyatt, 2008, GRADE: an emerging consensus on rating quality of evidence and strength of recommendations, The BMJ sourceNot checked yet

  Not checked in the free run.

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

Studies in animals have found that developmental exposure to air pollution is related to functional and structural brain effects.

“Studies in animals have also found that developmental exposure to air pollution is related to functional and structural brain effects [11–15].”

• cites [11] L Calderon-Garciduenas, 2009, Effects of a cyclooxygenase-2 preferential inhibitor in young healthy dogs exposed to air pollution: a pilot study, Toxicologic Pathology sourceNot checked yet

  Not checked in the free run.

• cites [12] A Campbell, 2009, Particulate matter induced enhancement of inflammatory markers in the brains of apolipoprotein E knockout mice, Journal of Nanoscience and Nanotechnology sourceNot checked yet

  Not checked in the free run.

• cites [13] ME Gerlofs-Nijland, 2010, Effect of prolonged exposure to diesel engine exhaust on proinflammatory markers in different regions of the rat brain, Particle and Fibre Toxicology sourceNot checked yet

  Not checked in the free run.

• cites [14] S Levesque, 2011, Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

• cites [15] D van Berlo, 2010, Comparative evaluation of the effects of short-term inhalation exposure to diesel engine exhaust on rat lung and brain, Archives of Toxicology sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Collectively, these findings led to our conclusion that positive relationships were observed between air pollution exposures generally and ASD, but that chance, bias, and confounding could not be ruled out with reasonable confidence because of the limitations present in the available data.

“Collectively, these findings led to our conclusion that positive relationships were observed between air pollution exposures generally and ASD, but that chance, bias, and confounding could not be ruled out with reasonable confidence because of the limitations present in the available data.”

May combine two claims.

Our review additionally included a meta-analysis, the results of which further demonstrated an association between air pollution, specifically PM, and ASD, but also revealed some uncertainties in the body of evidence that would not have been apparent except for the meta-analysis.

“However, our review additionally included a meta-analysis, the results of which further demonstrated an association between air pollution (PM) and ASD, but also revealed some uncertainties in the body of evidence that would not have been apparent except for the meta-analysis.”

May combine two claims.

Possible study design characteristics differed among included studies, but it is difficult to assign an exact explanation for the observed heterogeneity in results.

“There are possible study design characteristics that differed (for instance, the availability and quality of individual home addresses to estimate individual-level exposures), but it is difficult to assign an exact explanation for the observed heterogeneity in results.”

May combine two claims.

The available body of evidence on air pollution in general and ASD was wide, shallow, and except for PM, limited in its ability to strongly support a relationship if one exists.

“The available body of evidence on air pollution in general and ASD was wide, shallow, and except for PM, limited in their ability to strongly support a relationship if one exists.”

Classified as probably not a substantial claim.

This met our definition of limited evidence of toxicity for the association between early life exposure to air pollution generally and ASD.

“This met our definition of “limited evidence of toxicity” for the association between early life exposure to air pollution generally and ASD.”

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

The observed pattern of a larger summary effect estimate for PM2.5 than for PM10 is not unexpected.

“this pattern of association is not unexpected.”

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

Due to the complexity of assessing risk of bias of air pollution exposure assessments, the authors developed a novel risk of bias tool and piloted its use for this study.

“Due to the complexity of assessing the risk of bias of air pollution exposure assessments, we developed a novel risk of bias tool and piloted its use for this study.”

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

The authors of the prior review rated evidence based on IARC classifications and concluded that there was sufficient evidence for an association of ASD with PM2.5.

“The authors of this review rated evidence based on IARC classifications and concluded that there was “sufficient” evidence for an association of ASD with PM2.5.”

May combine two claims.

The only prior review of air pollutants and neuropsychological development that followed a prescribed systematic methodology was limited to published English language studies appearing during or after 2012 and did not include a meta-analysis.

“The only prior review of air pollutants and neuropsychological development that followed a prescribed systematic methodology was limited to published English language studies appearing during or after 2012 and did not include a meta-analysis [68].”

• cites [68] E Suades-González, 2015, Air pollution and neuropsychological development: a review of the latest evidence, Endocrinology sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The Navigation Guide classifications are based largely on the IARC classifications.

“The Navigation Guide classifications are based largely on the IARC classifications.”

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

Identifying the environmental contributors to ASD and neurodevelopment in general is a critical unmet clinical and public health need.

“Identifying the environmental contributors to ASD and neurodevelopment in general is a critical unmet clinical and public health need, as recognized by a recent consensus statement published by leading scientific and medical experts, along with children’s health advocates, which identifies the importance of environment as a risk factor for neurodevelopment [92].”

• cites [92] D Bennett, 2016, Project TENDR: Targeting Environmental Neuro-Developmental Risks The TENDR Consensus Statement, Environmental Health Perspectives sourceNot checked yet

  Not checked in the free run.

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

Without the cooperation of individual study authors, it would have been impossible to complete the meta-analysis.

“Without the cooperation of individual study authors, it would have been impossible to complete the meta-analysis.”

May combine two claims.

The occurrence of heterogeneity that lacked a clear methodological rationale is suggestive of randomness in the available data, was concerning to review authors, and was influential in the final rating of limited overall evidence.

“Further the occurrence of heterogeneity that lacked a clear methodological rationale is suggestive of randomness in the available data, was concerning to review authors, and this was influential in our final rating of “limited” overall evidence.”

May combine two claims.

While the meta-analysis suggested statistically significant effects for PM, these were based on very few studies and sensitivity analysis suggested that even a single added study within the range of ORs reported to date could lead to a summary effect that did not attain statistical significance, although an extreme OR estimate would be required to change the direction of the overall effect to less

“While the meta-analysis suggested statistically significant effects for PM, these were based on very few studies and sensitivity analysis suggested that even a single added study within the range of ORs reported in the body of research to date could lead to a summary effect evidence that did not attain statistical significance (although an extreme OR estimate would be require to change the”

May combine two claims.

The strongest available evidence supported associations between PM and ASD, and this was supported by the results of the meta-analysis.

“We found the strongest available evidence was supporting associations between PM and ASD, which was supported by the results of our meta-analysis.”

May combine two claims.

With the exception of PM, where estimates could fairly easily be standardized, the body of evidence was disparate and largely not combinable.

“As such, with the exception of PM, where estimates could fairly easily be standardized, the body of evidence was disparate and largely not combinable.”

May combine two claims.

Smaller particles have the ability to penetrate into the circulatory system and are thought to be more biologically active.

“Because smaller particles have the ability to penetrate into the circulatory system and are thought to be more biologically active [83–86]”

• cites [83] M Lippmann, 1980, Deposition, retention, and clearance of inhaled particles, British Journal of Industrial MedicineNot checked yet

  Not checked in the free run.

• cites [84] TM De Kok, 2006, Toxicological assessment of ambient and traffic-related particulate matter: a review of recent studies, Mutation Research sourceNot checked yet

  Not checked in the free run.

• cites [85] N Englert, 2004, Fine particles and human health—a review of epidemiological studies, Toxicology Letters sourceNot checked yet

  Not checked in the free run.

• cites [86] M Kampa, 2008, Human health effects of air pollution, Environmental Pollution sourceNot checked yet

  Not checked in the free run.