Mortality in Persons With Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder

This systematic review and meta-analysis evaluates the risk of both all-cause and cause-specific mortality among persons with autism spectrum disorder or attention-deficit/hyperactivity disorder and their first-degree relatives.

8 and 9, and eTable 5 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.
10 Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

10
Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
10 and 11 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

and 11
Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

10
Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.

11
Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

11
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

11
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).

RESULTS
Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
13 and 14, and Fig. 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. eTable 6 Study characteristics 17 Cite each included study and present its characteristics. 13, Table 1, and eTable 8 and 9 Risk of bias in studies 18 Present assessments of risk of bias for each included study. eTable 10

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.

Figures 3 and 4, and eFigures
Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.
14, Table 2, and eTable 12 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.

Search
S8 AND S9 AND S10 400    3) Non-Response rate a) same rate for both groups * b) non-respondents described c) rate different and no designation

NEWCASTLE -OTTAWA QUALITY ASSESSMENT SCALE COHORT STUDIES
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability Selection 1) Representativeness of the exposed cohort a) truly representative of the average in the community * b) somewhat representative of the average in the community * c) selected group of users (e.g. nurses, volunteers) d) no description of the derivation of the cohort 2) Selection of the non-exposed cohort a) drawn from the same community as the exposed cohort * b) drawn from a different source c) no description of the derivation of the non-exposed cohort 3) Ascertainment of exposure a) secure record (e.g. surgical records) * b) structured interview * c) written self-report d) no description 4) Demonstration that outcome of interest was not present at start of study a) yes * b) no Comparability 1) Comparability of cohorts on the basis of the design or analysis a) study controls for age and sex * b) study controls for any additional factor (e.g. medication, smoking, comorbidities…) * Outcome 1) Assessment of outcome a) independent blind assessment * b) record linkage * c) self-report d) no description 2) Was follow-up long enough for outcomes to occur a) yes * b) no 3) Adequacy of follow up of cohorts a) complete follow up -all subjects accounted for * b) subjects lost to follow up unlikely to introduce bias * c) follow up rate < 40% (select an adequate %) and/or no description of those lost d) no statement

eTable 10 (cont). Methodological quality assessment of included studies (Newcastle-Ottawa Scale)
Author Moderate risk Note: Risk of bias rating: 0-3 high risk of bias (low quality), 4-6 moderate risk of bias (moderate quality), 7-9 low risk of bias (high quality).

eTable 11. Grading certainty (or credibility) of evidence for summary estimates
Global Burden of Disease (GBD) criteria and GRADE system emphasize certainty (or credibility) of evidence based on randomized controlled data. For many risks in the biomedical literature (such as disease comorbidity), we will never have randomized controlled trials, and to restrict the assessment of exposures (or risks factors) to only those with trial evidence would lead us to ignore some of the most important determinants of health. Randomized controlled trials are unavailable for our research question. It is for this reason that we have used modified criteria of "convincing/high certainty" or "probable/moderate certainty" evidence for causality. If well designed and reported observational cohort studies form the evidence base the certainty rating starts with high/convincing evidence. If well designed and reported case-control studies form the evidence base the rating starts with moderate/probable evidence. Because the GRADE system does not yet have a scale for assessing non-interventional observational studies, we used a modified version to describe the validity and trustability of the evidence we presented in each meta-analysis. In brief, we rated the evidence as "convincing or high" when we are highly confident that the true effect lies close to that estimated. For example, evidence is judged as "convincing or high" if all of the following apply: • There are multiple cohort studies included in the analyses with no major limitations (low risk of bias according to NOS scale) • Summary effect estimate P value < 10 -6 • The summary estimate has a narrow confidence interval (95% predictive interval excluding null value) We rated the evidence as "probable or moderate" when we consider the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. For example, evidence might be judged as "probable or moderate" if any of the following applies: • There are only few studies and some have limitations but not major flaws (low/moderate risk of bias according to NOS scale) • Summary effect estimate P value < 10 -3 • The 95% predictive interval is wide Finally, we rated the evidence to be "low (limited, not conclusive)" when the true effect may be substantillay different from the estimate of its effect. "Low/limited-suggestive evidence" represents too limited evidence to conclude on a probable or convincing causal association, but where there is evidence suggestive of a direction of effect. "Low/limited-not conclusive evidence" consists of information that is so limited that no firm conclusion can be made for several reasons (e.g., the evidence might be limited by the amount of evidence in terms of the number of studies available, by inconsistency of direction of effect, by poor quality of studies, or by any combination of these factors). For example, evidence might be judged as "low quality" if any of the following apply: • There is only one study or studies have major methological flaws (high risk of bias according to NOS scale) • Summary effect estimate P value < 0.05 • There is considerable variation between study results

•
The confidence interval of the summary estimate of the effect is very wide (95% predictive interval including null value or 95% predictive interval was inestimable e.g. less than 3 studies) • Small study effects (sometimes called "publication bias")

Outcomes of interest
No of studies