Subclinical Thyroid Dysfunction and the Risk of Stroke: a Systematic Review and Meta-Analysis – Supplemental Material.

Legend of figure in supplemental material:

Figure S1. Funnel plots
1A. Funnel plot subclinical hyperthyroidism
1B. Funnel plot subclinical hypothyroidism

Funnel plots of the included studies for the association between subclinical thyroid function and the risk of stroke. The hazard ratios are plotted against the standard error of the logarithm of the Hazard Ratio. The vertical line represents the pooled Hazard Ratio per thyroid function group.

Example of electronic search strategy:

Medline (OvidSP):

("Thyroid Diseases"/ OR hyperthyroidism/ OR hypothyroidism/ OR "thyrotropin/bl"/ OR "thyroid function tests"/ OR (((thyroid*) ADJ3 (disease* OR abnormal* OR anomal* OR disorder* OR dysfunction* OR insufficien* OR failure* OR hyperfunction* OR subclinic* OR function*)) OR hypothyr* OR hyperthyr* OR dysthyr* OR ((thyrotropin) ADJ3 (blood OR level* OR serum)) OR ft4).ab,ti.) AND (mortality/ OR mortality.xs. OR "Cause of Death"/ OR "Survival Rate"/ OR survival/ OR exp "stroke"/ OR "Ischemic Attack, Transient"/ OR "Cerebrovascular Disorders"/ OR "brain ischemia"/ OR (mortalit* OR "death rate" OR surviv* OR ((cerebrovascular OR "cerebro vascular" OR "cerebral vascular") ADJ (accident OR disease*)) OR cva OR stroke OR "transient ischemic attack" OR "transient brain ischemia" OR "transient cerebral ischemia" OR "transient ischaemic attack" OR "transient brain ischaemia" OR "transient cerebral ischaemia" OR tia).ab,ti.) AND (exp "cohort studies"/ OR "controlled clinical trial".pt. OR "epidemiologic methods"/ OR "follow up"/ OR (cohort*).ab,ti.)

Inclusion and exclusion criteria for identified studies:

Inclusion:

-  Full-text published longitudinal cohort studies

-  Measurement of thyroid function with both serum TSH and thyroxine at baseline in adults

-  Followed up participants systematically over time

-  Assessing stroke and/or TIA events explicitly

-  Had a comparison group with euthyroidism

Exclusion:

-  Studies including only overt hypo and hyper

-  Cohorts studies including only participants taking thyroid altering medication

-  Studies including only stroke and TIA patients

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Table S1. Quality assessment of included studies
Name of cohort, year of publication (Reference) / Population studied § / Formal Adjudication Procedures for Stroke † / Methods for Stroke Ascertainment / Adjudication without Knowledge of Thyroid Status / Lost to Follow-up (%) / Adjustments
Frederiksberg Heart failure study, 2011 / P, 4 GP’s in 1 district (Denmark) / No / discharge registry of the Danish National Board of Health; diagnoses coded with ICD-10 / NR / NR / age, sex, atrial fibrillation
Health, Aging and Body Composition Study – HABC, 2005 / P, 2 centers (USA) / Yes / telephone interview or clinical visit; central adjudication / Yes / NR / age, sex, race, smoking status, diabetes, prevalent cardiovascular disease, poor or fair health, blood pressure, total cholesterol, creatinine, education, income and use of thyroid hormone or ace inhibitors
Nagasaki atomic bomb survivor study, 2004 / P, 1 clinical center (Japan) / No / self-report, information by GP ; central adjudication by physician at baseline; diagnoses of death coded with ICD-9 / No / NR / age, sex, smoking status
Birmingham, 2001 / P, 1 primary care practice, (UK) / No / UK National register of deaths; diagnoses coded with ICD-9 / NR / 1 individual / no
Cardiovascular Health Study – CHS, 2006 / P, 4 communities (USA) / Yes / semiannual telephone contact; adjudicated by the study’s morbidity and mortality subcommittee. / Yes¹ / NR / age, sex, disease status at baseline and use of thyroid-altering medication, atrial fibrillation
race, smoking, diabetes, LDL- Cholesterol, lipid lowering medication, hypertension, BMI, CRP.
4D study, 2013 / T, 178 dialysis centers (Germany) / Yes / central adjudicated by end point committee / NR / NR / age, sex, atorvastatin treatment
Systolic blood pressure, BMI, LVH, albumin, creatinine, NT-pro-BNP, ultrafiltration volume
Abbreviations: P = population-based study, T = clinical trial , GP = general practitioner, ICD = International Classification of Diseases, BMI = body mass index, LDL = low density lipoprotein, CRP = C-Reactive Protein, LVH = left ventricular hypertrophy
NR = not reported
1Ives DG, et al. Surveillance and Ascertainment of Cardiovascular Events: The Cardiovascular Health Study. Ann Epidemiol 1995
† A formal adjudication procedure was defined as having clear criteria for the outcome that were reviewed by experts for each potential case.
§ A population-based study was defined as a random sample of the general population
Table S2. Newcastle Ottawa Quality Assessment Scale for Cohorts of included studies
Study / Selection / Comparability / Outcome / Total
Frederiksberg Heart failure study, 2011 / **** / ** / ** / 8/9
Health, Aging and Body Composition Study – HABC, 2005 / **** / ** / * / 7/9
Nagasaki atomic bomb survivor study, 2004 / **** / ** / ** / 8/9
Birmingham, 2001 / *** / *** / 6/9
Cardiovascular Health Study – CHS, 2006 / ****1 / ** / ** / 8/9
Frederiksberg Heart failure study, 2011 / *** 2 / ** / * / 6/9
1Iv 1Ives DG, et al. Surveillance and ascertainment of cardiovascular events: the Cardiovascular Health Study. Ann Epidemiol, 1995.
2Wanner C, et al. Randomized controlled trial on the efficacy and safety of atorvastatin in patients with type 2 diabetes on hemodialysis (4D study): demographic and baseline characteristics. Kidney Blood Press Res, 2004
Table S3: PRISMA 2009 Checklist
SECTION/TOPIC / # / CHECKLIST ITEM / REPORTED ON PAGE #
TITLE
Title / 1 / Identify the report as a systematic review, meta-analysis, or both. / 1
ABSTRACT
Structured summary / 2 / Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. / 2
INTRODUCTION
Rationale / 3 / Describe the rationale for the review in the context of what is already known. / 3
Objectives / 4 / Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). / 3
METHODS
Protocol and registration / 5 / Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. / x
Eligibility criteria / 6 / Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. / 4
Information sources / 7 / Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. / 4
Search / 8 / Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. / Supplemental Material
Study selection / 9 / State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). / 5
Data collection process / 10 / Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. / 5
Data items / 11 / List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. / 5, Table 1
Risk of bias in individual studies / 12 / Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. / 5, 12
Summary measures / 13 / State the principal summary measures (e.g., risk ratio, difference in means). / 4
Synthesis of results / 14 / Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. / 6
Table S3: PRISMA 2009 Checklist (continued)
SECTION/TOPIC / # / CHECKLIST ITEM / REPORTED ON PAGE #
METHODS
Risk of bias across studies / 15 / Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). / 6
Additional analyses / 16 / Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. / 6
RESULTS
Study selection / 17 / Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. / Figure 1
Study characteristics / 18 / For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. / Table 1
Risk of bias within studies / 19 / Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). / 7
Results of individual studies / 20 / For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. / Figure 2
Synthesis of results / 21 / Present results of each meta-analysis done, including confidence intervals and measures of consistency. / Figure 2
Risk of bias across studies / 22 / Present results of any assessment of risk of bias across studies (see Item 15). / Supplemental Material
Additional analysis / 23 / Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). / Table 2
DISCUSSION
Summary of evidence / 24 / Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). / 10,12
Limitations / 25 / Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). / 10,11,12
Conclusions / 26 / Provide a general interpretation of the results in the context of other evidence, and implications for future research. / 12
FUNDING
Funding / 27 / Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. / 13
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

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Figure S1: Funnel plots

1A.

1B.

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