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1 Supplementary Online Material Collet T-H, Gussekloo J, Bauer DC, et al; Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. Published online April 23, doi: /archinternmed eappendix. emethods: Data Sources and Search Strategies etable. Definition of Subclinical Hyperthyroidism, Coronary Heart Disease (CHD) Mortality, CHD events and Atrial Fibrillation (AF) events efigure. Flow Chart of Studies Evaluated for Inclusion in the Individual Participant Data (IPD) Analysis

2 emethods. Data Sources and Search Strategies We updated the systematic literature search done for our recent IPD analysis on the risks associated with subclinical hypothyroidism 1, in MEDLINE and EMBASE databases, from 1950 to June 30, 2011, without language restriction, on the association between subclinical thyroid dysfunction and mortality (cardiovascular and total), non-fatal coronary heart disease, atrial fibrillation or heart failure. Our search was conducted on an Ovid (MEDLINE) server by using broadly defined Medical Subject Headings (MeSH): thyroid diseases, hypothyroidism, hyperthyroidism, thyroid hormones, thyrotropin, heart failure, atrial fibrillation, mortality, myocardial ischemia, survival, and cardiovascular diseases; and the following keywords: subclinical hypothyroidism, subclinical hyperthyroidism, subclinical dysthyroidism, and subclinical thyroid; a filter designed by knowledge information specialists from BMJ was used to extract prospective studies (MEDLINE cohort-study filter) 2 but without their year limitation. This search was conducted in EMBASE using similar terms. We also searched bibliographies of key articles and those articles included in this review..

3 etable. Definition of Subclinical Hyperthyroidism, Coronary Heart Disease (CHD) Mortality, CHD events and Atrial Fibrillation events Study Subclinical hyperthyroidism a T3 normal range Preexisting CVD CHD mortality Incident fatal and non-fatal CHD events Definition Incident CHD Separate data for Hard CHD events b AF events Methods of Cardiovascular Health Study 3 Health Aging, Body and Composition Study 4 Birmingham Study 5 EPIC-Norfolk Study 6 normal FT ng/dl (9-22 pmol/l) or missing FT4 (1/10, 10%) c normal FT ng/dl ( pmol/l) or missing FT4 (1/15, 6.7%) d normal FT pmol/l (no missing FT4) normal FT pmol/l (no missing FT4) 2-8 pmol/l (no missing FT3) Evidence of old MI on ECG, echocardiography, hospital discharge or physician diagnosis were adjudicated by Self-reported history of CHD, peripheral artery disease or heart failure at baseline Not Self-reported Medical records, death certificates, autopsy reports, and coroners reports reviewed by Hospital records, death certificates, and other support documents reviewed by Death certificates; causes of death coded with ICD9- CM Death certificates and hospital discharge: causes of death coded with ICD9- CM Incident CHD (MI, angina, coronary angioplasty, coronary artery surgery, atherosclerotic CHD mortality) Incident CHD (fatal or non-fatal acute MI, angina pectoris, angioplasty of coronary arteries, coronary artery surgery) Annual visits and phone calls every 6 months Interview and hospital records reviewed by Annual visits and phone calls every 6 months Interview, hospital records, other documents reviewed by Self-report, annual ECGs, AF ICD-9 coded AF on hospital discharge Minnesotacoded ECGs at baseline and at year 4 follow-up Not NA NA Not CHD mortality + CHD in hospital records (ICD9-CM ) NHS central register, district database, postal health questionnaires every 18 months Not Not

4 etable. Definition of Subclinical Hyperthyroidism, Coronary Heart Disease (CHD) Mortality, CHD events and Atrial Fibrillation events (cont.) Study Subclinical hyperthyroidism a T3 normal range Preexisting CVD CHD mortality Incident fatal and non-fatal CHD events Definition Incident CHD Separate data for Hard CHD events b AF events Methods of HUNT study 7 normal FT pmol/l or missing FT4 (2/97, 2.1%) e Normal total T nmol/l (missing for 3/97, 3.1%) e Self-reported angina, MI, stroke Death certificates; causes of death coded with ICD9- CM ; ICD10 I20-I25 Not National Cause of Death Registry linkage Not Not Leiden 85-plus Study 8 normal FT pmol/l (no missing FT4) pmol/l (no missing FT3) Medical records, physician interview and participant interview with ECG Causes of death from Statistics Netherlands, where all death certificates are coded by ; ICD10 I20-I25 Incident fatal and non-fatal MI, angina pectoris Annual general practitioner interview, ECG and records Minnesotacoded annual ECGs Pisa cohort 9 normal FT ng/dl ( pmol/l) (no missing FT4) ng/dl (no missing FT3) Medical records and self-reported CHD mortality, sudden death Death certificates, hospital records, general practitioner and patient interviews (if living) CHD mortality + non-fatal MI Hospital records, general practitioner and patient interviews every 6 months Not

5 etable. Definition of Subclinical Hyperthyroidism, Coronary Heart Disease (CHD) Mortality, CHD events and Atrial Fibrillation events (cont.) Study SHIP Study 10 Busselton Health Study 11 Brazilian Thyroid Study 12 Subclinical hyperthyroidism a normal FT pmol/l or missing FT4 (2/934, 0.2%) normal FT pmol/l or missing FT4 (1/ 49, 2.0%) normal FT ng/dl ( pmol/l) (no missing FT4) T3 normal range pmol/l (missing for 2/934, 0.2%) Preexisting CVD Methods for Self-reported Self-reported, ECG, and selfreported confirmation of CVD diagnosis Medical records (ECG, imaging) validated by CHD mortality Death certificates from local health authority; independent validation of cause of death; review with another expert if disagreement; coded with ICD10 I20-I25 Registrar General s list of deaths: coded with ICD9-CM Incident fatal and non-fatal CHD events Definition Incident CHD Separate data for Hard CHD events b AF events Methods of Not NA Not Minnesotacoded ECGs at baseline and at year 5 follow-up CHD mortality + hospital admission with a diagnosis of CHD Continuous linkage of hospital record diagnoses Not Minnesotacoded ECGs at baseline and at year 14 followup NA f NA f NA Not Not Abbreviations: AF: atrial fibrillation; CHD: coronary heart disease; CVD: cardiovascular disease; FT3: free triiodothyronine; FT4: free thyroxin; ICD: International Classification of Diseases; MI: myocardial infarction; NA: not applicable; T3: triiodothyronine; TSH: thyrotropin. a To convert FT4 from pmol/l to ng/dl, divide by b Hard CHD events were defined as non-fatal MI or CHD death, as in the Framingham Risk Score 13 c FT4 was measured only in participants with TSH 0.10 miu/l in this cohort 3 d FT4 was measured only in participants with TSH 0.10 miu/l in this cohort 4 e FT4 and total T3 were measured only in participants with TSH <0.20 miu/l in this cohort 7 f Not included in analyses of CHD mortality, because of unreliable estimates given the low number of CHD deaths (n = 10)

6 efigure. Flow Chart of Studies Evaluated for Inclusion in the Individual Participant Data (IPD) Analysis, adapted from the Flow Diagram in the PRISMA Statement 14 Records identified through database searching (n = 5410) Additional records identified from reference lists (n = 2) Records after duplicates removed (n = 5276) Records screened (n = 5276) Records excluded based on title and abstract (unrelated to the association between subclinical hyperthyroidism and the outcomes) (n = 5211) Full-text articles assessed for eligibility (n = 65) Full-text articles excluded (n = 55) due to No specific data on subclinical hyperthyroidism (n = 14) All patients treated for thyroid dysfunction (n = 3) First generation TSH assays (n = 3) No T4 measurement (n = 4) No prospective data on outcomes (n = 17) No numeric data on outcomes (n = 2) Reported the same study already selected without additional data to extract (n = 4) Review article, meeting abstract or editorial (n = 8) Studies meeting inclusion criteria (n = 10) Studies included in quantitative synthesis (IPD analysis) (n = 10)

7 References 1. Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. Sep ;304(12): Search filters (Medline cohort study filter). ClinicalEvidence website 2011; Accessed July 29th Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. Mar ;295(9): Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch. Intern. Med. Nov ;165(21): Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. Sep ;358(9285): Boekholdt SM, Titan SM, Wiersinga WM, et al. Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study. Clin. Endocrinol. (Oxf). Mar 2010;72(3): Asvold BO, Bjoro T, Nilsen TI, Gunnell D, Vatten LJ. Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study. Arch. Intern. Med. Apr ;168(8): Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. Dec ;292(21): Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch. Intern. Med. Jul ;167(14): Ittermann T, Haring R, Sauer S, et al. Decreased serum TSH levels are not associated with mortality in the adult northeast German population. Eur. J. Endocrinol. Mar 2010;162(3): Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch. Intern. Med. Nov ;165(21): Sgarbi JA, Matsumura LK, Kasamatsu TS, Ferreira SR, Maciel RM. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up: the Japanese-Brazilian thyroid study. Eur. J. Endocrinol. Mar 2010;162(3): Grundy SM. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. May ;285(19): Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Ann. Intern. Med. Jul

Records after duplicates removed (n = 2274) Records screened (n = 2274) Full-text articles assessed for eligibility (n = 16)

Supplemental Figure 1 Adapted from Prisma Flow Chart Records identified through database searching (n = 3093) Additional records identified through other sources (n = 2) Records after duplicates removed