Subclinical thyroid dysfunction; Prospective cohorts; Coronary Disease; Mortality
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Background Subclinical thyroid dysfunction, defined as abnormal thyroid-stimulating hormone (TSH) and normal thyroid hormone levels, is common, particularly among older adults. It has been associated with adverse cardiovascular, psychiatric and cognitive outcomes. We have recently shown in JAMA that subclinical hypothyroidism was associated with an increased risk of coronary heart disease (CHD) events and CHD mortality.However, controversy persists on the relevance of early diagnosis and systematic screening as well as on threshold TSH levels for treatment of subclinical thyroid dysfunction. Available data show substantial limitations: 1) existing cohorts do not have serial TSH measurements to assess the potentially higher risks of persistent subclinical hypothyroidism (about 15-65% normalized TSH over time); 2) only few prospective data are available to assess other potential risks, such as heart failure, cognitive functions or psychiatric outcomes, and risks associated with subclinical hyperthyroidism. Specific aims The main objective of this proposal is to identify and quantify the clinical risks associated with subclinical thyroid dysfunction in large prospective cohorts. The specific aims are:1. In a large population-based prospective cohort (the Prosper study with 5804 older adults): A. To measure the prevalence of persistent subclinical hypothyroidism, to quantify its association with cardiovascular events and to identify the main mediating factors. B. To identify and quantify association of subclinical hypothyroidism with change in cognitive function, in functional capacity and in depressive symptoms. 2. To expand our successful international collaboration (the Thyroid Studies Collaboration, with 62’000 individual participant data from 12 prospective cohorts) to assess: A. The risks of heart failure events (HF) and stroke associated with subclinical thyroid dysfunction. B. The risks of cardiovascular events, atrial fibrillation, cause-specific and total mortality associated with subclinical hyperthyroidism.Methods We will measure thyroid function in 5804 adults aged 70-82 years from the Prosper study at baseline and at 6 months to define persistent subclinical hypothyroidism. We will examine subsequent cardiovascular events (CHD, stroke) over 11-year follow-up. For mediating factors, we will examine cardiovascular risk factors and multiple biomarkers that have been associated with increased cardiovascular risk (routinely available in the Prosper study). Other outcomes will be 3.2-year change in cognitive function, in functional capacity and in depressive symptoms. Aim 2 will take advantage of the international collaboration we have formed with 12 prospective cohorts, yielding to 62,000 individual participant data, with 580,000 person-years of follow-up. We will collect and analyze additional outcomes: HF events, atrial fibrillation, stroke, cause-specific mortality, as well as required confounders for each of these outcomes. For power issues, multiple large prospective cohorts are needed to clarify these risks and subgroups at risk. Expected value of the proposed project This proposal will address both a gap of knowledge and a substantial clinical issue, namely the risks of subclinical thyroid dysfunction. Strengths of this proposal include the combination of: 1) analyses in a large, well-characterized cohort study, including both cardiovascular and neuropsychiatric outcomes, being the first to assess clinical risks associated with persistent subclinical hypothyroidism; 2) large power given older age and high risk of participants; 3) multiple mediating variables to better investigate potential mechanisms of associations with cardiovascular events; 4) unique international collaboration with 62,000 individual data from 12 prospective cohorts to clarify controversial risks mentioned under aim 2 that need multiple cohorts. This collaboration will have more power to answer these research questions than any single cohort worldwide and give the opportunity to analyze several subgroups that single cohorts could not examine. Given the controversy about these risks because of limited prospective cohort data, we anticipate that our study will advance scientific knowledge on these risks, which will help clarify controversy on thyroid screening and help refine a TSH threshold at which larger clinical benefits of treatment would be expected.