AS554 - The descriptive and etiologic epidemiology of abdominal adipose tissue depots in the WHI and cardio-metabolic risk

Investigator Names and Contact Information

Andrew Odegaard (aodegaar@uci.edu)

Introduction/Intent

A growing understanding of the underlying biology of adipose tissue suggests that the type, amount, and distribution are the characteristics that best inform the relationship between adiposity, healthy aging and disease risk; and likely explain the epidemiological relationships between anthropometric measures and disease outcomes. Yet, these relationships are largely inferred rather than evidence based since to obtain measures of specific adipose tissue depots researchers and clinicians have had to rely on imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). Issues such as cost, radiation, and availability make these methods impractical in the clinic and for large research studies. For example, the inference that higher visceral adipose tissue (VAT) levels are pernicious for health is based upon a smattering of smaller studies relying on one measurement with cross sectional analyses, or short term follow up. Studies with large, well defined populations, relevant follow up time, and a range of disease and aging outcomes have not been conducted- and these are the investigations that will truly move the scientific needle of knowledge related to adiposity and health. Therefore, to address this major gap we propose to apply a new technology to the existing Women’s Health Initiative (WHI) dual-energy absorptiometry scans (DXA) cohort that allows for the quantification of abdominal VAT and subcutaneous adipose tissue (SAT) from existing DXA scans. This new technology is 100% backward compatible with all modern Hologic fan-beam technology. It is also highly valid with gold-standard measures of abdominal adipose tissue depots (r ≥ .93 with CT). This ancillary study will create a new analytic cohort to address essential questions on the topic of adiposity, healthy aging, and disease risk in women. The aims of this ancillary study will be to 1) derive abdominal VAT and SAT from the existing WHI DXA scans compatible with the new technology at year 3 (N TBD), 6 (N~ 8200), and 9 (N~ 4600) based upon the published literature from the WHI. As part of the data derivation aim we will demonstrate the reliability of this new application, and the validity relative to a sub-sample of WHI participants who also underwent a concurrent MRI exam and have a gold-standard measure. The analytic aims of this ancillary study will provide novel descriptive epidemiologic insight into the patterns and predictors of abdominal VAT and SAT as post-menopausal women age. It will also be the largest ever study with a well-defined population to be able to examine essential questions on how levels of VAT and SAT associate with Cardio-Metabolic Health (E.G. incident type 2 diabetes, cardiovascular disease, metabolic healthy obesity, obesity paradox).

SPECIFIC AIMS

Excess adiposity, defined as overweight and obesity, and typically categorized by levels of body mass index (BMI), is associated with a spectrum of health risks, especially in the cardiometabolic arena, and is considered a modern day public health epidemic. The application of the measurement of BMI for overall body size and waist circumference (WC) as a means to quantify body fat distribution has been useful in epidemiologic studies to develop a basic understanding of the relationships between these measures and health risks related to excess adiposity. Yet, the simple measurement and basic utility of these measures does not address the growing knowledge of the complex biology of adipose tissue, which suggests that the type, amount, and distribution of adipose tissue is what explains the heterogeneous relationship between BMI and WC with disease outcomes. The central challenge of this topic is that the aforementioned insights related to type, amount, and distribution of adipose tissue are largely inferred since it has not been feasible to collect the imaging measures of VAT and SAT (i.e. from CT or MRI) from large, well defined cohorts with relevant follow up time and disease outcomes. However, the application of new technology to existing data is an approach that will allow the science on the topic to significantly move forward efficiently and in an economically feasible fashion. Therefore, we propose to apply a new technology from Hologic to the existing Women’s Health Initiative (WHI) DXA cohort that allows for the quantification of abdominal VAT and SAT from existing DXA scans. This new technology is 100% backward compatible with all modern Hologic fan-beam technology (QDR 4500 and above). It is also highly valid with gold-standard measures of abdominal adipose tissue depots (r ≥ .93 with CT). This ancillary study will create a new analytic cohort to address essential questions on the topic of adiposity, healthy aging, and disease risk in women. Dr. Odegaard is teaming with established WHI investigators from the University of Arizona who are expert on working with the DXA cohort from the WHI, and their collective expertise will prime this ancillary study for success. Hence, to develop an analytic resource that is able to address the fundamental questions related to VAT and SAT levels in relation to Cardio-Metabolic Health we are proposing the following aims:

Aim 1) To create a novel and powerful analytic resource able to address the significant unanswered questions related to body composition and Cardio-Metabolic Health we will derive abdominal VAT and SAT from the existing WHI DXA scans compatible with the new technology from Hologic at year 3 (N TBD), 6 (N~ 8200), and 9 (N~ 4600). As part of this data derivation aim we will demonstrate the reliability of this new application, and the validity relative to a sub-sample of WHI participants who also underwent a concurrent MRI exam with one of the DXA visits and thus have a gold-standard measure.

Aim 2) To provide evidence that will inform critical unanswered questions related to adipose deposition patterns in post-menopausal women, aging, and disease risk we will carry out a) novel descriptive epidemiologic analyses on the patterns of abdominal VAT and SAT that utilize the repeated measurements and relate them to clinically available anthropometric measures (BMI, waist) and b) examine hypothesized essential predictors of these patterns and cardiometabolic health in dietary intake, physical activity, and smoking.

Aim 3) To examine how levels of VAT and SAT associate with cardiometabolic outcomes we will examine levels and change in levels of VAT and SAT (where feasible) with the incidence of: a) type 2 diabetes and b) cardiovascular disease endpoints (CHD, Stroke, CHF, and PAD) in the context of base anthropometric measures (BMI and waist).

Applying this new technology to the existing, large and well-defined population of the WHI with adjudicated and valid endpoints would create an unparalleled analytic resource for addressing elemental health questions related to body size and adipose tissue depots and distribution, and topical contributions to “metabolic healthy obesity” and the “obesity paradox” in CVD (CHF). This ancillary study would position the WHI to be the leader in moving the science forward on the topic and address the fundamental question of what and how much these imaging measures add over standard anthropometric measures.