Our primary objective was to develop a consortium of biomarker and aerospace medicine leaders, with expertise in multiple different testing modalities, and with access to robust existing databases, to identify and validate novel strategies to enhance global CVD risk prediction over two time windows: 1) 10-20 years, representing the full career of the astronaut and 2) 2-5 years, representing the planning and operational phase of a manned mission to Mars. The team included many of the leading biomarker and imaging experts in the U.S. This team of collaborative investigators accessed data from multiple existing cohort studies to develop two distinct multi-modality risk prediction tools, one based on 10-year global CVD risk (Aim 2) and one based on 3-year CVD risk (Aim 3). These models evaluated novel testing modalities on top of standard risk factors, including coronary calcium (a measure of the extent of coronary atherosclerosis), multiple blood based protein biomarkers that reflect inflammation, cardiac injury, and cardiac stress, as well as ECG measurements of cardiac hypertrophy and imaging-based assessments of cardiac function. Finally, we proposed an exploratory aim to work with NASA researchers in the Human Research Program to explore the feasibility of transforming the Longitudinal Study of Astronaut Health (LSAH) into a prospective state-of-the-art cohort study of the astronaut corps.

The grant had 2 scientific aims (Aims 2 and 3). Aim 2 has been completed ahead of schedule with a major manuscript published, and Aim 3 analyses are ongoing with promising preliminary results. The primary scientific aims of the grant required pooling of data from large cohort studies. Each of these studies has a unique regulatory structure, scientific proposal system, and approval process. The goals of the first year of funding were to obtain the necessary approvals and data transfer agreements to being the data pooling process. This was accomplished during the first year, when we obtained approval for data transfer from the Dallas Heart Study (DHS), Multiethnic Study of Atherosclerosis (MESA), Atherosclerosis Risk in Communities (ARIC), and the Framingham Heart Study (FHS).

The goal for the second year of funding was to secure data transfer, and to perform harmonization of data elements. This goal was successful accomplished by the end of 2015, ahead of schedule. We then moved to analyses for Aim 2 of the grant. We derived in MESA and validation in DHS a multimodality risk prediction tool that led to marked improvement over traditional risk prediction algorithms both for predicting 10 year atherosclerotic risk as well as global and cause-specific CVD risk. Five screening tests (coronary calcium screening by CT, left ventricular hypertrophy by ECG, and elevated levels of NT-proBNP, hs-cTnT, and hs-CRP) markedly improved global CVD risk prediction compared with standard risk assessment strategies. We created a simple score, consisting of the number of abnormal CVD screening tests. In both MESA and DHS a > 25-fold gradient of risk for CVD was seen across the range of scores. Of particular relevance for NASA, participants with zero abnormal tests results have an extremely low risk for any CVD outcome over 10 years of follow-up. The findings replicate extremely well across the two distinct cohort studies. The final results were presented at the 2017 Human Research Program Investigators Workshop in Galveston, TX, and were published in Circulation in June 2017 (de Lemos et al. A Multimodality Strategy for Cardiovascular Risk Assessment: Performance in Two Population-Based Cohorts. Circulation. 2017; 135:2119-32. PMID: 28360032).

Analyses for Aim 3 are underway presently. These required data pooling due to the smaller number of events over short term follow-up. Preliminary results suggest that the multimodality strategy provides even more robust stratification of short term (3-year) risk compared with the 10-year risk models developed in Aim 2 and recently published.

Aim 4 was an exploratory aim, designed to explore the feasibility of transforming the Longitudinal Study of Astronaut Health into a prospective state-of-the-art cohort study of the astronaut corps. Although several productive discussions were held, we did not resolve whether such an ambitious study is feasible in the future.

The primary findings from this research were recently published (de Lemos et al. A Multimodality Strategy for Cardiovascular Risk Assessment: Performance in Two Population-Based Cohorts. Circulation. 2017; 135:2119-32. PMID: 28360032). The study findings provide strong evidence that a simple strategy including the most promising biomarkers from several different testing modalities substantially improves CVD risk prediction among individuals without known CVD. The tests prospectively selected included 12-lead electrocardiography for assessment of left ventricular hypertrophy (ECG-LVH), coronary artery calcium (CAC) measurement by computed tomography to identify subclinical atherosclerosis, and measurement of N-terminal pro-brain natriuretic peptide (a measure of cardiac neurohormonal activation from cardiac stress), high sensitivity cardiac troponin T (a marker of chronic myocardial injury), and high sensitivity C-reactive protein (a marker of inflammation). These tests were selected because they reflect distinct and relevant pathological processes, multiple reports from population-based studies demonstrate independent associations of these measurements with CVD outcomes, and sufficient data exist from which to generate a priori thresholds to define abnormal test results. A simple score including results from these 5 tests markedly improved the ability to identify who will (and will not) develop cardiovascular disease over a 10-year period. A simple application was developed that allows entry of test results and outputs the predicted risk.

All of the tests studied here are now available clinically in the U.S., following the U.S. FDA approved hs-cTnT assay in May 2017. Thus, the strategy studied and reported is ready for out of the box use by NASA flight surgeons. This strategy would be appropriate for screening of potential astronauts prior to selection as well as periodic (annual for biomarkers and ECG and q 3-5 years for CAC) monitoring while training. The multimodality testing strategy may help to individualize and more efficiently target cardiovascular prevention efforts in primary care. Although current prevention guidelines recommend a risk-based approach only when implementing statin and aspirin therapy, the role for targeting therapy based on risk in primary prevention is likely to expand in the future. The risk models are widely applicable for cardiac screening in primary care clinics or cardiac prevention clinics. The findings from this project will directly inform population screening for CVD, at the same time it provides an approach that is ready immediately for implementation by NASA flight surgeons in selection and monitoring of astronaut candidates.

The primary scientific aims of the grant required combining data from large cohort studies. The goals of the first year of funding were to obtain the necessary approvals and data transfer agreements to begin the data pooling process. This was accomplished during the first year, when we obtained approval for data transfer from the Dallas Heart Study, MESA, and ARIC, the Framingham Heart Study. The goal for the second year of funding was to secure data transfer, construct the consolidated database, and perform harmonization of data elements. This goal was successful accomplished by the end of 2015, ahead of schedule.

In year 3 we completed the analyses and presented and published the results for Aim 2 of our grant. The findings (described in main results in the Task Description section) demonstrate that 5 screening tests markedly improve global CVD risk prediction compared with standard risk assessment strategies. The findings of this study were published in June 2017 in Circulation (de Lemos et al. Circulation. 2017; 135:2119-32. PMID: 28360032) and have received both scientific and lay media attention. The paper already has an Altmetric Score of 105, placing it in the top 5% of all published articles, and includes reporting from 12 news media outlets. The results of these analyses are of direct relevance not only for astronaut screening but also for population screening in routine clinical practice.

The analyses for Aim 3 of the grant are ongoing. Preliminary results are available and demonstrate that the multimodality approach is also of value for 3 year risk prediction. Indeed, the results look even more robust at 3 years than at 10 years.

We did not make substantial progress towards Aim 4, which was an exploratory aim designed to explore the feasibility of transforming the Longitudinal Study of Astronaut Health into a prospective state-of-the-art cohort study of the astronaut corps. We held several meetings, including a face to face meeting in Dallas on May 19, 2015, that included Greg Hundley, and LSAH leadership Associate Director/Chief Scientist. A more dedicated approach will be necessary to get this off the ground if it emerges as a priority for NASA.

Significant progress has been made towards each of the four aims during year 2 of the grant, most notably the two scientific aims (Aims 2 and 3). With regard to Aim 1, the biomarker consortium had several teleconferences to 1) finalize a protocol for treating acute MI (myocardial infarction) in Space and 2) provide recommendations for implementing preliminary findings from this project on current astronaut screening. The primary scientific aims of the grant required pooling of data from large cohort studies. Each of these studies has a unique regulatory structure, scientific proposal system, and approval process. The goals of the first year of funding were to obtain the necessary approvals and data transfer agreements to begin the data pooling process. This was accomplished during the first year, when we obtained approval for data transfer from the Dallas Heart Study (DHS), MESA, Atherosclerosis Risk in Communities Study (ARIC), and the Framingham Heart Study.

The goal for the second year of funding was to secure data transfer, construct the consolidated database, and perform harmonization of data elements. This goal was successful accomplished by the end of 2015, ahead of schedule. Thus, we have already begun in depth data analyses for Aim 2, and will soon begin analyses for Aim 3. The analyses for Aim 2 have yielded very strong preliminary data, which were presented at the 2016 Human Research Program Investigators' Workshop in Galveston, TX, and are now being prepared for publication. These findings, developed in the DHS and replicated in MESA, demonstrate that 5 screening tests (coronary calcium screening by CT, left ventricular hypertrophy by ECG, and elevated levels of NT-proBNP, hs-cTnT, and hs-CRP) markedly improve global CVD risk prediction compared with standard risk assessment strategies. We have created a simple score, consisting of the number of abnormal CVD screening tests. In both DHS and MESA a >25-fold gradient of risk for CVD is seen across the range of scores. Of particular relevance for NASA, participants with zero abnormal tests results have an extremely low risk for any CVD outcome over 10 years of follow-up. The findings replicate extremely well across the two distinct cohort studies. We are pleased that we are ahead of schedule with regard to Aim 2 and on track to begin analyses for Aim 3 soon.

Aim 4 remains exploratory, designed to explore the feasibility of transforming the Longitudinal Study of Astronaut Health (LSAH) into a prospective state-of-the-art cohort study of the astronaut corps. A meeting was held in Dallas on May 19, 2015, that included Greg Hundley, MD, the director of this Aim, and LSAH leadership. This was a productive meeting, but much work remains before determining if such an ambitious study is feasible in the future.

Significant progress has been made towards each of the four aims. The Biomarker Consortium had several teleconferences followed by a face to face meeting at National Space Biomedical Research Institute (NSBRI) Consolidated Research Facility (CRF) on October 8, 2014 to initiate the collaboration needed to operationalize the scientific aims of the grant. The consortium has also contributed, as was designed, to advising NASA leadership regarding cardiovascular safety in space. Members of the Advisory Subcommittee, for example, have contributed towards development of a detailed, step-by-step protocol for the management of myocardial infarction (heart attack) in space. The primary scientific aims of the grant require pooling of data from large cohort studies. Each of these studies has a unique regulatory structure, scientific proposal system, and approval process.

The goals of the first year of funding were to obtain the necessary approvals and data transfer agreements to being the data pooling process. We have obtained approval for data transfer from the Dallas Heart Study, MESA, and Atherosclerosis Risk in Communities Study (ARIC), and have submitted the necessary documents for the Framingham Heart Study. This meets our timelines and positions us well for data transfer early in the second year of funding, which is right on schedule. We have also been working on harmonizing data definitions and data fields between the cohort databases, to facilitate pooling and analysis. Several notable areas of progress have occurred with regard to exploratory Aim 4, which will explore the feasibility of transforming the Longitudinal Study of Astronaut Health (LSAH) into a prospective state-of-the-art cohort study of the astronaut corps. First, Greg Hundley, MD, has been named the coordinator of this Aim. Second, LSAH leadership has expressed interest in moving forward with collaboration towards this Aim. Finally, a meeting is planned in Dallas on May 19, 2015 to further explore collaboration within the LSAH.

Our goal for the first year of funding was to complete the necessary planning, coordination, and infrastructure development to obtain the data for pooling for scientific Aims 2 and 3. So far, we have received approval to obtain MESA and ARIC data. UTSW (University of Texas Southwestern) has approved database agreements for both MESA and ARIC. Framingham database request has been submitted and is pending approval. The next meeting will occur in July, 2015. Our first Face-to-Face Biomarker project meeting was held on 10/8/2014 in Houston at NSBRI Consolidated Research Facility (CRF). Multiple speakers presented followed by comments from specially selected round table experts. Over lunch the meeting split into sub-committee sessions for the NASA Advisory and Research Sub-committee to strategize project startup. Another face-to-face meeting will be held in October of 2015. This meeting will occur annually and include work in progress presentations regarding progress towards Aims 2 and 3, discussion of priorities for NASA and the consortium, planning of new research initiatives, and review of new developments in the biomarker, imaging, and genetics fields. UT Southwestern Medical Center Institutional Review Board approved the project on 10/30/2014.

Next Steps:

1. LSAH meeting in Dallas in May 19, 2015 to meet and leverage the expertise of the biomarker consortium and the collaborative relationships with the Human Research Program at NASA to plan the transformation of the LSAH into a high-yield cohort study to comprehensively study the effects of training and spaceflight on astronaut health. 2. Data transfer from the cohort studies will begin for aims 2 and 3 and data will be pooled across the multiple cohort studies, including Dallas Heart Study, Framingham Heart Study, ARIC, and MESA. 3. Data definition harmonization is in progress and will be completed when the data pooling has been completed. 4. The statistical analysis plan is being developed and will be shared with collaborators and consultants prior to statistical analyses being performed. 5. A second face to face meeting will be held in October 2015.

Our primary objective is to develop a consortium of biomarker and aerospace medicine leaders, with expertise in multiple different testing modalities, and with access to robust existing databases, to identify and validate novel strategies to enhance global CVD risk prediction over two time windows: 1) 10-20 years, representing the full career of the astronaut and 2) 2-5 years, representing the planning and operational phase of a manned mission to Mars. The Biomarker Consortium will provide “real time” advice to NASA on the design of existing screening programs, the status of new biomarkers, and the interpretation of test results. The team of collaborative investigators will pool data from multiple existing cohort studies to develop two distinct multi-modality risk prediction tools, one based on 10-year global CVD risk and one based on 3-year CVD risk. These models will sequentially evaluate novel testing modalities on top of standard risk factors, including coronary calcium (a measure of the extent of coronary atherosclerosis), multiple blood based protein biomarkers that reflect inflammation, cardiac injury and cardiac stress, as well as imaging-based assessments of cardiac function. Finally, we will work directly with NASA researchers in the Human Research Program to explore the feasibility of transforming the Longitudinal Study of Astronaut Health into a prospective state-of-the-art cohort study of the astronaut corps. We will utilize the expertise of the Biomarker Consortium to design a novel program for study of the effects of training and spaceflight on astronaut health.