The National Center for Advancing Translational Sciences’ Intramural Training Program and Fellow Career Outcomes

The translational scientist skill sets are consistent with those currently being emphasized in biomedical research to prepare trainees for various career options. The framework of the National Center for Advancing Translational Sciences intramural research program and the career outcomes of its alumni will be of interest to those involved in the career preparedness of early-career scientists.

Caregiver Status and Diet Quality in Community Dwelling Older Adults

Objectives Prior studies on caregivers have focused mainly on the diet quality of their recipients, especially children. We investigated both cross-sectional and longitudinal associations of caregiver status and diet quality in older adults (mean 53.0 ± 9.0 years). Methods We studied participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (57.7% women, 62% African American) between wave 3 (2009–2013) and wave 4 (2013–2018). Caregiving was assessed at both waves, starting at wave 3. Healthy Eating Index-2010 (HEI2010) score, a measure of diet quality, was assessed from two 24-hour recalls at each wave on both occasions (mean 4.1 years follow-up). Baseline caregiving (at wave 3) was examined in relation to change in HEI between waves 3 and 4. Multivariable linear regression was performed for cross-sectional analysis; mixed-effects regression was performed for longitudinal analyses. Results are expressed as β-coefficients ± standard error of means (β±SE). Results After adjusting for age, sex, race and poverty status, more time spent taking care of grandchildren (N = 2033) was associated with poor diet quality (–1.51 ± 0.55, P = 0.006) in cross-sectional analysis (wave 4 caregiving and wave 4 HEI). However, in a separate cross-sectional analysis (wave 4 only) on dual (caring for both grandchildren and an elderly person) vs. single caregivers (either grandchildren or elderly) (N = 73; 24 men & 49 women) we found no difference in diet quality. The longitudinal analyses (N = 1848) demonstrated that diet quality did not change with caregiving over time for either grandchildren (P = 0.16) or others (not children & grandchildren) (P = 0.88). Overall, women tended to have better quality diet (P < 0.001) than men. Conclusions Among relatively older caregivers, cross-sectional analyses revealed an inverse effect of caregiving with diet quality. Longitudinal research is needed to evaluate the temporal associations of dual caregiving with subsequent diet quality changes over time. Funding Sources The first author is supported by a Postdoctoral Fellowship from the Intramural Research Program (IRP) at the National Institute on Aging (NIA). HANDLS is supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health, grant Z01-AG000513.

0353 Objectively Measured Sleep and Components of Metabolic Syndrome in Well-Functioning Older Adults

Introduction Prior studies tying sleep to metabolic syndrome in older adults have mostly used self-report sleep measures. We investigated the association between actigraphic sleep parameters and metabolic syndrome components in well-functioning older adults. Methods We studied 434 participants in the Baltimore Longitudinal Study of Aging (aged 71.1±12.8 years, 41.4% women) with 6.6±1.0 nights of wrist actigraphy and data on metabolic syndrome components: blood triglyceride (TG) level >150 mg/dL; high density lipoprotein (HDL) <50 mg/dL; and waist circumference (WC) >88.9 cm for women and >101.6 cm for men. Sleep parameters were the primary predictors and metabolic syndrome components the outcomes. Logistic regression was performed, and results are expressed as odds ratio (OR) with p-values. Results After adjusting for age, sex, race and education, higher sleep efficiency (SEFF; per 10%) was associated with a lower odds of high WC (SEFF OR=0.60, p=0.01) and, compared to participants in the intermediate total sleep time tertile (5.5 to 6.8 h), those in the shortest tertile (<5.5 h) had a slightly lower odds of high WC (TST OR=0.98, p=0.02). In adjusted models, greater wake after sleep onset (WASO; per 30 min), greater average wake bout length (WBL; per min), and lower SEFF (per 10%) were associated with a greater odds of poor HDL level (<50 mg/dL) (WASO OR=1.37, p=0.05; WBL OR=1.49, p=0.007; SEFF OR=0.72, p=0.04). After further adjustment for BMI and depressive symptoms, only the association between longer WBL and poor HDL level remained significant (OR=1.48, p=0.01). There were no associations between sleep parameters and TG level. Conclusion Among well-functioning older adults, greater WASO but lower TST and SE are associated with poorer metabolic syndrome components. Longitudinal research is needed to evaluate the temporal associations of objectively measured poor sleep and metabolic syndrome components and evaluate the roles of BMI and depressive symptoms in these associations. Support The first author is supported by a Postdoctoral Fellowship by the Intramural Research Program (IRP) at the National Institute on Aging (NIA). This study was supported in part by National Institute on Aging (NIA) grant R01AG050507, the NIA Intramural Research Program (IRP), and Research and Development Contract HHSN-260-2004-00012C.

Accelerating the Search for Interventions Aimed at Expanding the Health Span in Humans: The Role of Epidemiology

Background Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow. Methods Summary of workshop proceedings from the 2018–2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging. Results Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals. Conclusions Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span.

VIEWPOINT FROM THE INTRAMURAL RESEARCH PROGRAM

Dr. Ferrucci will review accomplishments of the Intramural Research Program and make projections for the future

Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria

ABSTRACTThe 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria. This guideline includes a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on the specific considerations for the different types of loss of function variants, nor did it provide decision-making pathways assimilating information about the variant type, its location within the gene, or any additional evidence for the likelihood of a true null effect. Furthermore, the ACMG/AMP guideline did not take into account the relative strengths for each evidence type and the final outcome of their combinations with respect to PVS1 strength. Finally, criteria specifying the genes for which PVS1 can be used are still missing. Here, as part of the Clinical Genomic Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group’s goal of refining ACMG/AMP criteria, we provide recommendations for applying the PVS1 rule using detailed guidance addressing all the above-mentioned gaps. We evaluate the performance of the refined rule using heterogeneous types of loss of function variants (n = 56) curated by seven disease-specific groups across ten genes. Our recommendations will facilitate consistent and accurate interpretation of predicted loss of function variants.GRANT NUMBERSResearch reported in this publication was supported by the National Human Genome Research Institute (NHGRI) under award number U41HG006834. LGB was supported by the Intramural Research Program of the NHGRI grant number HG200359 09.

Active surveillance criteria in the age of targeted biopsies.

116 Background: Many urologists are now using active surveillance (AS) to manage patients with low-risk prostate cancer. A variety of criteria have been proposed to select patients for AS. A key feature of these criteria is Gleason Group as determined by systematic or “random” biopsies (SB). In this study, we examined the progression of Gleason Group (GG) detected only on SB compared to patients with positive MRI-fusion or “targeted” biopsies (FB). Methods: A prospectively maintained database was queried for all patients who underwent an MRI guided FB and SB from 2007 to 2016 and chose AS as their primary management strategy. Patents with GG 1 or 2 were eligible. Patients were then followed with yearly PSA, exam, MRI and biopsy if warranted. FBs were reviewed to determine GG progression. We divided patients into those who had cancer detected on SB only and those who had positive FBs with or without a positive SB. Results: A total of 162 patients met our criteria with 73 having an initial positive FB and 89 having cancer only on SB and a negative FB. Median follow-up was 27.62 (4.14 – 96.56) and 33.83 (3.45-99.84) months, respectively. The two groups were similar in age (64.49 ± 6.57 vs. 62.08 ± 6.92 years, p = 0.03) and PSA (6.23 ± 4.23 vs. 5.67 ± 3.98 ng/ml, p = 0.39). The median time to pathologic progression for GG 1 patients with initial FB positive was 53.88 months and those with GG 1 on initial SB was 80.81 months (p = 0.003). The median time to pathologic progression for GG 2 patients with initial FB positive was 36.26 months and those with GG 2 on initial SB was 76.01 months (p = 0.099). Conclusions: Previously accepted AS criteria have been based on SBs. However, those patients placed on AS after a positive FB progressed fast than cancer detected only on SB. With MRI and FBs more routinely used in clinical practice, clinicians could use this information from FBs to better stratify and closely monitor patients during AS. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH.

Prediction of adverse pathology after radical prostatectomy on MPMRI in the PIRADS v2 era.

121 Background: As the use of MRI in the diagnosis of prostate cancer (PCa) becomes more established, knowledge of its utility as a prognostic tool is needed to better counsel patients. Here, we aim to assess the ability of mpMRI to predict adverse pathologic factors, such as extraprostatic extension (EPE), seminal vesicle invasion (SVI) or lymph node involvement (LNI) on final pathology after radical prostatectomy (RP). Methods: A prospectively maintained database was queried for all men who underwent mpMRI with current PI-RADS v2 scoring system, MRI/TRUS fusion biopsy (FBx), and RP at our institution (n = 112). Patient demographics, clinical data, imaging and pathology were recorded. Patients were stratified by presence of adverse pathology (AP), defined as EPE, SVI or LNI. Statistical analyses were used to identify mpMRI characteristics predictive of AP using STATA 13. Results: Patients with adverse pathology were middle aged, predominantly caucasian, and significantly higher PSA at baseline (Table 1). Having a PI-RADS 5 lesion was positively associated with AP (adjusted OR = 4.37, 95% CI = 1.20-15.87, p = 0.02). Mean lesion diameter on mpMRI was greater in patients with AP (p < 0.01). However, number of lesions (p = 0.12) and prostate volume on mpMRI (p = 0.88) were not associated with AP. Conclusions: The results of this study demonstrate that features on mpMRI, particularly a PI-RADS score of 5 and large lesion diameter, are predictive of adverse pathology. This information will prove valuable in developing an imaging-based prognostic model in the era of MRI and FBx. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH and NIH Medical Research Scholars Program[Table: see text]