Associate Chief of Staff for Research and Development, VA Palo Alto Health Care System
Chief Medical Officer, Palo Alto Cooperative Studies Program Coordinating Center, Veterans Health Administration (VHA)
Site Co-Director, BD-STEP (VA & NCI Big Data Scientist Training & Enhancement Program), VA Palo Alto Health Care System
Former co-Chair, VISN21 Pharmacy Benefits Management Endocrine Task Force, VHA
Population health, individual precision health, healthcare system management and quality in clinical practice
Molecular/genetic epidemiology, health services, big data health applications, patient centered decision making
Novel scalable clinical/translational study designs and methods to enhance efficiency and effectiveness
Use of electronic health records (EHR) and other data sources
Endocrinology and Metabolism (cardiometabolic diseases and glycemic dysregulation, bone and body composition, cancers, thyroid)
Aging and hormonal/metabolic transitions and dynamics
- Diabetes and Metabolism
- preventive health and risk prediction
- Endocrine aging (cardiometabolism, cancers, bone health, body composition, cognition)
- sex hormone imbalance
- Women’s health
Professor - University Medical Line, Medicine - Endocrinology, Gerontology, & Metabolism
Professor - University Medical Line (By courtesy), Epidemiology and Population Health
Member, Cardiovascular Institute
Member, Stanford Cancer Institute
Member, Wu Tsai Neurosciences Institute
Associate Chief of Staff for Research & Development, VA Palo Alto Health Care System (2018 - Present)
Chief Medical Officer, Palo Alto Cooperative Studies Program Coordinating Center, Veterans Affairs (2016 - Present)
Deputy Associate Chief of Staff for Research & Development, Veterans Affairs Palo Alto Health Care System (2017 - 2018)
Honors & Awards
Merck Seniors Fellow Award, The Endocrine Society (2006)
Young Investigator Award, American Society of Bone Mineral Research (2008)
HHMI-NIH Research Scholar, Howard Hughes Medical Institute - NIH (1997-1998)
Roadmap K12 Faculty Scholar, NIH (2007-2010)
New investigator Award, Rippel Foundation/AFAR (2007-2009)
Boards, Advisory Committees, Professional Organizations
Executive Committee Member, CSP2002: VA-IMPACT (2016 - Present)
Member, Admissions Committee for Stanford's PhD Program (Dept of Pop'n Health and Epidemiology) (2014 - Present)
Member, VA Palo Alto R&D Committee (2015 - 2017)
Co-Site Lead, VA Palo Alto Women's Health Practice-Based Research Network (PBRN) (2014 - 2018)
Board Member, PAVIR (2018 - Present)
Chair, VA VISN21 Endocrine Task Force (2014 - 2018)
Member, VA/NCI BD-STEP Executive Committee (2015 - Present)
Member, VA Palo Alto Center for Clinical Research Advisory Committee (2015 - Present)
Member, CHS Aging Working Group (2016 - Present)
Member, The Endocrine Society (2002 - Present)
Member, Society for Epidemiologic Research (2008 - Present)
Board Certification: American Board of Internal Medicine, Endocrinology, Diabetes and Metabolism (2021)
M.A. & B.A. (joint), Harvard University, Biological Sciences (1994)
MD, Harvard Medical School, Medicine (1999)
Ph.D., Stanford Univ. School of Medicine, Epidemiology
Residency: Stanford University Internal Medicine Residency (2001) CA
Fellowship: UCSF Endocrinology Fellowship (2005) CA
Fellowship, University of California, San Francisco at Mt. Zion (UCSF), Women's Health (2004)
Board Certification: American Board of Internal Medicine, Internal Medicine (2004)
Assessment, Testing and Measurement
Curriculum and Instruction
Diversity and Identity
Equity in Education
Leadership and Organization
Parents and Family Issues
Race and Ethnicity
Technology and Education
Current Research and Scholarly Interests
I am a clinical scientist (PhD epidemiology), endocrinologist, and CMO at VAPA Cooperative Studies Program Coordinating Center. My group is interested in pattern and prediction mapping along the life-course of interventions/outcomes and how healthcare system can positively impact health longitudinally. We use novel molecular epi, 'big' data like EHRs with advanced new designs/methods/technologies. We use both research based longitudinal cohorts, such as WHI, SWAN, CHS, SHS, plus clinical based electronic health records (EHR) 'big data'. We are interested in novel effective patient-clinician shared decision making and enhancing clinical data collection and analytics to drive value in evidence based health care practices.
My group strives for a bidirectional learning healthcare system with close partnerships among research activities, quality and process improvement, and clinical operations of health care system.
My group includes clinicians, biostatisticians, epidemiologists, biochemists, engineers, informaticians, data managers, and health services researchers. We lead efforts in:
1. Leveraging electronic health information to advance precision medicine (LEAP) using the longest running large VA EHR System and symbiotic conduct of clinical trials and observational cohorts using EHR (CSP#2012).
2. Stanford’s Health Information Exchange efforts (Diabetes Sandbox in Solano County) with Stanford’s Center for Population Health Sciences.
3. National VA's Million Veteran Program (MVP) -- large genetic epidemiology study of a million Veterans, with genetic/genomic data and EHR data.
4. U.S.’s All of Us initiative (formerly, Precision Medicine Initiative)
5. Training future ‘big data’ scientists in health care, emphasizing the need for clinical and clinician insights, epidemiology, biostatistics, health services, along with informatics, and molecular sciences. See VA-NCI BD-STEP.
As CMO at the VA's Cooperative Studies Program Coordinating Center at Palo Alto, I provide clinical and clinical research leadership for the Center, which sponsors and coordinates large multi-site clinical research studies. We innovate on novel and more efficient research designs, methods, and conduct to optimize positive impact on the healthcare system.
These interests cut across multiple complex chronic diseases, aging, & critical lifespan stages, for better insights to etiology & enhanced health care and patient decision making. Chronic conditions include cardiometabolic diseases, fractures, hormone-related cancers, cognitive decline.
I have worked in academe and Kaiser Permanente (East Bay; TPMG and Division of Research in Oakland).
Huge Thanks to participants of research studies, trainees, research collaborators, supporters/funders of research and operations, grants administrators, and institutional support locally & nationally (e.g., NIH, VA, Foundations).
See PhD program in Epidemiology and Clinical Research (Dept of Epidemiology and Population Health); Center for Population Health Sciences; Palo Alto VA Health Care System; VA Cooperative Studies Program Coordinating Center
Independent Studies (9)
- Directed Reading in Epidemiology
EPI 299 (Aut, Win, Spr, Sum)
- Directed Reading in Health Research and Policy
HRP 299 (Spr)
- Directed Reading in Medicine
MED 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Medicine
MED 280 (Aut, Win, Spr, Sum)
- Graduate Research
EPI 399 (Aut, Win, Spr, Sum)
- Graduate Research
MED 399 (Aut, Win, Spr, Sum)
- Medical Scholars Research
MED 370 (Aut, Win, Spr, Sum)
- Undergraduate Research
EPI 199 (Aut, Win, Spr, Sum)
- Undergraduate Research
MED 199 (Aut, Win, Spr, Sum)
- Directed Reading in Epidemiology
Master's Program Advisor
A translational genomics approach identifies IL10RB as the top candidate gene target for COVID-19 susceptibility.
NPJ genomic medicine
2022; 7 (1): 52
Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes that reduce COVID-19 host susceptibility is a critical next step. Using a translational genomics approach that integrates COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX), and perturbagen signatures, we identified IL10RB as the top candidate gene target for COVID-19 host susceptibility. In a series of validation steps, we show that predicted GReX upregulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes and that in vitro IL10RB overexpression is associated with increased viral load and activation of disease-relevant molecular pathways.
View details for DOI 10.1038/s41525-022-00324-x
View details for PubMedID 36064543
Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
View details for DOI 10.1038/s41591-022-01891-3
View details for PubMedID 35915156
A Population-Level Analysis of the Protective Effects of Androgen Deprivation Therapy Against COVID-19 Disease Incidence and Severity.
Frontiers in medicine
2022; 9: 774773
Background: The incidence and severity of coronavirus disease 19 (COVID-19) is substantially higher in men. Sex hormones may be a potential mechanism for differences in COVID-19 outcome in men and women. We hypothesized that men treated with androgen deprivation therapy (ADT) have lower incidence and severity of COVID-19.Methods: We conducted an observational study of male Veterans treated in the Veterans Health Administration from February 15th to July 15th, 2020. We developed a propensity score model to predict the likelihood to undergo Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing. We performed multivariable logistic regression modeling adjusted with inverse probability weighting to examine the relationship between ADT and COVID-19 incidence. We conducted logistic regression analysis among COVID-19 patients to test the association between ADT and COVID-19 severity.Results: We identified a large cohort of 246,087 VA male patients who had been tested for SARS-CoV-2, of whom 3,057 men were exposed to ADT, and 36,096 men with cancer without ADT. Of these, 295 ADT patients and 2,427 cancer patients not on ADT had severe COVID-19 illness. In the primary, propensity-weighted comparison of ADT patients to cancer patients not on ADT, ADT was associated with decreased likelihood of testing positive for SARS-CoV-2 (adjusted OR, 0.88 [95% CI, 0.81-0.95]; p = 0.001). Furthermore, ADT was associated with fewer severe COVID-19 outcomes (OR 0.72 [95% CI 0.53-0.96]; p = 0.03).Conclusion: ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Testosterone and androgen receptor signaling may confer increased risk for SARS-CoV-2 infection and contribute to severe COVID-19 pathophysiology in men.
View details for DOI 10.3389/fmed.2022.774773
View details for PubMedID 35602518
Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.
We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.
View details for DOI 10.1038/s41588-020-0637-y
View details for PubMedID 32541925
Genome-wide association study of peripheral artery disease in the Million Veteran Program.
Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.
View details for DOI 10.1038/s41591-019-0492-5
View details for PubMedID 31285632
- Patterns of Cardiometabolic Health as Midlife Women Transition to Menopause: A Prospective Multiethnic Study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2019; 104 (5): 1404–12
Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program.
The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n>600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).
View details for PubMedID 30275531
Triglyceride and HDL-C Dyslipidemia and Risks of Coronary Heart Disease and Ischemic Stroke by Glycemic Dysregulation Status: The Strong Heart Study.
High triglyceride (TG) levels and low HDL cholesterol (HDL-C) levels are risk factors for cardiovascular disease. It is unclear whether this relationship depends on glycemic dysregulation, sex, or LDL cholesterol (LDL-C) level.We studied 3,216 participants (40% men, 41% with diabetes) who were free of cardiovascular disease at baseline in a community-based, prospective cohort of American Indians (median follow-up 17.7 years). Cox models estimated hazard ratios (HRs) and 95% CIs for incident ischemic stroke and coronary heart disease (CHD) in relation to combined TG and HDL-C status, where a fasting TG level ≥150 mg/dL was "high" and a fasting HDL-C level <40 mg/dL for men (<50 mg/dL for women) was "low." Models included age, sex, BMI, smoking, diabetes, fasting LDL-C level, antihypertensive medications, physical activity, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio.Participants with high TG and low HDL levels had a 1.32-fold greater HR (95% CI 1.06-1.64) for CHD than those with normal TG and normal HDL levels. It was observed in participants with diabetes, but not in those without diabetes, that high TG plus low HDL levels were associated with a 1.54-fold greater HR (95% CI 1.15-2.06) for CHD (P value for interaction = 0.003) and a 2.13-fold greater HR (95% CI 1.06-4.29) for stroke (P value for interaction = 0.060). High TG and low HDL level was associated with CHD risk in participants with an LDL-C level of ≥130 mg/dL, but this was not observed in those participants with lower LDL-C levels. Sex did not appear to modify these associations.Adults with both high TG and low HDL-C, particularly those with diabetes, have increased risks of incident CHD and stroke. In particular, those with an LDL-C level ≥130 mg/dL may have an increased risk of incident stroke.
View details for DOI 10.2337/dc16-1958
View details for PubMedID 28122840
View details for PubMedCentralID PMC5360283
- Subclinical thyroid dysfunction and risk of hip fracture in older adults ARCHIVES OF INTERNAL MEDICINE 2010; 170
A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation.
Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P<5 * 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n=44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P<6.5 * 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.
View details for DOI 10.1038/s41588-022-01078-z
View details for PubMedID 35654975
A GENOME-WIDE ASSOCIATION STUDY OF CHRONIC ALT-BASED NAFLD IN THE MILLION VETERAN PROGRAM WITH HISTOLOGICAL AND RADIOLOGICAL VALIDATION
WILEY. 2021: 6A-7A
View details for Web of Science ID 000707188000010
A statistical quality assessment method for longitudinal observations in electronic health record data with an application to the VA million veteran program.
BMC medical informatics and decision making
2021; 21 (1): 289
To describe an automated method for assessment of the plausibility of continuous variables collected in the electronic health record (EHR) data for real world evidence research use.The most widely used approach in quality assessment (QA) for continuous variables is to detect the implausible numbers using prespecified thresholds. In augmentation to the thresholding method, we developed a score-based method that leverages the longitudinal characteristics of EHR data for detection of the observations inconsistent with the history of a patient. The method was applied to the height and weight data in the EHR from the Million Veteran Program Data from the Veteran's Healthcare Administration (VHA). A validation study was also conducted.The receiver operating characteristic (ROC) metrics of the developed method outperforms the widely used thresholding method. It is also demonstrated that different quality assessment methods have a non-ignorable impact on the body mass index (BMI) classification calculated from height and weight data in the VHA's database.The score-based method enables automated and scaled detection of the problematic data points in health care big data while allowing the investigators to select the high-quality data based on their need. Leveraging the longitudinal characteristics in EHR will significantly improve the QA performance.
View details for DOI 10.1186/s12911-021-01643-2
View details for PubMedID 34670548
Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program.
2020; 15 (8): e0237430
Given ongoing challenges in non-invasive non-alcoholic liver disease (NAFLD) diagnosis, we sought to validate an ALT-based NAFLD phenotype using measures readily available in electronic health records (EHRs) and population-based studies by leveraging the clinical and genetic data in the Million Veteran Program (MVP), a multi-ethnic mega-biobank of US Veterans.MVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for women without other causes of liver disease were compared to controls with normal ALT. Genetic variants spanning eight NAFLD risk or ALT-associated loci (LYPLAL1, GCKR, HSD17B13, TRIB1, PPP1R3B, ERLIN1, TM6SF2, PNPLA3) were tested for NAFLD associations with sensitivity analyses adjusting for metabolic risk factors and alcohol consumption. A manual EHR review assessed performance characteristics of the NAFLD phenotype with imaging and biopsy data as gold standards. Genetic associations with advanced fibrosis were explored using FIB4, NAFLD Fibrosis Score and platelet counts.Among 322,259 MVP participants, 19% met non-invasive criteria for NAFLD. Trans-ethnic meta-analysis replicated associations with previously reported genetic variants in all but LYPLAL1 and GCKR loci (P<6x10-3), without attenuation when adjusted for metabolic risk factors and alcohol consumption. At the previously reported LYPLAL1 locus, the established genetic variant did not appear to be associated with NAFLD, however the regional association plot showed a significant association with NAFLD 279kb downstream. In the EHR validation, the ALT-based NAFLD phenotype yielded a positive predictive value 0.89 and 0.84 for liver biopsy and abdominal imaging, respectively (inter-rater reliability (Cohen's kappa = 0.98)). HSD17B13 and PNPLA3 loci were associated with advanced fibrosis.We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.
View details for DOI 10.1371/journal.pone.0237430
View details for PubMedID 32841307
IMPLEMENTATION OF A DISTRIBUTED RESEARCH NETWORK VIRTUAL DATA WAREHOUSE FOR A MULTI-CENTER OBSERVATIONAL STUDY
LIPPINCOTT WILLIAMS & WILKINS. 2019: 925–26
View details for Web of Science ID 000619263200433
- Association of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study BONE 2019; 120: 321–26
Social Relationships and Risk of Type 2 Diabetes Among Postmenopausal Women.
The journals of gerontology. Series B, Psychological sciences and social sciences
We examined whether social relationship variables (social support, social strain, social network size, and stressful life events) were associated with risk of developing type 2 diabetes among postmenopausal women.139,924 postmenopausal women aged 50-79 years without prevalent diabetes at baseline were followed for a mean of 14 years. 19,240 women developed diabetes. Multivariable Cox proportional hazard models tested associations between social relationship variables and diabetes incidence after consideration of demographics, depressive symptoms, and lifestyle behaviors. We also examined moderating effects of obesity and race/ethnicity, and we tested whether social variable associations were mediated by lifestyle or depressive symptoms.Compared with the lowest quartile, women in the highest social support quartile had lower risk of diabetes after adjusting for demographic factors, health behaviors, and depressive symptoms (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.89-0.97). Social strain (HR = 1.09, 95% CI = 1.04-1.13) and stressful life events (HR = 1.10, 95% CI = 1.05-1.15) were associated with higher diabetes risks. The association between diabetes and social strain was stronger among African American women. Social relationship variables had direct relationships to diabetes, as well as indirect effects partially mediated by lifestyle and depressive symptoms.Social support, social strain, and stressful life events were associated with diabetes risk among postmenopausal women independently of demographic factors and health behaviors. In addition to healthy behaviors such as diet and physical activity, healthy social relationships among older women may be important in the prevention of diabetes.
View details for DOI 10.1093/geronb/gbz047
View details for PubMedID 31112615
Association of APOL1 Risk Alleles with Cardiovascular Disease in African Americans in the Million Veteran Program.
Approximately 13% of African-American individuals carry two copies of the APOL1 risk alleles G1 or G2, which are associated with 1.5-2.5 fold increased risk of chronic kidney disease (CKD). There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease, independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease (CAD), peripheral artery disease (PAD), and stroke among African American individuals in the Million Veteran Program (MVP).We performed a time-to-event analysis of retrospective electronic health record (EHR) data using Cox proportional hazard and competing risks Fine and Gray sub-distribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident CAD amongst individuals without CKD during the 12.5 year follow up period. Separately we analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association.Among 30,903 African American MVP participants, 3,941 (13%) carried the two APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with two risk alleles had slightly higher risk of developing CAD compared to those with no risk alleles (Hazard Ratio (HR): 1.11, 95% Confidence Interval (CI): 1.01-1.21, p=0.039). Similarly, modest associations were identified with incident stroke (HR: 1.20, 95% CI: 1.05-1.36, p=0.007) and PAD (HR: 1.15, 95% CI:1.01-1.29, p=0.031). When modeling both cardiovascular and renal outcomes, APOL1 was strongly associated with incident renal disease, while no significant association with the cardiovascular disease endpoints could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with cardiovascular disease subsets.APOL1 risk variants display a modest association with cardiovascular disease and this association is likely mediated by the known APOL1 association with CKD.
View details for DOI 10.1161/CIRCULATIONAHA.118.036589
View details for PubMedID 31337231
- Unplanned Hospital Encounters After Endoscopic Retrograde Cholangiopancreatography in 3 Large North American States GASTROENTEROLOGY 2019; 156 (1): 119-+
- 27-Hydroxycholesterol, an Endogenous SERM, and Risk of Fracture in Postmenopausal Women: A Nested Case-Cohort Study in the Women's Health Initiative JOURNAL OF BONE AND MINERAL RESEARCH 2019; 34 (1): 59–66
Effect of Genetic Variation in Loss of Function Variants in PCSK9 on Atherosclerotic Vascular Disease
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000528619403432
Associations of Joint Trajectories of Appendicular Lean Mass and Grip Strength with Risk of Non-Spine Fractures
WILEY. 2018: 434
View details for Web of Science ID 000450475402127
Microvascular Complications and Risk of Incident Hip Fracture in Type 2 Diabetes: A National Cohort
WILEY. 2018: 103
View details for Web of Science ID 000450475400312
Validation of Established Genetic Loci for Non-Alcoholic Fatty Liver Disease (NAFLD) and Their Contribution to NAFLD Phenotype in 194,457 Individuals Enrolled in the Million Veteran Program
WILEY. 2018: 210A–211A
View details for Web of Science ID 000446020500351
Incidence of Second Malignancy in Patients with Papillary Thyroid Cancer from Surveillance, Epidemiology, and End Results 13 Dataset.
Journal of thyroid research
2018; 2018: 8765369
Increased risk of second primary malignancy (SPM) in papillary thyroid cancer (PTC) has been reported. Here, we present the most updated incidence rates of second primary malignancy from original diagnosis of PTC by using the data from the Surveillance, Epidemiology, and End Results. In this cohort, 3,200 patients developed SPM, a substantially higher number than in the reference population of 2,749 with observed to expected ratio (O/E) of 1.16 (95% CI; 1.12-1.21). Bone and joint cancer had the highest O/E ratio of 4.26 (95% confidence interval [CI] 2.33-7.15) followed by salivary gland (O/E 4.15; 95% CI 2.76-6.0) and acute lymphocytic leukemia (O/E 3.98; 95% CI 2.12-6.8). Mean age at the diagnosis of SPM was 64.4 years old. Interestingly, incidence of colorectal cancer was lower in thyroid cancer survivors compared to general population (large intestine O/E 0.3; 95% CI 0.06-0.88, rectum O/E 0.6; 95% CI 0.41-0.85); however, this was not observed in patients who underwent radiation therapy. The incidence of SPM at all sites was higher during 2000-2012 compared to 1992-1999 (O/E 1.24 versus 1.10). Surprisingly, patients with micropapillary cancer had higher incidence of SPM than counterparts with a larger tumor in radiation group (O/E of 1.40 versus 1.15). O/E of all cancers were higher in males compared to females with O/E of 1.41 versus 1.17 during the period of 2000-2012. Diagnosis of PTC before age 50, especially at age 30-34, was associated with higher incidence of overall SPM (age 30-34; O/E 1.43; 95% CI; 1.19-1.71). Efficient monitoring strategies that include age at the time of thyroid cancer diagnosis, exposure to radiation, gender, and genetic susceptibility may successfully detect SPM earlier in the disease course. This is especially important given the excellent prognosis of the initial thyroid cancer itself.
View details for DOI 10.1155/2018/8765369
View details for PubMedID 30046434
View details for PubMedCentralID PMC6038658
A Temporal Examination of Platelet Counts as a Predictor of Prognosis in Lung, Prostate, and Colon Cancer Patients.
2018; 8 (1): 6564
Platelets, components of hemostasis, when present in excess (>400 K/μL, thrombocytosis) have also been associated with worse outcomes in lung, ovarian, breast, renal, and colorectal cancer patients. Associations between thrombocytosis and cancer outcomes have been made mostly from single-time-point studies, often at the time of diagnosis. Using laboratory data from the Department of Veterans Affairs (VA), we examined the potential benefits of using longitudinal platelet counts in improving patient prognosis predictions. Ten features (summary statistics and engineered features) were derived to describe the platelet counts of 10,000+ VA lung, prostate, and colon cancer patients and incorporated into an age-adjusted LASSO regression analysis to determine feature importance, and predict overall or relapse-free survival, which was compared to the previously used approach of monitoring for thrombocytosis near diagnosis (Postdiag AG400 model). Temporal features describing acute platelet count increases/decreases were found to be important in cancer survival and relapse-survival that helped stratify good and bad outcomes of cancer patient groups. Predictions of overall and relapse-free survival were improved by up to 30% compared to the Postdiag AG400 model. Our study indicates the association of temporally derived platelet count features with a patients' prognosis predictions.
View details for PubMedID 29700384
Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study.
2018; 116: 239–47
Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear.We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY.We analyzed baseline (1989-1993) blood samples from 933 men ≥65 years of age from the prospective Cardiovascular Health Study. Particulate matter ≤10 μm (PM10), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR.Increased PM10 was associated with mLOY, namely decreased mLRR (p-trend = 0.03). Compared with the lowest tertile (≤28.5 μg/m3), the middle (28.5-31.0 μg/m3; β = -0.0044, p = 0.09) and highest (≥31 μg/m3; β = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (β = -0.00035, p = 0.06) and smoking pack-years (β = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants.PM10 may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.
View details for PubMedID 29698900
- Metabolic Obesity Phenotypes and Risk of Breast Cancer in Postmenopausal Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION 2017; 26 (12): 1730–35
Older Men with Decreasing Hemoglobin Have a Higher Risk of Future Hip Fracture: The Cardiovascular Health Study
WILEY. 2017: S98–S99
View details for Web of Science ID 000418869201100
Older Men with Anemia Have Increased Fracture Risk Independent of Bone Mineral Density.
journal of clinical endocrinology and metabolism
Extreme low hemoglobin values have been linked to increased risk of fracture at different sites in a small number of studies. However, careful assessment of a clinically relevant cutoff for anemia and cross sectional and longitudinal bone mineral density (BMD) measures is lacking.To determine whether men with anemia were at increased risk of fracture after accounting for bone density and bone loss.Cross-sectional analysis (at visit 3) and prospective analysis (from baseline to visit 3) in the Osteoporotic Fractures in Men (MrOS), a multi-site longitudinal cohort study.6 communities in the U.S.3632 community-dwelling men (>65 years) in MrOS at baseline (2000-2002) who were able to walk without assistance and did not have a hip replacement or fracture and had complete blood counts (CBCs) at visit 3 (2007-2009).Adjudicated spine and non-spine fractures during a median 7.2 years follow up.Analytic baseline characteristics associated with fractures or anemia (Hgb < 12g/dL) were included into multivariable models. Anemia was associated with increased risk of any (HR 1.67; 95% CI 1.26-2.21) and non-spine (HR 1.70; 95% CI 1.25-2.31) fractures. A model including change in BMD slightly attenuated the association with any (HR 1.60; 95% CI 1.20-2.13) and non-spine fractures (HR 1.57; 95% CI 1.14-2.15). Including absolute BMD did not significantly alter the anemia-fracture association. Anemia was not associated with spine fracture.Community-dwelling older men with anemia had a 57-72% increase in non-spine fracture risk independent of bone density and bone loss over time.
View details for DOI 10.1210/jc.2017-00266
View details for PubMedID 28368469
Bone Density Loss Is Associated With Blood Cell Counts
JOURNAL OF BONE AND MINERAL RESEARCH
2017; 32 (2): 212-220
Hematopoiesis depends on a supportive microenvironment. Preclinical studies in mice have demonstrated that osteoblasts influence the development of blood cells, particularly erythrocytes, B lymphocytes, and neutrophils. However, it is unknown whether osteoblast numbers or function impact blood cell counts in humans. We tested the hypothesis that men with low BMD or greater BMD loss have decreased circulating erythrocytes and lymphocytes and increased myeloid cells. We performed a cross-sectional analysis and prospective analysis in the Osteoporotic Fractures in Men (MrOS), a multi-site longitudinal cohort study. 2571 community-dwelling men (>65 years) who were able to walk without assistance, did not have a hip replacement or fracture and had complete blood counts (CBCs) at the third study visit were analyzed. Multivariable (MV)-adjusted logistic regression estimated odds of white blood cell subtypes (highest and lowest quintile vs middle), and anemia (clinically defined) associated with BMD by DXA scan (at visit 3), annualized percent BMD change (baseline to visit 3), and high BMD loss (>0.5%/year, from baseline to visit 3) at the femoral neck (FN) and total hip (TH). MV adjusted models included age, BMI, cancer history, smoking status, alcohol intake, corticosteroid use, self-reported health, thiazide use and physical activity. At visit 3 greater TH BMD loss (per standard deviation) was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Annualized BMD loss of >0.5% was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Similar results were observed for FN BMD regarding anemia and lymphocytes. We concluded that community-dwelling older men with declining hip BMD over about 7 years had increased risks of anemia, lower lymphocyte count, and higher neutrophil count, consistent with pre-clinical studies. Bone health and hematopoiesis may have greater interdependency than previously recognized. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/jbmr.3000
View details for Web of Science ID 000396935300004
Evidence for use of Teriparatide in Spinal Fusion Surgery in Osteoporotic Patients.
Osteoporosis is defined as a bone mineral density (BMD) less than 2.5 standard deviations below the mean BMD at peak bone mass, or the presence of a fragility fracture. In the setting of osteoporosis, early hardware loosening is thought to cause decreased spinal fusion rates. The two mainstays of osteoporosis treatment are bisphosphonates and Teriparatide. Teriparatide, a form of synthetic parathyroid hormone (PTH), is an anabolic agent that increases osteoblast activity and, thereby, bone mass. Preclinical studies in animal models show that Teriparatide increases spinal fusion rates. Early clinical studies show that teriparatide both increases spinal fusion rates and decreases hardware loosening in the setting of postmenopausal osteoporosis. Ongoing additional trials will help formulate preoperative screening recommendations, determine the optimal duration of pre- and post-operative Teriparatide treatment, and investigate its utility in men.
View details for DOI 10.1016/j.wneu.2016.11.135
View details for PubMedID 27923758
Prevalence and risk of fracture diagnoses in women across the adult life span: a national cross-sectional study.
2016; 27 (11): 3177-3186
In a national sample of women veterans, the rate of lower limb fracture diagnosis was the highest across ages 18-74 years; rates of fracture diagnosis of other skeletal sites peaked in women aged 75+. Women with two or more primary care visits or mental healthcare visits had elevated odds of fracture diagnosis.We assessed the prevalence and healthcare utilization characteristics associated with a diagnosis of any fracture in women of all adult ages within the Veterans Health Administration.In 344,488 women during fiscal year 2012, logistic regression models for fracture diagnosis included age, race/ethnicity, residence, number of primary care visits, number of mental healthcare visits, and degree of service-connected disability.Lower limb fracture diagnosis was most prevalent across ages 18-74 years and peaked in women aged 55-64 years. In women aged 75+, the prevalence rates of fracture diagnosis at the hip (102, 95 % CI = 88-115 per 10,000 women), upper limb (100, 95 % CI = 87-114 per 10,000 women), and lower limb (84, 95 % CI = 72-97 per 10,000 women) were the highest. Fractures at other skeletal sites peaked in those aged 75+ years. Black women had the lowest odds of a fracture diagnosis, followed by Asian/Pacific Islander and Hispanic women compared to non-Hispanic White (by 25-51 %, P < 0.05). Having two or more primary care visits or any mental health visit was each associated with an increased risk. Women with five or more primary care visits had a 3.36-fold (95 % CI = 3.02-3.75) greater odds than those with no such visit, and separately, women with five or more mental health visits had a 1.51-fold (95 % CI = 1.43-1.60) greater odds. Women with a fracture diagnosis had higher overall healthcare costs than those without (P < 0.001).Prevalence of fracture diagnosis differed by age, race/ethnicity, and skeletal site of fracture. Fracture diagnosis may identify women veterans with greater overall healthcare needs.
View details for PubMedID 27349559
Environmental tobacco smoke and risk of late-diagnosis incident fibroids in the Study of Women's Health across the Nation (SWAN).
Fertility and sterility
2016; 106 (5): 1157-1164
To assess the longitudinal relationship of environmental tobacco smoke (ETS) exposure during midlife, and its interaction with active smoking, with the risk of late-diagnosis incident uterine fibroids during the menopausal transition.Thirteen-year prospective cohort study.Not applicable.Community-based, multiracial/ethnic cohort of 2,575 women aged 42 to 52 years at baseline, undergoing the menopausal transition.Questionnaire and blood draws.Discrete-time proportional odds models were used to estimate the conditional odds ratio (OR) and 95% confidence interval (CI) of incident fibroids, adjusted for menopausal status, race/ethnicity, study site, age, education, estradiol levels, sex hormone use, body mass index, timing of blood draw, age at menarche, alcohol use, and smoking status and pack-years.As part of SWAN, at each near-annual study visit, ETS exposure, smoking, and fibroid occurrence were self-reported via questionnaire, and blood draws were collected. Women who were exposed to ETS (≥1 person-hour/week) had 1.28 (95% CI, 1.03, 1.60) times the adjusted odds of incident fibroids in the ensuing year compared the unexposed. The odds were elevated in never smokers (adjusted OR 1.34; 95% CI, 1.06, 1.70) and former smokers (adjusted OR 2.57; 95% CI, 1.05, 7.23).In midlife, ETS exposure was associated with an increased risk of late-diagnosis incident fibroids in women undergoing the menopausal transition.
View details for DOI 10.1016/j.fertnstert.2016.06.025
View details for PubMedID 27445196
View details for PubMedCentralID PMC5048612
Triglyceride Levels and Fracture Risk in Midlife Women: Study of Women's Health Across the Nation (SWAN).
The Journal of clinical endocrinology and metabolism
2016; 101 (9): 3297-305
Unfavorable lipid levels contribute to cardiovascular disease and may also harm bone health.Our objective was to investigate relationships between fasting plasma lipid levels and incident fracture in midlife women undergoing the menopausal transition.This was a 13-year prospective, longitudinal study of multiethnic women in five US communities, with near-annual assessments.At baseline, 2062 premenopausal or early perimenopausal women who had no history of fracture were included.Fasting plasma total cholesterol, triglycerides (TG), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol at baseline and follow-up visits 1 and 3-7.Incident nontraumatic fractures 1) 2 or more years after baseline, in relation to a single baseline level of lipids; and 2) 2-5 years later, in relation to time-varying lipid levels. Cox proportional hazards modelings estimated hazard ratios and 95% confidence interval (CI).Among the lipids, TG levels changed the most, with median levels increased by 16% during follow-up. An increase of 50 mg/dl in baseline TG level was associated with a 1.1-fold increased hazards of fracture (adjusted hazard ratio, 1.11; 95% CI, 1.04-1.18). Women with baseline TG higher than 300 mg/dl had an adjusted 2.5-fold greater hazards for fractures (95% CI, 1.13-5.44) than women with baseline TG lower than 150 mg/dl. Time-varying analyses showed a comparable TG level-fracture risk relationship. Associations between total cholesterol, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol levels and fractures were not observed.Midlife women with high fasting plasma TG had an increased risk of incident nontraumatic fracture. Secondary Abstract: Midlife women with fasting plasma triglyceride (TG) of at least 300 mg/dl had 2.5-fold greater hazards of fracture in 2 years later and onward, compared to those with TG below 150 mg/dl, in a multiethnic cohort. Time-varying analyses revealed comparable results.
View details for DOI 10.1210/jc.2016-1366
View details for PubMedID 27294327
View details for PubMedCentralID PMC5010577
- Circulating Sex Hormones and Risk of Uterine Fibroids: Study of Women's Health Across the Nation (SWAN) JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2016; 101 (1): 122-129
Subclinical Thyroid Dysfunction and Hip Fracture and Bone Mineral Density in Older Adults: The Cardiovascular Health Study
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2014; 99 (8): 2657-2664
Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear.We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults.A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex.No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95% CI 0.52-1.21 for two time points] or men (HR 1.27, 95% CI 0.82-1.95 for a single and HR 1.09, 95% CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95% CI 0.55-2.25 in women and HR 1.78, 95% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites.Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidism and hip fracture risk or BMD in older men and women. Additional data are needed to improve the precision of estimates for subclinical hyperthyroidism and in men.
View details for DOI 10.1210/jc.2014-1051
View details for Web of Science ID 000342341200036
View details for PubMedCentralID PMC4121038
Subclinical Hypothyroidism, Weight Change, and Body Composition in the Elderly: The Cardiovascular Health Study
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2014; 99 (4): 1220-1226
Subclinical hypothyroidism is common in the elderly, yet its relationship with weight and body composition is unclear.We examined the relationship between subclinical hypothyroidism and weight change and body composition in older adults.A total of 427 subclinically hypothyroid and 2864 euthyroid U.S. individuals ≥65 years old enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of 6-year weight change were performed, compared by thyroid status. A cross-sectional analysis of thyroid status and body composition was performed in a subset of 1276 participants who had dual-energy x-ray absorptiometry scans. Models were risk factor-adjusted and stratified by sex.Overall, participants lost weight during follow-up (-0.38 kg/y in men, -0.37 kg/y in women). Subclinical hypothyroidism, when assessed at a single time point or persisting over 2 years, was not associated with a difference in weight change compared with euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared with euthyroidism. A TSH level 1 mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51-kg higher baseline weight in women only (P < .001) but not with weight change in either sex. A 1 ng/dL higher free T4 level was associated with lower baseline weight and 0.32 kg/y greater weight loss in women only (P = .003). Baseline weight and weight change did not differ by T3 levels.Our data do not support a clinically significant impact of subclinical hypothyroidism on weight status in the elderly.
View details for DOI 10.1210/jc.2013-3591
View details for PubMedID 24432998
Age, body mass, usage of exogenous estrogen, and lifestyle factors in relation to circulating sex hormone-binding globulin concentrations in postmenopausal women.
2014; 60 (1): 174-185
Circulating concentrations of sex hormone-binding globulin (SHBG) have been associated with cardiovascular diseases, type 2 diabetes, metabolic syndrome, and hormone-dependent cancers; however, correlates of SHBG concentrations are not well understood.We comprehensively investigated correlates of SHBG concentrations among 13 547 women who participated in the Women's Health Initiative and who had SHBG measurements. We estimated study- and ethnicity-specific associations of age, reproductive history, usage of exogenous estrogen, body mass index (BMI), and lifestyle factors such as physical activity, smoking, alcohol consumption, coffee intake, and dietary factors with SHBG concentrations. These estimates were pooled using random-effects models. We also examined potential nonlinear associations using spline analyses.There was no significant ethnic difference in the age-adjusted mean concentrations of SHBG. Age, exogenous estrogen use, physical activity, and regular coffee intake were positively associated with SHBG concentrations, whereas BMI was inversely associated with SHBG concentrations after adjustment for potential confounding factors. Similar patterns were observed among both ever users and never users of exogenous estrogen. The spline analysis indicated nonlinear relations of regular intake of coffee, age, and BMI with SHBG concentrations. Two or more cups/day of regular coffee consumption and age of 60 years or older were associated with higher SHBG concentrations; the inverse BMI-SHBG relation was especially strong among women whose BMI was below 30.In this large sample of postmenopausal women, age, exogenous estrogen use, physical activity, regular coffee intake, and BMI were significant correlates of SHBG concentrations, presenting potential targets for interventions.
View details for DOI 10.1373/clinchem.2013.207217
View details for PubMedID 24048437
Sex Hormone Levels and Risk of Breast Cancer With Estrogen Plus Progestin
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
2013; 105 (19): 1496-1503
Although high endogenous sex hormone levels and estrogen plus progestin (E+P) therapy are associated with increased breast cancer risk, it is unknown whether pretreatment levels of sex hormones modify E+P effect on breast cancer.We conducted a nested case-control study within the Women's Health Initiative randomized clinical trial of E+P. The trial enrolled 16608 postmenopausal women aged 50 to 79 years with intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone, and sex hormone-binding globulin [SHBG]) and year 1 (estrogens and SHBG) using sensitive assays. All statistical tests were two-sided.Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (P trend = .04), bioavailable estradiol (P trend = .03), estrone (P trend = .007), and estrone sulfate (P trend = .007). E+P increased all measured estrogens and SHGB at year 1 (all P < .001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval [CI] = 1.28 to 4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI = 0.44 to 2.09) in the highest total estradiol quartile; P interaction = .04).Women with lower pr-treatment endogenous estrogen levels were at greater risk of breast cancer during E+P therapy compared with those with higher levels. Further studies are warranted to confirm these findings.
View details for DOI 10.1093/jnci/djt243
View details for Web of Science ID 000325482100013
View details for PubMedID 24041978
View details for PubMedCentralID PMC3787910
Fibroblast Growth Factor 23, Bone Mineral Density, and Risk of Hip Fracture Among Older Adults: The Cardiovascular Health Study
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2013; 98 (8): 3323-3331
Context: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis. Objective: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults. Design and Setting: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease. Participants: Participants included 2008 women and 1329 men ≥65 years from the 1996 to 1997 Cardiovascular Health Study visit. Main Outcome Measures: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants. Results: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95% CI = 0.01-0.06 g/cm(2)). During 9.6 ± 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95% CI = 0.78-1.15, and 1.09 with 95% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions). Conclusions: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.
View details for DOI 10.1210/jc.2013-1152
View details for Web of Science ID 000322781300050
View details for PubMedID 23771921
Thyroid hormones and thyroid disease in relation to perchlorate dose and residence near a superfund site.
Journal of exposure science and environmental epidemiology
2013; 23 (4): 399-408
Perchlorate is a widely occurring contaminant, which can competitively inhibit iodide uptake and thus thyroid hormone production. The health effects of chronic low dose perchlorate exposure are largely unknown. In a community-based study, we compared thyroid function and disease in women with differing likelihoods of prior and current perchlorate exposure. Residential blocks were randomly selected from areas: (1) with potential perchlorate exposure via drinking water; (2) with potential exposure to environmental contaminants; and (3) neighboring but without such exposures. Eligibility included having lived in the area for ≥6 months and aged 20-50 years during 1988-1996 (during documented drinking water well contamination). We interviewed 814 women and collected blood samples (assayed for thyroid stimulating hormone and free thyroxine) from 431 interviewed women. Daily urine samples were assayed for perchlorate and iodide for 178 premenopausal women with blood samples. We performed multivariable regression analyses comparing thyroid function and disease by residential area and by urinary perchlorate dose adjusted for urinary iodide levels. Residential location and current perchlorate dose were not associated with thyroid function or disease. No persistent effect of perchlorate on thyroid function or disease was found several years after contaminated wells were capped.
View details for DOI 10.1038/jes.2012.90
View details for PubMedID 22968349
Factors Related to Age at Natural Menopause: Longitudinal Analyses From SWAN
AMERICAN JOURNAL OF EPIDEMIOLOGY
2013; 178 (1): 70-83
Early age at the natural final menstrual period (FMP) or menopause has been associated with numerous health outcomes and might be a marker of future ill health. However, potentially modifiable factors affecting age at menopause have not been examined longitudinally in large, diverse populations. The Study of Women's Health Across the Nation (SWAN) followed 3,302 initially premenopausal and early perimenopausal women from 7 US sites and 5 racial/ethnic groups, using annual data (1996-2007) and Cox proportional hazards models to assess the relation of time-invariant and time-varying sociodemographic, lifestyle, and health factors to age at natural FMP. Median age at the FMP was 52.54 years (n = 1,483 observed natural FMPs). Controlling for sociodemographic, lifestyle, and health factors, we found that racial/ethnic groups did not differ in age at the FMP. Higher educational level, prior oral contraceptive use, and higher weight at baseline, as well as being employed, not smoking, consuming alcohol, having less physical activity, and having better self-rated health over follow-up, were significantly associated with later age at the FMP. These results suggest that age at the natural FMP reflects a complex interrelation of health and socioeconomic factors, which could partially explain the relation of late age at FMP to reduced morbidity and mortality.
View details for DOI 10.1093/aje/kws421
View details for Web of Science ID 000321449400007
View details for PubMedID 23788671
View details for PubMedCentralID PMC3698989
Persistent Subclinical Hypothyroidism and Cardiovascular Risk in the Elderly: The Cardiovascular Health Study
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2013; 98 (2): 533-540
Use of a single set of thyroid function tests to define subclinical hypothyroidism may lead to misclassification over time and could influence findings from longitudinal studies. Objective: We assessed the risks of coronary heart disease (CHD), heart failure (HF), and cardiovascular (CV) death in older adults with persistent subclinical hypothyroidism.The study included 679 subclinically hypothyroid and 4184 euthyroid U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study and not taking thyroid preparations.We measured the 10-yr risk of incident CHD, HF, and CV death from persistent subclinical hypothyroidism, overall and stratified by degree of TSH elevation (4.5-6.9, 7.0-9.9, and 10.0-19.9 mU/liter).There was no association between persistent subclinical hypothyroidism and incident CHD [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.93-1.36], HF (HR, 1.05; 95% CI, 0.97-1.27), or CV death (HR, 1.07; 95% CI, 0.87-1.31) in adjusted analyses in which subclinical hypothyroidism was modeled as a time-varying exposure using up to four serial thyroid function tests. When subclinical hypothyroidism was stratified by degree of TSH elevation, no significant associations were found in any stratum. Findings were similar in fixed exposure analyses in which only participants with testing 2 yr apart were considered, with no association between persistent or transient subclinical hypothyroidism and incident CHD, HF, or CV death.Our data do not support increased risk of CHD, HF, or CV death in older adults with persistent subclinical hypothyroidism.
View details for Web of Science ID 000316270900047
View details for PubMedID 23162099
- Sex hormone levels and risk of breast cancer with estrogen plus progestin Journal of the National Cancer Institute 2013
Quantifying Mediating Effects of Endogenous Estrogen and Insulin in the Relation between Obesity, Alcohol Consumption, and Breast Cancer
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2012; 21 (7): 1203-1212
Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting.We combined data from two case-cohort studies based in the Women's Health Initiative-Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model.A five-unit increase in body mass index (BMI) was associated with 50.0 [95% confidence interval (CI), 23.2-76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8% (95% CI, 2.9-68.4) could be attributed to estradiol and 65.8% (95% CI, 13.6-273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95% CI, 18.8-161.1) for BMI when restricted to estrogen receptor positive (ER(+)) cases. Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 (95% CI, 45.8-284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ER(+) breast cancers.The relation of BMI with breast cancer was partly mediated through estradiol and, to a greater extent, through insulin.The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight and obese postmenopausal women to reduce breast cancer risk.
View details for DOI 10.1158/1055-9965.EPI-12-0310
View details for Web of Science ID 000306210100025
View details for PubMedID 22564867
Bone mineral density loss in relation to the final menstrual period in a multiethnic cohort: Results from the Study of Women's Health Across the Nation (SWAN)
JOURNAL OF BONE AND MINERAL RESEARCH
2012; 27 (1): 111-118
The objective of this study was to describe the time of onset and offset of bone mineral density (BMD) loss relative to the date of the final menstrual period (FMP); the rate and amount of BMD decline during the 5 years before and the 5 years after the FMP; and the independent associations between age at FMP, body mass index (BMI), and race/ethnicity with rates of BMD loss during this time interval. The sample included 242 African American, 384 white, 117 Chinese, and 119 Japanese women, pre- or early perimenopausal at baseline, who had experienced their FMP and for whom an FMP date could be determined. Loess-smoothed curves showed that BMD loss began 1 year before the FMP and decelerated (but did not cease) 2 years after the FMP, at both the lumbar spine (LS) and femoral neck (FN) sites. Piecewise, linear, mixed-effects regression models demonstrated that during the 10-year observation period, at each bone site, the rates and cumulative amounts of bone loss were greatest from 1 year before through 2 years after the FMP, termed the transmenopause. Postmenopausal loss rates, those occurring between 2 and 5 years after the FMP, were less than those observed during transmenopause. Cumulative, 10-year LS BMD loss was 10.6%; 7.38% was lost during the transmenopause. Cumulative FN loss was 9.1%; 5.8% was lost during the transmenopause. Greater BMI and African American heritage were related to slower loss rates, whereas the opposite was true of Japanese and Chinese ancestry.
View details for DOI 10.1002/jbmr.534
View details for Web of Science ID 000298479000011
View details for PubMedID 21976317
Sex Hormone Levels and Risks of Estrogen Receptor-Negative and Estrogen Receptor-Positive Breast Cancers
JOURNAL OF THE NATIONAL CANCER INSTITUTE
2011; 103 (7): 562-570
Endogenous sex hormone levels are associated with risks of breast cancer overall and estrogen receptor (ER)-positive breast tumors; however, their associations with ER-negative tumors remain unclear.In a case-cohort study within the Women's Health Initiative Observational Study among postmenopausal women aged 50-79 years, we examined associations between endogenous testosterone and estradiol levels and the risks of ER-negative and ER-positive breast cancers. Serum levels of bioavailable testosterone and estradiol were assessed at the baseline visit in 317 invasive breast cancer case subjects and in a subcohort of 594 women. Bioavailable sex hormone levels were calculated using the total hormone level and the sex hormone-binding globulin concentration (measured by radioimmunoassays and a chemiluminescent immunoassay, respectively). Cox proportional hazards regression was used for statistical analysis. All statistical tests were two-sided.The unadjusted absolute rates of ER-negative breast cancer for testosterone quartiles 1-4 were 0.34, 0.20, 0.23, and 0.21 per 10,000 person-years, respectively. Compared with women in the lowest quartile of testosterone level, those in quartile 2 had a 56% lower risk of ER-negative cancer (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.23 to 0.85), those in quartile 3 had a 45% lower risk (HR = 0.55, 95% CI = 0.30 to 1.01), and those in quartile 4 had a 49% lower risk (HR = 0.51, 95% CI = 0.28 to 0.94), independent of other risk factors. Estradiol level was not associated with ER-negative breast cancer. ER-positive breast cancer risk increased with higher testosterone levels (P(trend) = .04), but this trend was not statistically significant after adjustment for estradiol (P(trend) = .15). ER-positive cancer risk was approximately twofold higher in women with estradiol levels in quartiles 2-4 compared with women in quartile 1, independent of risk factors.Higher serum levels of bioavailable testosterone are associated with lower risks of ER-negative breast cancer in postmenopausal women.
View details for DOI 10.1093/jnci/djr031
View details for Web of Science ID 000289307800009
View details for PubMedID 21330633
View details for PubMedCentralID PMC3071353
- Sex hormones and risk of estrogen receptor (ER)-negative and ER-positive breast cancer JOURNAL OF THE NATIONAL CANCER INSTITUTE 2011; 103
- Prospective Study of Endogenous Circulating Estradiol and Risk of Stroke in Older Women OBSTETRICAL & GYNECOLOGICAL SURVEY 2010; 65 (8): 510-511
Prospective Study of Endogenous Circulating Estradiol and Risk of Stroke in Older Women
ARCHIVES OF NEUROLOGY
2010; 67 (2): 195-201
To test the hypothesis that circulating endogenous estradiol is associated with stroke risk in older postmenopausal women. Stroke incidence increases after menopause, when endogenous estrogen levels fall, yet exogenous estrogen increases strokes in older postmenopausal women. The relation between endogenous estrogen and stroke is unclear.Prospective case-control study.Study of Osteoporotic Fractures.Women at least age 65 years (99% follow-up) who were not taking estrogen at baseline.Free estradiol index (FEI) was calculated by dividing total estradiol by sex hormone-binding globulin concentrations measured in banked baseline serum. Using logistic regression, odds ratios were estimated for a first-ever atherothrombotic stroke associated with endogenous FEI in 196 women who had a subsequent validated stroke (median follow-up, 8 years) compared with 219 randomly selected women who did not. Potential mediators were assessed in multivariable models.The age-adjusted odds of atherothrombotic stroke increased with increasing FEI quartiles (P(trend) = .007). Women in the highest FEI quartile had an age-adjusted 2.31-fold (odds ratio, 2.31; 95% confidence interval, 1.28-4.17) higher odds than women in the lowest quartile. Women with greater central adiposity had a suggestively stronger association (P = .08). Atherogenic dyslipidemia, type 2 diabetes mellitus, and C-reactive protein level were potential mediators of this relation.Endogenous estradiol level is an indicator of stroke risk in older postmenopausal women, especially in those with greater central adiposity. Potential mediators, including atherogenic dyslipidemia, insulin resistance, and inflammation, might underlie this association. Whether estradiol, independent of atherogenic adiposity, influences such mediators and stroke risk needs to be determined. Estrogen-altering agents might be harmful or beneficial depending on endogenous estradiol levels, especially in women with greater central adiposity.
View details for Web of Science ID 000274374600009
View details for PubMedID 20142527
- In PCOS, adrenal steroids are regulated differently in the morning versus in response to nutrient intake FERTILITY AND STERILITY 2010; 93 (4): 1192-99
Cardiovascular Disease in Women-Challenges Deserving a Comprehensive Translational Approach
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
2009; 2 (3): 251-255
Heart disease in women is associated with high levels of morbidity and mortality. Although many of the underlying causes are similar for both genders, cardiovascular disease among women has some unique features, including higher coronary heart disease mortality, higher frequency of sudden cardiac death without previous symptoms, and increased mortality among older women compared to men following a myocardial infarction. During recent years, increasing efforts have been placed on identifying preventive measures, but translation of knowledge from epidemiological studies and clinical trials remain incomplete, particularly in women. The recent launch of the National Institutes of Health's Clinical and Translational Science Award program offers opportunities to address these gaps and represent a unique opportunity to foster a new generation of researchers familiar with important issues regarding women's cardiovascular health.
View details for DOI 10.1007/s12265-009-9106-9
View details for Web of Science ID 000284690600005
View details for PubMedID 19655023
- Homocysteine levels and risk of hip fracture in postmenopausal women JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM 2009; 9 (4): 1207-13
Estrogen, aging and the cardiovascular system.
2009; 5 (1): 93-103
Estrogen is a powerful hormone with pleiotropic effects. Estrogens have potent antioxidant effects and are able to reduce inflammation, induce vasorelaxation and alter gene expression in both the vasculature and the heart. Estrogen treatment of cultured cardiac myocytes and endothelial cells rapidly activates NFkappaB, induces heat-shock protein (HSP)-72, a potent intracellular protective protein, and protects cells from simulated ischemia. In in vivo models, estrogens protect against ischemia and trauma/hemorrhage. Estrogens may decrease the expression of soluble epoxide hydrolase, which has deleterious effects on the cardiovascular system through metabolism of epoxyeicosatrienoic acids. Natural (endogenous) estrogens in premenopausal women appear to protect against cardiovascular disease and yet controlled clinical trials have not indicated a benefit from estrogen replacement postmenopause. Much remains to be understood in regards to the many properties of this powerful hormone and how changes in this hormone interact with aging-associated changes. The unexpected negative results of trials of estrogen replacement postmenopause probably arise from our lack of understanding of the many effects of this hormone.
View details for DOI 10.2217/147966188.8.131.52
View details for PubMedID 19371207
- Hip fractures and heart failure: Findings from the Cardiovascular Health Study EUROPEAN HEART JOURNAL 2009; 31 (1): 77-84
Serum 25-hydroxyvitamin D concentrations and risk for hip fractures
ANNALS OF INTERNAL MEDICINE
2008; 149 (4): 242-?
The relationship between serum 25-hydroxyvitamin D [25(OH) vitamin D] concentration and hip fractures is unclear.To see whether low serum 25(OH) vitamin D concentrations are associated with hip fractures in community-dwelling women.Nested case-control study.40 clinical centers in the United States.400 case-patients with incident hip fracture and 400 control participants matched on the basis of age, race or ethnicity, and date of blood draw. Both groups were selected from 39 795 postmenopausal women who were not using estrogens or other bone-active therapies and who had not had a previous hip fracture.Serum 25(OH) vitamin D was measured and patients were followed for a median of 7.1 years (range, 0.7 to 9.3 years) to assess fractures.Mean serum 25(OH) vitamin D concentrations were lower in case-patients than in control participants (55.95 nmol/L [SD, 20.28] vs. 59.60 nmol/L [SD, 18.05]; P = 0.007), and lower serum 25(OH) vitamin D concentrations increased hip fracture risk (adjusted odds ratio for each 25-nmol/L decrease, 1.33 [95% CI, 1.06 to 1.68]). Women with the lowest 25(OH) vitamin D concentrations (< or =47.5 nmol/L) had a higher fracture risk than did those with the highest concentrations (> or =70.7 nmol/L) (adjusted odds ratio, 1.71 [CI, 1.05 to 2.79]), and the risk increased statistically significantly across quartiles of serum 25(OH) vitamin D concentration (P for trend = 0.016). This association was independent of number of falls, physical function, frailty, renal function, and sex-steroid hormone levels and seemed to be partially mediated by bone resorption.Few case-patients were nonwhite women. Bone mineral density and parathyroid hormone levels were not accounted for in the analysis.Low serum 25(OH) vitamin D concentrations are associated with a higher risk for hip fracture.
View details for Web of Science ID 000258526700003
View details for PubMedID 18711154
View details for PubMedCentralID PMC2743412
Non-Hodgkin lymphoma in women: Reproductive factors and exogenous hormone use
AMERICAN JOURNAL OF EPIDEMIOLOGY
2008; 168 (3): 278–88
Few studies of reproductive hormone exposures and non-Hodgkin lymphoma (NHL) have examined NHL subtypes. Associations between reproductive hormonal factors and risk of all NHL and of two predominant subtypes, diffuse large-cell lymphoma (DLCL) (n = 233) and follicular lymphoma (n = 173), were investigated among women (n = 581) in a large, population-based, case-control study (1,591 cases, 2,515 controls). Controls (n = 836) identified by random digit dialing were frequency matched by age and county to incident NHL cases ascertained in the San Francisco Bay Area of California in 1988-1993. Adjusted unconditional logistic regression was used to obtain odds ratios. More than four pregnancies indicated a possible lower risk of all NHL (odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.55, 1.2; p-trend = 0.06) and of DLCL (OR = 0.53, 95% CI: 0.31, 0.90; p-trend = 0.01). Exclusive use of menopausal hormone therapy for > or =5 years was associated with a reduced risk of all NHL (OR = 0.68, 95% CI: 0.48, 0.98) and of DLCL (OR = 0.50, 95% CI: 0.30, 0.85). Oral contraceptive use indicated a lower risk of all NHL (OR = 0.68, 95% CI: 0.49, 0.94), and perhaps DLCL (OR = 0.79, 95% CI: 0.51, 1.2), and of follicular lymphoma (OR = 0.75, 95% CI: 0.46, 1.2). Results suggest that endogenous and exogenous reproductive hormones confer different risks by NHL subtype and are associated with a reduced risk of DLCL in women.
View details for DOI 10.1093/aje/kwn119
View details for Web of Science ID 000257786100005
View details for PubMedID 18550561
View details for PubMedCentralID PMC2727261
Associations of serum sex hormone-binding globulin and sex hormone concentrations with hip fracture risk in postmenopausal women
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2008; 93 (5): 1796-1803
Endogenous estradiol, testosterone, and SHBG may influence the risk of hip fracture.From the Women's Health Initiative Observational Study, 39,793 eligible postmenopausal women did not have a previous hip fracture and were not using estrogen or other bone-active therapies. Of these, 400 who had a first-time nonpathological hip fracture (median follow-up, 7 yr) were matched to 400 controls by age, ethnicity, and baseline blood draw date. Estradiol, testosterone, and SHBG were measured in banked baseline serum.Compared with women in the lowest tertiles, those with bioavailable testosterone in the highest tertile had a lower risk [odds ratio (OR) = 0.62; 95% confidence interval (CI) = 0.44-0.88]; those with bioavailable estradiol in the highest tertile had a lower risk (OR = 0.44; 95% CI = 0.29-0.66), and those with SHBG in the highest tertile had a higher risk (OR = 1.90; 95% CI = 1.31-2.74) of hip fracture. In models with all three hormones and potential confounders, high SHBG remained a strong independent risk factor (OR = 1.76; 95% CI = 1.12-2.78), high bioavailable testosterone remained protective (OR = 0.64; 95% CI = 0.40-1.00), but estradiol no longer was associated (OR = 0.72; 95% CI = 0.42-1.23).High serum SHBG is associated with an increased risk of subsequent hip fracture and high endogenous testosterone with a decreased risk, independent of each other, serum estradiol concentration, and other putative risk factors. But endogenous estradiol has no independent association with hip fracture.
View details for DOI 10.1210/jc.2007-2358
View details for Web of Science ID 000255663100037
View details for PubMedID 18334588
- Potential role of ultra-sensitive estradiol assays in estimating the risk of breast cancer and fractures STEROIDS 2008; 73 (13): 1318-21
- Exogenous hormone use, reproductive factors and risk of non-Hodgkin lymphoma AMERICAN JOURNAL OF EPIDEMIOLOGY 2008; 168 (3): 278-88
- Cystatin-c and incidence of hip fracture in postmenopausal women JOURNAL OF THE GERIATRICS SOCIETY 2008; 56 (8): 1434-41
Standardization of steroid hormone assays: Why, how, and when?
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2007; 16 (9): 1713-1719
Lack of standardization of high-quality steroid hormone assays is a major deficiency in epidemiologic studies. In postmenopausal women, reported levels of serum 17beta-estradiol (E(2)) are highly variable and median normal values differ by approximately a 6-fold factor. A particular problem is the use of E(2) assays for prediction of breast cancer risk and osteoporotic fractures, where assay sensitivity may be the most important factor. Identification of women in the lowest categories of E(2) levels will likely provide prognostic information that would not be available in a large group of women in whom E(2) levels are undetectable by less sensitive assays. Detailed and costly methods involving extraction and chromatography in conjunction with RIA provide generally acceptable E(2) results in postmenopausal serum, whereas less tedious, direct immunoassays suffer from inadequate specificity and sensitivity. Studies comparing the two types of methods generally report higher E(2) values with the direct methods as a result of cross-reactivity with other steroids and reduced correlation with biological variables such as body mass index. Similar problems exist with measurements of E(2) and estrone in men, and estrone and testosterone in women. Interest in mass spectrometry-based assays is increasing as potential gold standard methods with enhanced sensitivity and specificity; however, these assays require costly instrumentation and highly trained personnel. Taking all of these issues into consideration, we propose establishment of standard pools of premenopausal, postmenopausal, and male serum, and utilization of these for cross-comparison of various methods on an international basis. An oversight group could then establish standards based on these comparisons and set agreed upon confidence limits of various hormones in the pools. These criteria would allow validation of sensitivity, specificity, precision, and accuracy of current steroid hormone assay methodology and provide surrogates until a true gold standard can be developed.
View details for DOI 10.1158/1055-9965.EPI-06-0765
View details for Web of Science ID 000249643600003
View details for PubMedID 17855686
Reproductive risk factors for cutaneous melanoma in women: A case-control study
AMERICAN JOURNAL OF EPIDEMIOLOGY
2007; 165 (5): 505-513
Reproductive hormonal factors may have a potential role in cutaneous melanoma. This study estimated the risk of melanoma in women related to self-reported changes in nevi during pregnancy, while using oral contraceptives and/or hormone replacement therapy. Trained interviewers administered a questionnaire obtaining information about oral contraceptive use, hormone replacement therapy, reproductive history, sun exposure, occupation, and medical history from 318 Caucasian women newly diagnosed between 1991 and 1992 from two pigmented lesion clinics in San Francisco, California, and Philadelphia, Pennsylvania. A total of 395 frequency-matched control participants were recruited from hospital-affiliated outpatient clinics. Clinicians conducted skin examinations to assess the number and type of nevi, extent of freckling, solar damage, and skin type. For women aged less than 55 years, there was an association between a livebirth 5 years before diagnosis (odds ratio = 2.6, 95% confidence interval: 1.3, 5.3) and between number of births and melanoma risk (for > or = 3 births: odds ratio = 3.3, 95% confidence interval: 1.7, 6.5; ptrend < 0.001). Changes in nevi during recent pregnancies were a risk factor for melanoma, based upon small numbers (odds ratio = 2.9, 95% confidence interval: 1.1, 8.1). Oral contraceptive use and hormone replacement therapy were not associated with melanoma risk.
View details for DOI 10.1093/aje/kwk040
View details for Web of Science ID 000244427100004
View details for PubMedID 17158470
Comparison of methods to measure low serum estradiol levels in postmenopausal women
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2006; 91 (10): 3791-3797
Accurate measurement of low serum estradiol (E(2) < 30 pg/ml or < 110 pmol/liter) is needed to study relationships between endogenous E(2) and risks of diseases in older women.The objective of this study was to determine whether an extraction-based (indirect) assay or a non-extraction-based (direct) assay correlates better with mass spectrometry and body mass index (BMI).In a pilot study of 40 postmenopausal women, endogenous E(2) measurements from three indirect and four direct assay methods and gas chromatography-tandem mass spectrometry (GC-MS/MS) were compared. A confirmatory study compared an indirect and a direct assay, selected among those in the pilot study, to GC-MS/MS; this study was conducted in 374 postmenopausal women not taking hormone therapy from the Ultra Low-dose TRansdermal estrogen Assessment (ULTRA) trial.Pearson correlation coefficients among E(2) measurements by assay methods and BMI, and their confidence intervals, by bias-corrected bootstrap method, were used.In the pilot study, E(2) by three indirect assays correlated better (P < 0.03) with GC-MS/MS and with BMI than measurements by four direct assays. In the confirmatory study, the indirect assay correlated better (P < 0.01) with GC-MS/MS and BMI than the direct assay. Measurements by the indirect and direct assays were overestimated, but deviations in direct assay measurements were less precise. Mean E(2) by the indirect and direct assays were higher (by 14 and 68%, respectively) and less reproducible than by GC-MS/MS.Until mass spectrometry is practical for wide use, extraction-based indirect assays may be preferable for measuring low postmenopausal serum E(2).
View details for DOI 10.1210/jc.2005-2378
View details for Web of Science ID 000241100900015
View details for PubMedID 16882749
- Making sense of puzzling genetic association studies: A team approach ANNALS OF INTERNAL MEDICINE 2006; 145 (4): 302-304
Endogenous estradiol, testosterone, and risk of hip fracture in older women: The women's health initiative
7th International Symposium on Osteoporosis
SPRINGER LONDON LTD. 2006: S141–S141
View details for Web of Science ID 000245980600045
Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2006; 15 (2): 359-363
First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis.We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis.In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years.In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.
View details for DOI 10.1158/1055-9965.EPI-05-0687
View details for PubMedID 16492929
Sex hormones, risk factors, and risk of estrogen receptor-positive breast cancer in older women: A long-term prospective study
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2005; 14 (5): 1047-1051
Antiestrogens reduce the risk of estrogen receptor-positive (ER+) but not ER-negative (ER-) breast cancer. Women at high risk of ER+ cancer would be the most likely to benefit from these treatments, but the best approach to predicting ER+ cancer is uncertain.We prospectively assessed putative risk factors for breast cancer and archived serum at -190 degrees C from a community-based cohort of 7,676 women ages > or =65 years who had no history of breast cancer. Follow-up for breast cancer over 10.5 years was 99% complete. Using a case-cohort design, we measured baseline levels of estradiol and testosterone in 196 cases of invasive ER+ cancer and 378 randomly selected controls.Women whose testosterone level in highest two quintiles had a 4-fold increased risk of ER+ breast cancer (P < 0.0001). High estradiol concentration also indicated an increased risk but was not a significant predictor after adjustment for testosterone. Women with >16 years of education had a 2.1 times increased risk (P = 0.03) of ER+ cancer, but no other risk factors were significantly related to an increased risk of ER+ cancer. Women with a family history of breast cancer had a 2.9-fold increased risk of ER- cancer (P = 0.002) but no increased risk of ER+ cancer (relative hazard = 1.2, 0.8-1.8).High serum testosterone and advanced education predicted ER+ breast cancer. If confirmed, high testosterone level may be more accurate than family history of breast cancer and other conventional risk factors for identifying older women who are most likely to benefit from antiestrogen chemoprevention.
View details for Web of Science ID 000229032000003
View details for PubMedID 15894651
- New physiologic approach to prevention of postmenopausal osteoporosis (book chapter) Postmenopausal Osteoporosis: Hormones and Other Therapies Taylor & Francis Medical Books. 2005
Histopathologic features of ovaries at increased risk for carcinoma - A case-control analysis
87th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology
LIPPINCOTT WILLIAMS & WILKINS. 1999: 151–57
In this study, the pathogenesis of ovarian carcinoma was investigated by performing a masked histopathologic comparison of benign ovaries removed from 61 women predicted to be at increased risk for developing carcinoma (cases) with ovaries removed from 121 women without known predisposing conditions (controls). The cases included 26 women who had a unilateral invasive carcinoma and 35 women undergoing prophylactic oophorectomy for a family history of ovarian cancer. As predicted by previously developed models, epithelial inclusion cysts were identified more frequently with advancing age in both cases and controls. However, the mean and maximum number of cysts per slide in a woman were not increased among cases. Surface epithelial "atypia," a designation based on a composite impression of multiple features, was found in 13% of cases compared with 3% of controls (relative risk 7.1; 95% confidence interval, 1.9 to 26.1), but this result was based on small numbers. None of the other histologic features examined was found more often in cases following age-adjustment. Reexamination of sections with well-preserved surface epithelium or inclusion cysts under oil immersion demonstrated several differences in the detection of specific features between cases and controls and increased detection of "atypia" among cases, but none of these findings reached statistical significance. It is concluded that there may be subtle differences in the surface epithelium of ovaries predisposed to developing cancer as compared with controls, but these changes are difficult to identify reliably with light microscopy. Future etiologic studies should attempt to optimize specific handling and include molecular studies and epidemiologic analyses.
View details for Web of Science ID 000079372000009
View details for PubMedID 10202673
- Survival after breast cancer in BRCA1/2 Ashkenazi Jewish carriers JOURNAL OF THE NATIONAL CANCER INSTITUTE 1999; 91 (3): 259-63
Diabetes susceptibility at IDDM2 cannot be positively mapped to the VNTR locus of the insulin gene
1996; 39 (5): 594-599
An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5' of the INS locus. Patients and control subjects were genotyped at INS/+ 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS/ + 1140 allele '+' were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele '+' (53 vs 31%, p < 0.001) giving an odds ratio of 2.6 (95%CI 1.6-4.2). By multilocus analysis, the TH/RsaI allele '+' identified a subset of INS/ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95%CI 2.9-10.4) than allele + 1140 '+' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.
View details for Web of Science ID A1996UH67800012
View details for PubMedID 8739920
INCIDENCE OF RENAL-FAILURE IN NIDDM - THE OKLAHOMA INDIAN DIABETES STUDY
1994; 43 (4): 572-579
The incidence of and risk factors for renal failure were determined in 912 Oklahoma Indians with non-insulin-dependent diabetes mellitus in a follow-up study conducted between 1987 and 1990. The incidence rate was 15.7/1,000 person-years after an average follow-up time of 10.2 years. Among those who had no qualitatively positive proteinuria at baseline, the incidence of renal failure was 10.3/1,000 person-years compared with 19.3- and 56.2/1,000 person-years, respectively, in those with slight and heavy proteinuria at baseline. Fasting plasma glucose (FPG) > or = 11.1 mM (200 mg/dl) increased the risk of renal failure to 2.9-fold (95% confidence interval [CI] = 1.9-4.6) higher than a level < 7.8 mM (140 mg/dl), and twofold (95% CI = 1.4-3.1) higher than a level between 7.8 (140 mg/dl) and 11.1 mM (200 mg/dl). The hypertensive patient had twice the incidence of renal failure than the normotensive subject (rate ratio = 2.1, 95% CI = 1.4-3.0). Patients with a lower blood pressure under antihypertensive medication had a lower incidence of renal failure than those whose hypertension remained uncontrolled with or without use of medication. Significant independent risk factors for renal failure, identified from Cox's proportional hazards model, were duration of diabetes, FPG, age, hypertension, and insulin use (P < 0.05). In patients without proteinuria at baseline, FPG and hypertension were significant predictors of renal failure as identified by multivariate analyses, whereas in patients who had proteinuria at baseline, insulin use was significant. Thus, hyperglycemic and hypertension control are suggested strongly for diabetic Oklahoma Indians as potential strategies to prevent the development of renal failure.
View details for Web of Science ID A1994NC85900011
View details for PubMedID 8138063
LOWER-EXTREMITY AMPUTATION - INCIDENCE, RISK-FACTORS, AND MORTALITY IN THE OKLAHOMA INDIAN DIABETES STUDY
1993; 42 (6): 876-882
Oklahoma Indians with NIDDM (n = 1012) underwent a baseline examination in 1972-1980. The incidence of and risk factors for first lower-extremity amputation were estimated. The mortality rates of amputees using data from 875 patients who had no previous history of amputation and who underwent follow-up examination between 1987 and 1991 are presented. The mean age of the 875 patients was 51.6 +/- 10.8 yr, and the mean duration of diabetes was 6.6 +/- 6.1 yr. After a mean follow-up time of 9.9 +/- 4.3 yr, the incidence rate of first LEA among diabetic Oklahoma Indians was 18.0/1000 person-yr. The incidence rate was two times higher in men than in women. In both sexes, significant risk factors (P < 0.05) were retinopathy and duration of diabetes. Fasting plasma glucose, use of insulin, and systolic blood pressure were significant for men only. For women, plasma cholesterol and diastolic blood pressure were additional risk factors. Compared with the mortality rate of 33.5/1000 person-yr among nonamputees, the rate among amputees was 55.5/1000 person-yr. The 5-yr survival rate after first amputation was 40.4%. For the amputees, the most common causes of death were diabetes (37.3%), cardiovascular disease (29.1%), and renal disease (7.3%). The incidence and mortality rates in diabetic Oklahoma Indians were higher than those reported in Pima Indians and other diabetic populations. To lower the incidence of lower-extremity amputation in this high-risk population, preventive action through education, foot care programs, and early detection of lesions must be intensified.
View details for Web of Science ID A1993LD94000011
View details for PubMedID 8495811