Metabolomics Biomarkers for Fatty Acid Intake and Biomarker-Calibrated Fatty Acid Associations with Chronic Disease Risk in Postmenopausal Women.

BACKGROUND: A substantial observational literature relating specific fatty acid classes to chronic disease risk may be limited by its reliance on self-reported dietary data. OBJECTIVES: We aimed to develop biomarkers for saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acid densities, and to study their associations with cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) in Women's Health Initiative (WHI) cohorts. METHODS: Biomarker equations were based primarily on serum and urine metabolomics profiles from an embedded WHI human feeding study (n = 153). Calibration equations were based on biomarker values in a WHI nutritional biomarker study (n = 436). Calibrated intakes were assessed in relation to disease incidence in larger WHI cohorts (n = 81,894). Participants were postmenopausal women, aged 50-79 when enrolled at 40 United States Clinical Centers (1993-1998), with a follow-up period of ∼20 y. RESULTS: Biomarker equations meeting criteria were developed for SFA, MUFA, and PUFA densities. That for SFA density depended somewhat weakly on metabolite profiles. On the basis of our metabolomics platforms, biomarkers were insensitive to trans fatty acid intake. Calibration equations meeting criteria were developed for SFA and PUFA density, but not for MUFA density. With or without biomarker calibration, SFA density was associated positively with risk of CVD, cancer, and T2D, but with small hazard ratios, and CVD associations were not statistically significant after controlling for other dietary variables, including trans fatty acid and fiber intake. Following this same control, PUFA density was not significantly associated with CVD risk, but there were positive associations for some cancers and T2D, with or without biomarker calibration. CONCLUSIONS: Higher SFA and PUFA diets were associated with null or somewhat higher risk for clinical outcomes considered in this population of postmenopausal United States women. Further research is needed to develop even stronger biomarkers for these fatty acid densities and their major components. This study is registered with clinicaltrials.gov identifier: NCT00000611.

Metabolomics-Based Biomarker for Dietary Fat and Associations with Chronic Disease Risk in Postmenopausal Women.

BACKGROUND: The Women's Health Initiative (WHI) randomized, controlled Dietary Modification (DM) trial of a low-fat dietary pattern suggested intervention benefits related to breast cancer, coronary heart disease (CHD), and diabetes. Here, we use WHI observational data for further insight into the chronic disease implications of adopting this type of low-fat dietary pattern. OBJECTIVES: We aimed to use our earlier work on metabolomics-based biomarkers of carbohydrate and protein to develop a fat intake biomarker by subtraction, to use the resulting biomarker to develop calibration equations that adjusts self-reported fat intake for measurement error, and to study associations of biomarker-calibrated fat intake with chronic disease risk in WHI cohorts. Corresponding studies for specific fatty acids will follow separately. METHODS: Prospective disease association results are presented using WHI cohorts of postmenopausal women, aged 50-79 y when enrolled at 40 United States clinical centers. Biomarker equations were developed using an embedded human feeding study (n = 153). Calibration equations were developed using a WHI nutritional biomarker study (n = 436). Calibrated intakes were associated with cancer, cardiovascular diseases, and diabetes incidence in WHI cohorts (n = 81,954) over an approximate 20-y follow-up period. RESULTS: A biomarker for fat density was developed by subtracting protein, carbohydrate, and alcohol densities from one. A calibration equation was developed for fat density. Hazard ratios (95% confidence intervals) for 20% higher fat density were 1.16 (1.06, 1.27) for breast cancer, 1.13 (1.02, 1.26) for CHD, and 1.19 (1.13, 1.26) for diabetes, in substantial agreement with findings from the DM trial. With control for additional dietary variables, especially fiber, fat density was no longer associated with CHD, with hazard ratio (95% confidence interval) of 1.00 (0.88, 1.13), whereas that for breast cancer was 1.11 (1.00, 1.24). CONCLUSIONS: WHI observational data support prior DM trial findings of low-fat dietary pattern benefits in this population of postmenopausal United States women. TRIAL REGISTRATION NUMBER: This study is registered with clinicaltrials.gov identifier: NCT00000611.

Long-term Trajectories of Physical Function Decline in Women With and Without Cancer.

Importance: Patients with cancer experience acute declines in physical function, hypothesized to reflect accelerated aging driven by cancer-related symptoms and effects of cancer therapies. No study has examined long-term trajectories of physical function by cancer site, stage, or treatment compared with cancer-free controls. Objective: Examine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls. Design, Setting, and Participants: This prospective cohort study enrolled patients from 1993 to 1998 and followed up until December 2020. The Women's Health Initiative, a diverse cohort of postmenopausal women, included 9203 incident cancers (5989 breast, 1352 colorectal, 960 endometrial, and 902 lung) matched to up to 5 controls (n = 45 358) on age/year of enrollment and study arm. Exposures: Cancer diagnosis (site, stage, and treatment) via Medicare and medical records. Main Outcomes and Measures: Trajectories of self-reported physical function (RAND Short Form 36 [RAND-36] scale; range: 0-100, higher scores indicate superior physical function) estimated from linear mixed effects models with slope changes at diagnosis and 1-year after diagnosis. Results: This study included 9203 women with cancer and 45 358 matched controls. For the women with cancer, the mean (SD) age at diagnosis was 73.0 (7.6) years. Prediagnosis, physical function declines of survivors with local cancers were similar to controls; after diagnosis, survivors experienced accelerated declines relative to controls, whose scores declined 1 to 2 points per year. Short-term declines in the year following diagnosis were most severe in women with regional disease (eg, -5.3 [95% CI, -6.4 to -4.3] points per year in regional vs -2.8 [95% CI, -3.4 to -2.3] for local breast cancer) or who received systemic therapy (eg, for local endometrial cancer, -7.9 [95% CI, -12.2 to -3.6] points per year with any chemotherapy; -3.1 [95% CI, -6.0 to -0.3] with radiation therapy alone; and -2.6 [95% CI, -4.2 to -1.0] with neither, respectively). While rates of physical function decline slowed in the later postdiagnosis period (eg, women with regional colorectal cancer declined -4.3 [95% CI, -5.9 to -2.6] points per year in the year following diagnosis vs -1.4 [95% CI, -1.7 to -1.0] points per year in the decade thereafter), survivors had estimated physical function significantly below that of age-matched controls 5 years after diagnosis. Conclusions and Relevance: In this prospective cohort study, survivors of cancer experienced accelerated declines in physical function after diagnosis, and physical function remained below that of age-matched controls even years later. Patients with cancer may benefit from supportive interventions to preserve physical functioning.

Bone Turnover Markers Are Not Associated With Hip Fracture Risk: A Case-Control Study in the Women's Health Initiative.

Current guidelines recommend that serum C-terminal telopeptide of type I collagen (CTX) and serum procollagen type 1 aminoterminal propeptide (PINP), measured by standardized assays, be used as reference markers in observational and interventional studies. However, there are limited data to determine whether serum CTX and PINP are associated with hip fracture risk among postmenopausal women. We determined the associations of serum CTX and serum PINP with hip fracture risk among postmenopausal women aged 50 to 79 years at baseline. We performed a prospective case-control study (400 cases, 400 controls) nested in the Women's Health Initiative Observational Study, which enrolled participants at 40 US clinical centers. Cases were women with incident hip fracture not taking osteoporosis medication; hip fractures were confirmed using medical records. Untreated controls were matched by age, race/ethnicity, and date of blood sampling. Serum CTX and serum PINP were analyzed on 12-hour fasting blood samples. The main outcome measure was incident hip fracture risk (mean follow-up 7.13 years). After adjustment for body mass index, smoking, frequency of falls, history of fracture, calcium and vitamin D intake, and other relevant covariates, neither serum CTX level nor serum PINP level was statistically significantly associated with hip fracture risk (CTX ptrend = 0.22, PINP ptrend = 0.53). Our results do not support the utility of serum CTX level or PINP level to predict hip fracture risk in women in this age group. These results will inform future guidelines regarding the potential utility of these markers in fracture prediction. © 2018 American Society for Bone and Mineral Research.

Use of Colorectal Cancer Screening Among People With Mobility Disability.

GOALS: We aimed to assess use of colorectal cancer screening (CRCS) as per United States Preventive Task Force guidelines among people with mobility disability using a nationally representative data set. BACKGROUND: Individuals with mobility disability have decreased access to health care services, but the impact of mobility disability on CRCS has not been investigated. STUDY: Data from the 2013 National Health Interview Survey were used to estimate sociodemographic characteristics of adults with mobility disability, prevalence of CRCS, and odds of CRCS given mobility disability among Americans aged 50 to 75. RESULTS: In total, 56.8% of the entire sample (n=81,953,585) were up-to-date with CRCS. Mobility disability was not associated with CRCS status on univariable analysis but was significantly associated after adjustment for covariates including age and comorbidities, with an inverse relationship between the degree of mobility disability and odds of CRCS. Odds ratio for CRCS given progressively severe disability were 0.78 (0.66 to 0.93), 0.71 (0.53 to 0.94), 0.65 (0.31 to 1.19). CONCLUSIONS: The present study indicates reduced CRCS among people with mobility disability and highlights the need for CRCS to be especially targeted toward this group. Future research should identify the specific systemic, social, and/or physical barriers to CRCS for this subgroup so that they can be addressed.

Association between survival time with metastatic breast cancer and aggressive end-of-life care.

PURPOSE: For women with stage IV breast cancer (BC), the association between survival time (ST) and use of aggressive end-of-life (EOL) care is unknown. METHODS: We used the SEER-Medicare database to identify women with stage IV BC diagnosed 2002-2011 who died by 12/31/2012. Aggressive EOL care was defined as receipt in the last month of life: >1 ED visit, >1 hospitalization, ICU admission, life-extending procedures, hospice admission within 3 days of death, IV chemotherapy within 14 days of death, and/or ≥10 unique physician encounters in the last 6 months of life. Receipt of aggressive EOL care and hospice in the last month of life were determined using claims, and multivariable analysis was used to identify factors associated with receipt. Costs of care were also evaluated. RESULTS: We identified 4521 eligible patients. Of these, 2748 (60.8%) received aggressive EOL care. Factors associated with aggressive EOL care were race (OR 1.45, 95% CI 1.19-1.81 for blacks compared to whites) and more frequent oncology office visits (OR 1.56, 95% CI 1.28-1.90). Patients who lived >12 months after diagnosis were less likely to receive aggressive EOL care (OR 0.44, 95% CI 0.38-0.52), and more likely to utilize hospice (OR 1.43, 95% CI 1.21-1.69) compared to patients who lived ≤6 months. Patients with a shorter ST had significantly higher costs of care per-month-alive compared to patients with longer ST. CONCLUSION: Patients with a shorter ST were more likely to receive aggressive EOL care and had higher costs of care compared to patients who lived longer.

Influence of Staphylococcus aureus on Outcomes after Valvular Surgery for Infective Endocarditis.

BACKGROUND: As Staphylococcus aureus (SA) remains one of the leading cause of infective endocarditis (IE), this study evaluates whether S. aureus is associated with more severe infections or worsened outcomes compared to non-S. aureus (NSA) organisms. METHODS: All patients undergoing valve surgery for bacterial IE between 1995 and 2013 at our institution were included in this study (n = 323). Clinical data were retrospectively collected from the chart review. Patients were stratified according to the causative organism; SA (n = 85) and NSA (n = 238). Propensity score matched pairs (n = 64) of SA versus NSA were used in the analysis. RESULTS: SA patients presented with more severe IE compared to NSA patients, with higher rates of preoperative vascular complications, preoperative septic shock, preoperative embolic events, preoperative stroke, and annular abscess. Among the matched pairs, there were no significant differences in 30-day (9.4% SA vs. 7.8% NSA, OR = 1.20, p = 0.76) or 1-year mortality (20.3% SA vs. 14.1% NSA, OR = 1.57, p = 0.35) groups, though late survival was significantly worse in SA patients. There was also no significant difference in postoperative morbidity between the two matched groups. CONCLUSIONS: SA IE is associated with a more severe clinical presentation than IE caused by other organisms. Despite the clearly increased preoperative risk, valvular surgery may benefit SA IE patients by moderating the post-operative mortality and morbidity.

Factors and Costs Associated With Delay in Treatment Initiation and Prolonged Length of Stay With Inpatient EPOCH Chemotherapy in Patients With Hematologic Malignancies.

Reducing delays related to inpatient chemotherapy may reduce healthcare costs. Using a national database, we identified patients with lymphoma/leukemia with ≥1 etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) chemotherapy claim and evaluated chemotherapy initiation delay (ID), >1 day from admission. Standard tests/procedures prior to initiation were evaluated. Among 4453 inpatient cycles, 19.7% had ID, odds ratio 2.28 (95% confidence interval: 1.83-2.85) with cycle 1 compared to cycle 2, and mean costs were higher in patients with ID than without ID (p < .0001). Prior to cycle 1, patients were more likely to undergo routine diagnostic procedures compared to subsequent cycles. Efforts to perform routine procedures prior to admission may reduce hospital length of stay and costs.

Use and Costs of Disease Monitoring in Women With Metastatic Breast Cancer.

PURPOSE: The optimal frequency of monitoring patients with metastatic breast cancer (MBC) is unknown; however, data suggest that intensive monitoring does not improve outcomes. We performed a population-based analysis to evaluate patterns and predictors of extreme use of disease-monitoring tests (serum tumor markers [STMs] and radiographic imaging) among women with MBC. METHODS: The SEER-Medicare database was used to identify women with MBC diagnosed from 2002 to 2011 who underwent disease monitoring. Billing dates of STMs (carcinoembryonic antigen and/or cancer antigen 15-3/cancer antigen 27.29) and imaging tests (computed tomography and/or positron emission tomography) were recorded; if more than one STM or imaging test were completed on the same day, they were counted once. We defined extreme use as > 12 STM and/or more than four radiographic imaging tests in a 12-month period. Multivariable analysis was used to identify factors associated with extreme use. In extreme users, total health care costs and end-of-life health care utilization were compared with the rest of the study population. RESULTS: We identified 2,460 eligible patients. Of these, 924 (37.6%) were extreme users of disease-monitoring tests. Factors significantly associated with extreme use were hormone receptor-negative MBC (odds ratio [OR], 1.63; 95% CI, 1.27 to 2.08), history of a positron emission tomography scan (OR, 2.92; 95% CI, 2.40 to 3.55), and more frequent oncology office visits (OR, 3.14; 95% CI, 2.49 to 3.96). Medical costs per year were 59.2% higher in extreme users. Extreme users were more likely to use emergency department and hospice services at the end of life. CONCLUSION: Despite an unknown clinical benefit, approximately one third of elderly women with MBC were extreme users of disease-monitoring tests. Higher use of disease-monitoring tests was associated with higher total health care costs. Efforts to understand the optimal frequency of monitoring are needed to inform clinical practice.

Serum Tumor Marker Use in Patients With Advanced Solid Tumors.

PURPOSE: There is substantial variability in the frequency of serum tumor marker testing in patients with advanced solid tumors. We performed a retrospective analysis to evaluate the frequency of serum tumor marker use. METHODS: Patients with a diagnosis of advanced cancer with outpatient visits between July 1, 2013, and June 30, 2014, at a single center were included. Tumor and stage were determined by International Classification of Diseases, Ninth Revision codes and confirmed with tumor registry and medical record review. For each patient, we recorded the dates of each of the following tumor markers: a-fetoprotein, CA-125, CA 15-3, CA 19-9, CA 27-29, and carcinoembryonic antigen. We evaluated the number of tests per patient over 12 months and the maximum number of tests per patient per month. RESULTS: We included 928 patients in the analysis. The mean number of any individual test per patient was seven tests, and the maximum number was 35 tests; the mean number of total tests per patient was 12 tests, and the maximum number was 70 tests; 16.3% of patients had more than 12 individual tests per year. In a 1-month span, 34.3% of patients had more than one individual test. CA 19-9 and carcinoembryonic antigen were the most commonly overused tests. CONCLUSION: We found a high rate of serum tumor marker testing use in patients with advanced solid tumors. Given the increasing costs of cancer care, efforts should be made to determine the benefit of serum tumor markers in the follow-up care of patients with advanced solid tumors.