Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2-4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early stage disease. Together, these findings suggest that increased whole–body protein breakdown is an early event in development of PDAC.

Objective: Identify risk factors for urinary incontinence in middle-aged women.Study Design: Cross-sectional analysis of 83,355 Nurses' Health Study II participants. Since 1989, women have provided health information on mailed questionnaires; in 2001, at age 37-54 years, information on urinary incontinence was requested. We examined adjusted odds ratios of incontinence using logistic regression.Results: 43% of women reported incontinence. After adjustment, African-American (OR=0.49, 95% CI 0.40-0.60) and Asian-American women (OR=0.57, 95% CI 0.46-0.72) were at reduced odds of severe incontinence compared to Caucasians. Increased age, body mass index, and parity were all positively associated with incontinence, as were current smoking, type 2 diabetes, and hysterectomy. Women aged 50-54 years had 1.81 times the odds of severe incontinence compared to women <40 years (95% CI 1.66-1.97); women with BMI ≥ 30 kg/m 2 had 3.10 times the odds of severe incontinence compared to BMI 22-24 kg/m 2 (95% CI 2.91-3.30).Conclusions: Urinary incontinence is highly prevalent among these middle-aged women. Potential risk factors include age, race/ethnicity, body mass index, parity, smoking, diabetes, and hysterectomy.

Background Rigorous studies are necessary to demonstrate suitability of metabolomics platforms to profile metabolites in archived plasma within epidemiologic studies of human disease, for which attenuation of effect estimates due to measurement error is a key concern. Methods Using a liquid chromatography-tandem mass spectrometry platform, we quantified 257 metabolites from archived plasma to evaluate metabolite inter-assay reproducibility, reproducibility with delayed processing, and within-person reproducibility over time. Inter-assay reproducibility was assessed with coefficients of variation (CVs) from 60 duplicate plasma samples donated by Nurses’ Health Study and Health Professionals Follow-up Study participants, and 20 quality control pool plasma replicates. Metabolite reproducibility over a 24- to 48-hour processing delay (n=48 samples) and within-person reproducibility over 1-2 years (n=80 samples) were assessed using Spearman and intraclass correlation coefficients (ICCs). Results CVs were <20% for 92% of metabolites and generally were similar by plasma anticoagulant type (Heparin or EDTA) and fasting time. Approximately 75% of metabolites were reproducible over delays in processing of blood specimens (Spearman correlation or ICC ≥0.75, comparing immediate and 24-hour delayed processing). Carbohydrates and purine/pyrimidine derivatives were most adversely affected by the processing delay. Ninety percent of metabolites were reproducible over 1-2 years within individuals (Spearman correlation or ICC ≥0.4). Conclusions For potential use in epidemiologic studies, the majority of plasma metabolites had low CVs and were reproducible over a 24-hour processing delay and within individuals over 1-2 years. Certain metabolites, such as carbohydrates and purine/pyrimidine derivatives, may be challenging to evaluate if samples have delayed processing.