Brian W. Whitcomb

Lipid Adjustment in the Analysis of Environmental Contaminants and Human Health Risks

The literature on exposure to lipophilic agents such as polychlorinated biphenyls (PCBs) is conflicting, posing challenges for the interpretation of potential human health risks. Laboratory variation in quantifying PCBs may account for some of the conflicting study results. For example, for quantification purposes, blood is often used as a proxy for adipose tissue, which makes it necessary to model serum lipids when assessing health risks of PCBs. Using a simulation study, we evaluated four statistical models (unadjusted, standardized, adjusted, and two-stage) for the analysis of PCB exposure, serum lipids, and health outcome risk (breast cancer). We applied eight candidate true causal scenarios, depicted by directed acyclic graphs, to illustrate the ramifications of misspecification of underlying assumptions when interpreting results. Statistical models that deviated from underlying causal assumptions generated biased results. Lipid standardization, or the division of serum concentrations by serum lipids, was observed to be highly prone to bias. We conclude that investigators must consider biology, biologic medium (e.g., nonfasting blood samples), laboratory measurement, and other underlying modeling assumptions when devising a statistical plan for assessing health outcomes in relation to environmental exposures.

The metabolic syndrome, diabetes, and subclinical atherosclerosis assessed by coronary calcium.

OBJECTIVES We compared the prevalence and extent of coronary artery calcium (CAC) among persons with the metabolic syndrome (MetS), diabetes, and neither condition. BACKGROUND The prevalence and extent of CAC has not been compared among those with MetS, diabetes, or neither condition. METHODS Of 1,823 persons (36% female) age 20 to 79 years who had screening for CAC by computed tomography, 279 had MetS, 150 had diabetes, and the remainder (n = 1,394) had neither condition. Metabolic syndrome was defined with >or=3 of the following: body mass index >or=30 kg/m(2); high-density lipoprotein cholesterol <40 mg/dl if male or <50 mg/dl if female; triglycerides >or=150 mg/dl; blood pressure >or=130/85 mm Hg or on treatment; or fasting glucose 110 to 125 mg/dl. The prevalence and odds of any and significant (>or=75th percentile) CAC among these groups and by number of MetS risk factors were determined. RESULTS Those with neither MetS nor diabetes, MetS, or diabetes had a prevalence of CAC of 53.5%, 58.8%, and 75.3% (p < 0.001), respectively, among men and 37.6%, 50.8%, and 52.6% (p < 0.001), respectively, among women. Coronary artery calcium increased by the number (0 to 5) of MetS risk factors (from 34.0% to 58.3%) (p < 0.001). Forty-one percent of subjects with MetS had either a >20% 10-year risk of CHD or CAC >or=75th percentile for age and gender. Risk factor-adjusted odds for the presence of CAC were 1.40 (95% confidence interval [CI] 1.05 to 1.87) among those with MetS and 1.67 (95% CI 1.12 to 2.50) among those with diabetes, versus those with neither condition. CONCLUSIONS Those with MetS or diabetes have an increased likelihood of CAC compared with those having neither condition.

Use of the Social Security Administration Death Master File for ascertainment of mortality status

ObjectivesInternet sources that use the Social Security Administrations (SSA) Death Master File have demonstrated high sensitivity among males for detection of mortality status in comparisons to the National Death Index, but the sensitivity has not been investigated for other demographic groups.MethodsThe authors used the SSA Death Master File to determine the mortality status of 374 decedents from the ongoing Patient Outcomes Study at Cedars-Sinai Medical Center whose deaths were confirmed by physicians using hospital records.ResultsDecedents identified by the SSA Death Master File were significantly older than those not identified. Foreign-born decedents were significantly less likely to be identified as dead than American-born decedents. Gender and marital status were not significant factors for identification by the SSA Death Master File.ConclusionThe results of this study suggest that Internet sources may be used as an inexpensive and effective tool for determination of mortality status. However, among certain populations use of these databases alone may provide incomplete information.

Effect of daily fiber intake on reproductive function: the BioCycle Study

BACKGROUND High-fiber diets have been associated with decreased breast cancer risk, likely mediated by the effect of fiber on lowering circulating estrogen concentrations. The influence of fiber on aspects of reproduction, which include ovulation, has not been well studied in premenopausal women. OBJECTIVE The objective was to determine if fiber consumption is associated with hormone concentrations and incident anovulation in healthy, regularly menstruating women. DESIGN The BioCycle Study was a prospective cohort study conducted from 2004 to 2006 that followed 250 women aged 18-44 y for 2 cycles. Dietary fiber consumption was assessed < or =4 times/cycle by using 24-h recall. Outcomes included concentrations of estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which were measured < or =8 times/cycle, and incident anovulation. RESULTS Dietary fiber consumption was inversely associated with hormone concentrations (estradiol, progesterone, LH, and FSH; P < 0.05) and positively associated with the risk of anovulation (P = 0.003) by using random-effects models with adjustment for total calories, age, race, and vitamin E intake. Each 5-g/d increase in total fiber intake was associated with a 1.78-fold increased risk (95% CI: 1.11, 2.84) of an anovulatory cycle. The adjusted odds ratio of 5 g fruit fiber/d was 3.05 (95% CI: 1.07, 8.71). CONCLUSIONS These findings suggest that a diet high in fiber is significantly associated with decreased hormone concentrations and a higher probability of anovulation. Further study of the effect of fiber on reproductive health and of the effect of these intakes in reproductive-aged women is warranted.

Physical activity interventions in pregnancy and risk of gestational diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a common complication of pregnancy associated with an increased incidence of pregnancy complications, adverse pregnancy outcomes, and maternal and fetal risks of chronic health conditions later in life. Physical activity has been proposed to reduce the risk of GDM and is supported by observational studies, but experimental research assessing its effectiveness is limited and conflicting. We aimed to use meta-analysis to synthesize existing randomized controlled studies of physical activity and GDM. DATA SOURCES: We searched MEDLINE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for eligible studies. METHODS OF STUDY SELECTION: The following combination of keywords was used: (pregnant or pregnancy or gestation or gestate or gestational or maternity or maternal or prenatal) AND (exercise or locomotion or activity or training or sports) AND (diabetes or insulin sensitivity or glucose tolerance) AND (random* or trial). Eligibility was restricted to studies that randomized participants to an exercise-only-based intervention (ie, separate from dietary interventions) and presented data regarding GDM risk. Two authors performed the database search, assessment of eligibility, and abstraction of data from included studies, and a third resolved any discrepancies. A total of 469 studies was retrieved, of which 10 met inclusion criteria and could be used for analysis (3,401 participants). TABULATION, INTEGRATION, AND RESULTS: Fixed-effects models were used to estimate summary relative risk (RR) and 95% confidence interval (CI) and I 2 to assess heterogeneity. There was a 28% reduced risk (95% CI 9–42%) in the intervention group compared with the control group (RR 0.72, P=.005). Heterogeneity was low (I 2=12%) and nonsignificant (P=.33). CONCLUSION: The results from this meta-analysis suggest that physical activity in pregnancy provides a slight protective effect against the development of GDM. Studies evaluating type, timing, duration, and compliance of physical activity regimens are warranted to best inform obstetric guidelines.

The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis

OBJECTIVE To evaluate the effect of recombinant LH in assisted reproduction technology (ART) cycles in patients of advanced reproductive age. DESIGN A systematic review and meta-analysis. SETTING Published randomized controlled clinical trials comparing recombinant LH plus recombinant FSH versus recombinant FSH only in patients of advanced reproductive age. PATIENT(S) Patients 35 years and older undergoing assisted reproduction. INTERVENTION(S) Recombinant LH plus recombinant FSH controlled ovarian hyperstimulation (COH) versus recombinant FSH stimulation only in assisted reproduction cycles. MAIN OUTCOME MEASURE(S) Implantation and clinical pregnancy. RESULT(S) Seven trials were identified that met inclusion criteria and comprised 902 assisted reproduction technology cycles. No differences in serum E(2) on the day of hCG administration were reported in any trials. Two trials reported lower oocyte yield and one trial reported lower metaphase II oocyte yield in the recombinant LH-supplemented group. One trial reported higher fertilization rates in the recombinant LH-supplemented group. In a fixed effect model, implantation was higher in the recombinant LH-supplemented group (odds ratio 1.36, 95% confidence interval 1.05-1.78). Similarly, clinical pregnancy was increased in the recombinant LH-supplemented group (odds ratio 1.37, 95% confidence interval 1.03-1.83). CONCLUSION(S) The addition of recombinant LH to ART cycles may improve implantation and clinical pregnancy in patients of advanced reproductive age.

Endogenous Reproductive Hormones and C-reactive Protein Across the Menstrual Cycle The BioCycle Study

C-reactive protein (CRP) is one of the most commonly used markers of acute phase reaction in clinical settings and predictors of cardiovascular risk in healthy women; however, data on its physiologic regulation in premenopausal women are sparse. The objective of this study was to evaluate the association between endogenous reproductive hormones and CRP in the BioCycle Study (2005-2007). Women aged 18-44 years from western New York were followed prospectively for up to 2 menstrual cycles (n = 259). Serum levels of CRP, estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to 8 times per cycle, timed by fertility monitors. CRP levels varied significantly across the cycle (P < 0.001). More women were classified as being at elevated risk of cardiovascular disease (CRP, >3 mg/L) during menses compared with other phases (12.3% vs. 7.4%; P < 0.001). A 10-fold increase in estradiol was associated with a 24.3% decrease in CRP (95% confidence interval: 19.3, 29.0). A 10-fold increase in luteal progesterone was associated with a 19.4% increase in CRP (95% confidence interval: 8.4, 31.5). These results support the hypothesis that endogenous estradiol might have antiinflammatory effects and highlight the need for standardization of CRP measurement to menstrual cycle phase in reproductive-aged women.

To preserve or not to preserve: how difficult is the decision about fertility preservation?

The decision to pursue fertility preservation (FP) after a cancer diagnosis is complex. We examined the prevalence of high decisional conflict and specific factors that influence this decision using the Decisional Conflict Scale (DCS).

Associations between urinary phthalate concentrations and semen quality parameters in a general population

STUDY QUESTION Are urinary phthalate concentrations associated with altered semen quality parameters among males recruited from the general population? SUMMARY ANSWER Urinary levels of metabolites of phthalate diesters are associated with lower total sperm counts, larger sperm head sizes, and higher percentages of morphologically abnormal sperm. WHAT IS KNOWN ALREADY High dose experiments in rats implicate phthalates as anti-androgens. Studies involving infertile men seeking care suggest that phthalates influence measures of semen quality raising concern about the implications for men in the general population. STUDY DESIGN, SIZE, DURATION This prospective cohort study comprised 501 male partners in couples discontinuing contraception to become pregnant, who were recruited from 16 US counties using population-based sampling frameworks from 2005 to 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS Urine and semen samples were obtained at baseline from 473 (94%) men, of whom 378 (80%) men provided a second sample the following month. Urine was analyzed for 14 monoester metabolites of phthalate diesters by high-performance liquid chromatography coupled to tandem mass spectrometry. Semen samples were analyzed for 34 quality parameters categorized as general, motility, morphology, sperm head and sperm chromatin structure. MAIN RESULTS AND THE ROLE OF CHANCE Urinary mono-[2-(carboxymethyl) hexyl] phthalate (MCMHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-benzyl phthalate (MBzP), and mono-isononyl phthalate (MNP) were significantly associated with lower total sperm counts and concentrations, larger sperm head sizes, higher proportions of megalo head sperm morphology, and/or other morphological changes. Urinary mono-methyl phthalate (MMP) and mono-cyclohexyl phthalate (MCPP) were significantly associated with lower sperm motility, and urine mono-2-ethylhexyl phthalate (MEHP) was significantly associated with higher sperm motility. LIMITATIONS, REASONS FOR CAUTION While adverse associations were observed, the implications of the findings for couple fecundity and fertility remain to be established. Cautious interpretation is needed in light of reliance on a single measurement of phthalate measure and no correction for multiple comparisons.

Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference

BackgroundElevated serum bilirubin has been associated with reduced risk of cardiovascular disease (CVD). However, serum bilirubin is also related with several potential confounders related to CVD, such as obesity. Mendelian randomization has been proposed as a method to address challenges to validity from confounding and reverse causality. It utilizes genotype to estimate causal relationships between a gene product and physiological outcomes. In this report, we demonstrate its use in assessing direct causal relations between serum bilirubin levels and CVD risk factors, including obesity, cholesterol, measures of vascular function and blood pressure.MethodsStudy subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels.ResultsSerum bilirubin levels were inversely associated with levels of several cardiovascular disease risk factors, including body mass index (p = 0.003), LDL (p = 0.0005) and total cholesterol (p = 0.0002). In contrast, UGT1A1*28 genotype, a known cause of elevated bilirubin levels, was not significantly associated with any of these traditional CVD risk factors. We did observe an association between genotype and brachial artery diameter (p = 0.003) and cold pressor reactivity (p = 0.01).ConclusionsOur findings imply that the observed association of serum bilirubin levels with body mass index and cholesterol are likely due to confounding and suggest that previously established CVD benefits of increased bilirubin may in part be mediated by the early regulation of vascular structure and reactivity.