Implementation and evaluation of a new methane model within a dynamic global vegetation model: LPJ-WHyMe v1.3.1

For the first time, a model that simulates methane emissions from northern peatlands is incorporated directly into a dynamic global vegetation model. The model, LPJ-WHyMe (LPJ <B>W</B>etland <B>Hy</B>drology and <B>Me</B>thane), was previously modified in order to simulate peatland hydrology, permafrost dynamics and peatland vegetation. LPJ-WHyMe simulates methane emissions using a mechanistic approach, although the use of some empirical relationships and parameters is unavoidable. The model simulates methane production, three pathways of methane transport (diffusion, plant-mediated transport and ebullition) and methane oxidation. A sensitivity test was conducted to identify the most important factors influencing methane emissions, followed by a parameter fitting exercise to find the best combination of parameter values for individual sites and over all sites. A comparison of model results to observations from seven sites resulted in normalised root mean square errors (NRMSE) of 0.40 to 1.15 when using the best site parameter combinations and 0.68 to 1.42 when using the best overall parameter combination

Clinical validity assessment of a breast cancer risk model combining genetic and clinical information

_Background:_ The extent to which common genetic variation can assist in breast cancer (BCa) risk assessment is unclear. We assessed the addition of risk information from a panel of BCa-associated single nucleotide polymorphisms (SNPs) on risk stratification offered by the Gail Model.

_Methods:_ We selected 7 validated SNPs from the literature and genotyped them among white women in a nested case-control study within the Women’s Health Initiative Clinical Trial. To model SNP risk, previously published odds ratios were combined multiplicatively. To produce a combined clinical/genetic risk, Gail Model risk estimates were multiplied by combined SNP odds ratios. We assessed classification performance using reclassification tables and receiver operating characteristic (ROC) curves. 

_Results:_ The SNP risk score was well calibrated and nearly independent of Gail risk, and the combined predictor was more predictive than either Gail risk or SNP risk alone. In ROC curve analysis, the combined score had an area under the curve (AUC) of 0.594 compared to 0.557 for Gail risk alone. For reclassification with 5-year risk thresholds at 1.5% and 2%, the net reclassification index (NRI) was 0.085 (Z = 4.3, P = 1.0×10^-5^). Focusing on women with Gail 5-year risk of 1.5-2% results in an NRI of 0.195 (Z = 3.8, P = 8.6×10^−5^).

_Conclusions:_ Combining clinical risk factors and validated common genetic risk factors results in improvement in classification of BCa risks in white, postmenopausal women. This may have implications for informing primary prevention and/or screening strategies. Future research should assess the clinical utility of such strategies.
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On Two-Stage Hypothesis Testing Procedures Via Asymptotically Independent Statistics

Kooperberg and LeBlanc (2008) proposed a two-stage testing procedure to screen for significant interactions in genome-wide association (GWA) studies by a soft threshold on marginal associations (MA), though its theoretical properties and generalization have not been elaborated. In this article, we discuss conditions that are required to achieve strong control of the Family-Wise Error Rate (FWER) by such procedures for low or high-dimensional hypothesis testing. We provide proof of asymptotic independence of marginal association statistics and interaction statistics in linear regression, logistic regression, and Cox proportional hazard models in a randomized clinical trial (RCT) with a rare event. In case-control studies nested within a RCT, a complementary criterion, namely deviation from baseline independence (DBI) in the case-control sample, is advocated as a screening tool for discovering significant interactions or main effects. Simulations and an application to a GWA study in Women’s Health Initiative (WHI) are presented to show utilities of the proposed two-stage testing procedures in pharmacogenetic studies

The Gambian Bone and Muscle Ageing Study: Baseline Data from a Prospective Observational African Sub-Saharan Study

The Gambian Bone and Muscle Ageing Study is a prospective observational study investigating bone and muscle ageing in men and women from a poor, subsistence farming community of The Gambia, West Africa. Musculoskeletal diseases, including osteoporosis and sarcopenia, form a major part of the current global non-communicable disease burden. By 2050, the vast majority of the world’s ageing population will live in low- and middle-income countries with an estimated two-fold rise in osteoporotic fracture. The study design was to characterise change in bone and muscle outcomes and to identify possible preventative strategies for fracture and sarcopenia in the increasing ageing population. Men and women aged ≥40 years from the Kiang West region of The Gambia were recruited with stratified sampling by sex and age. Baseline measurements were completed in 488 participants in 2012 who were randomly assigned to follow-up between 1.5 and 2 years later. Follow-up measurements were performed on 465 participants approximately 1.7 years after baseline measurements. The data set comprises a wide range of measurements on bone, muscle strength, anthropometry, biochemistry, and dietary intake. Questionnaires were used to obtain information on health, lifestyle, musculoskeletal pain, and reproductive status. Baseline cross-sectional data show preliminary evidence for bone mineral density and muscle loss with age. Men had greater negative differences in total body lean mass with age than women following adjustments for body size. From peripheral quantitative computed tomography scans, greater negative associations between bone outcomes and age at the radius and tibia were shown in women than in men. Ultimately, the findings from The Gambian Bone and Muscle Ageing Study will contribute to the understanding of musculoskeletal health in a transitioning population and better characterise fracture and sarcopenia incidence in The Gambia with an aim to the development of preventative strategies against both

Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group.

Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option

Eating Pattern Response to a Low-Fat Diet Intervention and Cardiovascular Outcomes in Normotensive Women: The Women's Health Initiative.

BackgroundWomen without cardiovascular disease (CVD) or hypertension at baseline assigned to intervention in the Women's Health Initiative Dietary Modification (DM) trial experienced 30% lower risk of coronary heart disease (CHD), whereas results in women with hypertension or prior CVD could have been confounded by postrandomization use of statins.ObjectivesIntervention participants reported various self-selected changes to achieve the 20% total fat goals. Reviewed are intervention compared with comparison group HRs for CHD, stroke, and total CVD in relation to specific dietary changes in normotensive participants.MethodsDietary change was assessed by comparing baseline with year 1 FFQ data in women (n = 10,371) without hypertension or CVD at baseline with intake of total fat above the median to minimize biases due to use of the FFQ in trial eligibility screening.ResultsIntervention participants self-reported compensating reduced energy intake from total fat by increasing carbohydrate and protein. Specifically they increased plant protein, with those in the upper quartile (increased total protein by ≥3.3% of energy) having a CHD HR of 0.39 (95% CI: 0.22, 0.71), compared with 0.92 (95% CI: 0.57, 1.48) for those in the lower quartile of change (decreased total protein ≥0.6% of energy), with P-trend of 0.04. CHD HR did not vary significantly with change in percentage energy from carbohydrate, and stroke HR did not vary significantly with any macronutrient changes. Scores reflecting adherence to recommended dietary patterns including the Dietary Approaches to Stop Hypertension Trial and the Healthy Eating Index showed favorable changes in the intervention group.ConclusionsIntervention group total fat reduction replaced with increased carbohydrate and some protein, especially plant-based protein, was related to lower CHD risk in normotensive women without CVD who reported high baseline total fat intake. This trial was registered at clinicaltrials.gov as NCT00000611. Link to the WHI trial protocol: https://www.whi.org/about/SitePages/Dietary%20Trial.aspx

Proteomic risk markers for coronary heart disease and stroke: validation and mediation of randomized trial hormone therapy effects on these diseases

Background: We previously reported mass spectrometry-based proteomic discovery research to identify novel plasma proteins related to the risk of coronary heart disease (CHD) and stroke, and to identify proteins with concentrations affected by the use of postmenopausal hormone therapy. Here we report CHD and stroke risk validation studies for highly ranked proteins, and consider the extent to which protein concentration changes relate to disease risk or provide an explanation for hormone therapy effects on these outcomes. Methods: Five proteins potentially associated with CHD (beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), thrombospondin-1(THBS1), complement factor D pre-protein (CFD), and insulin-like growth factor binding protein 1 (IGFBP1)) and five potentially associated with stroke (B2M, IGFBP2, IGFBP4, IGFBP6, and hemopexin (HPX)) had high discovery phase significance level ranking and an available ELISA assay, and were included in case-control validation studies within the Women’s Health Initiative (WHI) hormone therapy trials. Protein concentrations, at baseline and 1 year following randomization, were assessed for 358 CHD cases and 362 stroke cases, along with corresponding disease-free controls. Disease association, and mediation of estrogen-alone and estrogen plus progestin effects on CHD and stroke risk, were assessed using logistic regression. Results: B2M, THBS1, and CFD were confirmed (P <0.05) as novel CHD risk markers, and B2M, IGFBP2, and IGFBP4 were confirmed as novel stroke disease risk markers, while the assay for HPX proved to be unreliable. The change from baseline to 1 year in B2M was associated (P <0.05) with subsequent stroke risk, and trended similarly with subsequent CHD risk. Change from baseline to 1 year in IGFBP1 was also associated with CHD risk, and this change provided evidence of hormone therapy effect mediation. Conclusions: Plasma B2M is confirmed to be an informative risk marker for both CHD and stroke. The B2M increase experienced by women during the first year of hormone therapy trial participation conveys cardiovascular disease risk. The increase in IGFBP1 similarly conveys CHD risk, and the magnitude of the IGFBP1 increase following hormone therapy may be a mediator of hormone therapy effects. Plasma THBS1 and CFD are confirmed as CHD risk markers, and plasma IGFBP4 and IGFBP2 are confirmed as stroke risk markers. Clinical trials registration ClinicalTrials.gov identifier: NCT0000061

Data analysis methods and the reliability of analytic epidemiologic research.

Publications that compare randomized controlled trial and cohort study results on the effects of postmenopausal estrogen-plus-progestin therapy are reviewed. The 2 types of studies agree in identifying an early elevation in coronary heart disease risk, and a later developing elevation in breast cancer risk. Effects among women who begin hormone therapy within a few years after the menopause may be comparatively more favorable for coronary heart disease and less favorable for breast cancer. These analyses illustrate the potential of modern data analysis methods to enhance the reliability and interpretation of epidemiologic data

Sex hormone associations with breast cancer risk and the mediation of randomized trial postmenopausal hormone therapy effects

Introduction: Paradoxically, a breast cancer risk reduction with conjugated equine estrogens (CEE) and a risk elevation with CEE plus medroxyprogesterone acetate (CEE + MPA) were observed in the Women’s Health Initiative (WHI) randomized controlled trials. The effects of hormone therapy on serum sex hormone levels, and on the association between baseline sex hormones and disease risk, may help explain these divergent breast cancer findings. Methods: Serum sex hormone concentrations were measured for 348 breast cancer cases in the CEE + MPA trial and for 235 cases in the CEE trial along with corresponding pair-matched controls, nested within the WHI trials of healthy postmenopausal women. Association and mediation analyses, to examine the extent to which sex hormone levels and changes can explain the breast cancer findings, were conducted using logistic regression. Results: Following CEE treatment, breast cancer risk was associated with higher concentrations of baseline serum estrogens, and with lower concentrations of sex hormone binding globulin. However, following CEE + MPA, there was no association of breast cancer risk with baseline sex hormone levels. The sex hormone changes from baseline to year 1 provided an explanation for much of the reduced breast cancer risk with CEE. Specifically, the treatment odds ratio (95% confidence interval) increased from 0.71 (0.43, 1.15) to 0.92 (0.41, 2.09) when the year 1 measures were included in the logistic regression analysis. In comparison, the CEE + MPA odds ratio was essentially unchanged when these year 1 measures were included. Conclusions: Breast cancer risk remains low following CEE use among women having favorable baseline sex hormone profiles, but CEE + MPA evidently produces a breast cancer risk for all women similar to that for women having an unfavorable baseline sex hormone profile. These patterns could reflect breast ductal epithelial cell stimulation by CEE + MPA that is substantially avoided with CEE, in conjunction with relatively more favorable effects of either regimen following a sustained period of estrogen deprivation. These findings may have implications for other hormone therapy formulations and routes of delivery. Trial registration clinicaltrials.gov identifier: NCT00000611