GADGETS: a genetic algorithm for detecting epistasis using nuclear families.

MOTIVATION: Epistasis may play an etiologic role in complex diseases, but research has been hindered because identification of interactions among sets of single nucleotide polymorphisms (SNPs) requires exploration of immense search spaces. Current approaches using nuclear families accommodate at most several hundred candidate SNPs. RESULTS: GADGETS detects epistatic SNP-sets by applying a genetic algorithm to case-parent or case-sibling data. To allow for multiple epistatic sets, island subpopulations of SNP-sets evolve separately under selection for evident joint relevance to disease risk. The software evaluates the identified SNP-sets via permutation testing and provides graphical visualization. GADGETS correctly identified epistatic SNP-sets in realistically simulated case-parent triads with 10 000 candidate SNPs, far more SNPs than competitors can handle, and it outperformed competitors in simulations with many fewer SNPs. Applying GADGETS to family-based oral-clefting data from dbGaP identified SNP-sets with possible epistatic effects on risk. AVAILABILITY AND IMPLEMENTATION: GADGETS is part of the epistasisGA package at https://github.com/mnodzenski/epistasisGA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Pain of local anesthetic injection of lidocaine during subsequent stages of Mohs micrographic surgery: A multicenter prospective cohort study.

BACKGROUND: Patients awake during staged cutaneous surgery procedures may experience procedure-related pain. OBJECTIVE: To determine whether the level of pain associated with local anesthetic injections prior to each Mohs stage increases with subsequent Mohs stages. METHODS: Multicenter longitudinal cohort study. Patients rated pain (visual analog scale: 1-10) after anesthetic injection preceding each Mohs stage. RESULTS: Two hundred fifty-nine adult patients presenting for Mohs who required multiple Mohs stages at 2 academic medical centers were enrolled; 330 stages were excluded due to complete anesthesia from prior stages, and 511 stages were analyzed. Mean visual analog scale pain ratings were nominally but not significantly different for subsequent stages of Mohs surgery (stage 1: 2.5; stage 2: 2.5; stage 3: 2.7: stage 4:2.8: stage 5: 3.2; P = .770). Between 37% and 44% experienced moderate pain, and 9.5% and 12.5% severe pain, during first as versus subsequent stages (P > .05) LIMITATIONS: Both academic centers were in urban areas. Pain rating is inherently subjective. CONCLUSIONS: Patients did not report significantly increased anesthetic injection pain level during subsequent stages of Mohs.

Genome-wide associations for birth weight and correlations with adult disease.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Delays in breast cancer care by race and sexual orientation: Results from a national survey with diverse women in the United States.

BACKGROUND: Despite known differences in breast cancer by both race and sexual orientation, data on the intersectional experiences of Black sexual minority women (BSMW) along the care continuum are scant. This study sought to understand delays in breast cancer care by examining the intersection of race and sexual orientation. METHODS: This online, cross-sectional survey enrolled racially and sexually diverse women aged ≥ 35 years who had been diagnosed with breast cancer within the prior 10 years or had an abnormal screening in the prior 24 months. The authors calculated summary statistics by race/sexual orientation categories, and they conducted univariate and multivariable modeling by using multiple imputation for missing data. RESULTS: BSMW (n = 101) had the highest prevalence of care delays with 5.17-fold increased odds of a care delay in comparison with White heterosexual women (n = 298) in multivariable models. BSMW reported higher intersectional stigma and lower social support than all other groups. In models adjusted for race, sexual orientation, and income, intersectional stigma was associated with a 2.43-fold increase in care delays, and social support was associated with a 32% decrease in the odds of a care delay. CONCLUSIONS: Intersectional stigma may be an important driver of breast cancer inequities for BSMW. Reducing stigma and ensuring access to appropriate social support that addresses known barriers can be an important approach to reducing inequities in the breast cancer care continuum.

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

Maternal metabolites during pregnancy are associated with newborn outcomes and hyperinsulinaemia across ancestries.

AIMS/HYPOTHESIS: We aimed to determine the association of maternal metabolites with newborn adiposity and hyperinsulinaemia in a multi-ethnic cohort of mother-newborn dyads. METHODS: Targeted and non-targeted metabolomics assays were performed on fasting and 1 h serum samples from a total of 1600 mothers in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, underwent an OGTT at ~28 weeks gestation and whose newborns had anthropometric measurements at birth. RESULTS: In this observational study, meta-analyses demonstrated significant associations of maternal fasting and 1 h metabolites with birthweight, cord C-peptide and/or sum of skinfolds across ancestry groups. In particular, maternal fasting triacylglycerols were associated with newborn sum of skinfolds. At 1 h, several amino acids, fatty acids and lipid metabolites were associated with one or more newborn outcomes. Network analyses revealed clusters of fasting acylcarnitines, amino acids, lipids and fatty acid metabolites associated with cord C-peptide and sum of skinfolds, with the addition of branched-chain and aromatic amino acids at 1 h. CONCLUSIONS/INTERPRETATION: The maternal metabolome during pregnancy is associated with newborn outcomes. Maternal levels of amino acids, acylcarnitines, lipids and fatty acids and their metabolites during pregnancy relate to fetal growth, adiposity and cord C-peptide, independent of maternal BMI and blood glucose levels.

Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.

AIMS/HYPOTHESIS: Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. METHODS: The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA1c values during pregnancy. RESULTS: Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA1c measures, ORs for each child adiposity outcome were in the range of 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose, 1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA1c. Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls. CONCLUSIONS/INTERPRETATION: Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.

Fat mass estimation in neonates: anthropometric models compared with air displacement plethysmography.

Newborn adiposity, a nutritional measure of the maternal-fetal intra-uterine environment, is representative of future metabolic health. An anthropometric model using weight, length and flank skinfold to estimate neonatal fat mass has been used in numerous epidemiological studies. Air displacement plethysmography (ADP), a non-invasive technology to measure body composition, is impractical for large epidemiological studies. The study objective was to determine the consistency of the original anthropometric fat mass estimation equation with ADP. Full-term neonates were studied at 12-72 h of life with weight, length, head circumference, flank skinfold thickness and ADP measurements. Statistical analyses evaluated three models to predict neonatal fat mass. Lin's concordance correlation coefficient, mean prediction error and root mean squared error between the predicted and observed ADP fat mass values were used to evaluate the models, where ADP was considered the gold standard. A multi-ethnic cohort of 468 neonates were studied. Models (M) for predicting fat mass were developed using 349 neonates from site 1, then independently evaluated in 119 neonates from site 2. M0 was the original anthropometric model, M1 used the same variables as M0 but with updated parameters and M2 additionally included head circumference. In the independent validation cohort, Lin's concordance correlation estimates demonstrated reasonable accuracy (model 0: 0·843, 1: 0·732, 2: 0·747). Mean prediction error and root mean squared error in the independent validation was much smaller for M0 compared with M1 and M2. The original anthropometric model to estimate neonatal fat mass is reasonable for predicting ADP, thus we advocate its continued use in epidemiological studies.

Assessing Skin Biopsy Rates for Histologic Findings Indicative of Nonpathological Cutaneous Disease.

BACKGROUND: Recent increase in skin biopsies has been attributed to an epidemic of skin cancer. This may be avoidable, with potential savings. OBJECTIVE: To determine whether the increase in skin biopsies is attributable to increasing frequency of biopsies associated with histology lacking pathological cutaneous disease. Pathological cutaneous disease was defined as (1) a malignancy, precancerous lesion, or lesion of uncertain behavior; or (2) disease symptomatic or associated with adverse quality of life impact. PATIENTS AND METHODS: Retrospective cohort study, 2006 to 2013 of dermatology practice serving Florida and Ohio. Data were a consecutive sample of skin biopsies for diagnosis of dermatologic disease. RESULTS: A total of 267,706 biopsies by an average of 52 providers per month from January 06 to December 13 were analyzed. Number of biopsies per visit increased 2% per year (RR: 1.02, CI: 1.00-1.04). Likelihood of biopsy associated with histology indicative of nonpathological cutaneous disease did not increase over time (OR: 0.99, CI: 0.95-1.03, p = .6302). CONCLUSION: Rates of biopsies associated with nonpathological cutaneous disease is not increasing. Overall biopsy rates per visit have gradually increased; this seems attributable to greater rates of detection of pathological dermatologic disease.

Massively parallel quantification of the regulatory effects of noncoding genetic variation in a human cohort.

We report a novel high-throughput method to empirically quantify individual-specific regulatory element activity at the population scale. The approach combines targeted DNA capture with a high-throughput reporter gene expression assay. As demonstration, we measured the activity of more than 100 putative regulatory elements from 95 individuals in a single experiment. In agreement with previous reports, we found that most genetic variants have weak effects on distal regulatory element activity. Because haplotypes are typically maintained within but not between assayed regulatory elements, the approach can be used to identify causal regulatory haplotypes that likely contribute to human phenotypes. Finally, we demonstrate the utility of the method to functionally fine map causal regulatory variants in regions of high linkage disequilibrium identified by expression quantitative trait loci (eQTL) analyses.

Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity.

Importance: The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear. Objective: To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years' postpartum. Design, Setting, and Participants: The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016). Exposures: Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose level ≥180 mg/dL; 2-hour plasma glucose level ≥153 mg/dL). Main Outcomes and Measures: Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes). Results: The analytic cohort included 4697 mothers (mean [SD] age, 41.7 [5.7] years) and 4832 children (mean [SD] age, 11.4 [1.2] years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio [OR], 3.44 [95% CI, 2.85 to 4.14]; risk difference [RD], 25.7% [95% CI, 21.7% to 29.7%]). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, -0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%). Conclusions and Relevance: Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.

Mixture model normalization for non-targeted gas chromatography/mass spectrometry metabolomics data.

BACKGROUND: Metabolomics offers a unique integrative perspective for health research, reflecting genetic and environmental contributions to disease-related phenotypes. Identifying robust associations in population-based or large-scale clinical studies demands large numbers of subjects and therefore sample batching for gas-chromatography/mass spectrometry (GC/MS) non-targeted assays. When run over weeks or months, technical noise due to batch and run-order threatens data interpretability. Application of existing normalization methods to metabolomics is challenged by unsatisfied modeling assumptions and, notably, failure to address batch-specific truncation of low abundance compounds. RESULTS: To curtail technical noise and make GC/MS metabolomics data amenable to analyses describing biologically relevant variability, we propose mixture model normalization (mixnorm) that accommodates truncated data and estimates per-metabolite batch and run-order effects using quality control samples. Mixnorm outperforms other approaches across many metrics, including improved correlation of non-targeted and targeted measurements and superior performance when metabolite detectability varies according to batch. For some metrics, particularly when truncation is less frequent for a metabolite, mean centering and median scaling demonstrate comparable performance to mixnorm. CONCLUSIONS: When quality control samples are systematically included in batches, mixnorm is uniquely suited to normalizing non-targeted GC/MS metabolomics data due to explicit accommodation of batch effects, run order and varying thresholds of detectability. Especially in large-scale studies, normalization is crucial for drawing accurate conclusions from non-targeted GC/MS metabolomics data.

Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes.

AIMS/HYPOTHESIS: Maternal obesity increases the risk for large-for-gestational-age birth and excess newborn adiposity, which are associated with adverse long-term metabolic outcomes in offspring, probably due to effects mediated through the intrauterine environment. We aimed to characterise the maternal metabolic milieu associated with maternal BMI and its relationship to newborn birthweight and adiposity. METHODS: Fasting and 1 h serum samples were collected from 400 European-ancestry mothers in the Hyperglycaemia and Adverse Pregnancy Outcome Study who underwent an OGTT at ∼28 weeks gestation and whose offspring had anthropometric measurements at birth. Metabolomics assays were performed using biochemical analyses of conventional clinical metabolites, targeted MS-based measurement of amino acids and acylcarnitines and non-targeted GC/MS. RESULTS: Per-metabolite analyses demonstrated broad associations with maternal BMI at fasting and 1 h for lipids, amino acids and their metabolites together with carbohydrates and organic acids. Similar metabolite classes were associated with insulin resistance with unique associations including branched-chain amino acids. Pathway analyses indicated overlapping and unique associations with maternal BMI and insulin resistance. Network analyses demonstrated collective associations of maternal metabolite subnetworks with maternal BMI and newborn size and adiposity, including communities of acylcarnitines, lipids and related metabolites, and carbohydrates and organic acids. Random forest analyses demonstrated contribution of lipids and lipid-related metabolites to the association of maternal BMI with newborn outcomes. CONCLUSIONS/INTERPRETATION: Higher maternal BMI and insulin resistance are associated with broad-based changes in maternal metabolites, with lipids and lipid-related metabolites accounting, in part, for the association of maternal BMI with newborn size at birth.

Transversions have larger regulatory effects than transitions.

BACKGROUND: Transversions (Tv's) are more likely to alter the amino acid sequence of proteins than transitions (Ts's), and local deviations in the Ts:Tv ratio are indicative of evolutionary selection on genes. Whether the two different types of mutations have different effects in non-protein-coding sequences remains unknown. Genetic variants primarily impact gene expression by disrupting the binding of transcription factors (TFs) and other DNA-binding proteins. Because Tv's cause larger changes in the shape of a DNA backbone, we hypothesized that Tv's would have larger impacts on TF binding and gene expression. RESULTS: Here, we provide multiple lines of evidence demonstrating that Tv's have larger impacts on regulatory DNA including analyses of TF binding motifs and allele-specific TF binding. In these analyses, we observed a depletion of Tv's within TF binding motifs and TF binding sites. Using massively parallel population-scale reporter assays, we also provided empirical evidence that Tv's have larger effects than Ts's on the activity of human gene regulatory elements. CONCLUSIONS: Tv's are more likely to disrupt TF binding, resulting in larger changes in gene expression. Although the observed differences are small, these findings represent a novel, fundamental property of regulatory variation. Understanding the features of functional non-coding variation could be valuable for revealing the genetic underpinnings of complex traits and diseases in future studies.

Nonablative Fractional Laser Resurfacing for Acne Scarring in Patients With Fitzpatrick Skin Phototypes IV-VI.

BACKGROUND: There is a paucity of studies investigating laser resurfacing in Fitzpatrick skin phototypes (SPT) IV to VI. OBJECTIVE: To assess the efficacy and safety of fractional nonablative laser resurfacing in the treatment of acne scarring in patients with SPT IV to VI. METHODS AND MATERIALS: The authors conducted a randomized, investigator-blinded and rater-blinded, split-face comparative study of adults with SPT IV to VI and facial acne scars treated with 2 different density settings and the same fluence. RESULTS: Quantitative global scarring grading system (QGSGS) scores were significantly improved from baseline at 16 and 24 weeks (p = .0277). Improvements in QGSGS scores after higher and lower density treatments were statistically similar (p = .96). The live-blinded dermatologist, the blinded dermatologist photoraters, and the patients rated scars as being significantly more improved by visual analog scale at weeks 16 and 24 compared with baseline (p < .001) for both treatment densities. Five of 7 and 3 of 7 patients in the higher and lower density group, respectively, experienced mild or moderate hyperpigmentation as an investigator observed site reaction. CONCLUSION: The nonablative 1550-nm fractional laser is safe and efficacious in treating acne scaring in Fitzpatrick skin types IV to VI. Self-limited postinflammatory hyperpigmentation was a common occurrence, especially with higher treatment densities.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.

IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Metabomxtr: an R package for mixture-model analysis of non-targeted metabolomics data.

SUMMARY: Non-targeted metabolomics technologies often yield data in which abundance for any given metabolite is observed and quantified for some samples and reported as missing for other samples. Apparent missingness can be due to true absence of the metabolite in the sample or presence at a level below detectability. Mixture-model analysis can formally account for metabolite 'missingness' due to absence or undetectability, but software for this type of analysis in the high-throughput setting is limited. The R package metabomxtr has been developed to facilitate mixture-model analysis of non-targeted metabolomics data in which only a portion of samples have quantifiable abundance for certain metabolites. AVAILABILITY AND IMPLEMENTATION: metabomxtr is available through Bioconductor. It is released under the GPL-2 license. CONTACT: dscholtens@northwestern.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A systematic review of reporting in randomized controlled trials in Dermatologic Surgery: Jadad scores, power analysis, and sample size determination.

BACKGROUND: Dermatologic surgery is a fruitful research area that has spawned numerous randomized control trials (RCTs). OBJECTIVE: To assess the quality of reporting of randomization, blinding, sample size, and power analysis in RCTs published in the journal Dermatologic Surgery. MATERIALS AND METHODS: Randomized control trials published in Dermatologic Surgery between 1995 and 2012 were assessed regarding the quality of trial reporting. Data extraction performed independently by 2 data extractors. RESULTS: Dramatic increases in the numbers of RCTs in dermatologic surgery were noted in successive 5-year periods, from 39 in 1995 to 1999 to 66 in 2000 to 2004 and 131 in 2005 to 2009. The median Jadad score for articles from 1995 to 1999 was 1 and was 2 for articles since 2000. Subjects per study were 20 during 1995 to 1999, 25.5 from 2000 to 2004, and over 30 since 2005. Power analysis with sample size determination was reported in 0 articles during 1995 to 1999; greater than 13% of articles since 2005. Alpha level was specified for 37% of RCTs from 1995 to 1999 and 64% to 70% since 2005. CONCLUSION: During the last 20 years, the number of RCTs in Dermatologic Surgery has grown rapidly, almost doubling every 5 years, because the number of subjects per study has also increased and the quality of reporting has significantly improved.

Subcision with and without suction for acne scars: a split-faced, rater-blinded randomized control trial.

Therapeutic options for acne scars include subcision and suction with microdermabrasion, but these treatment modalities have not been studied in conjunction. To compare effectiveness of subcision alone versus subcision with suction for the treatment of facial acne scars. Randomized, split-faced, evaluator-blinded control trial. Participants underwent one subcision treatment on both sides of the face followed by 10 sessions of suction to one side. Photographs at baseline, 1-month, and 4-months were assessed. Primary outcome measures were the validated Acne Scar Severity Scale (ASSS) (0 = no acne scarring, 4 = severe), Acne Scar Improvement Grading Scale (ASIGS) (-100 to 100%), and modified Quantitative Global Scarring Grades (QGSG) (point-based questionnaire instrument), as well as subject preference. Twenty-eight treatment areas and 154 treatments were analyzed. Dermatologist raters found no differences between subcision alone and subcision-suction at 1-month or 4-months. Mean subject-assessed percent improvement for subcision-suction was higher than that for subcision alone at 1-month (37% versus 24%, p = 0.04) but not at 4-months (p = 0.37). Subjects preferred combination therapy to monotherapy at 1-month (50% vs. 21%) and 4-months (43% vs. 21%). While blinded raters did not detect significant differences, subjects perceived combination treatment as working more quickly than monotherapy, and preferred combination treatment at all time points.Clinical trial registration NCT01696513 on Clinicaltrials.gov.