Testing gene-gene interactions in genome wide association studies.

Detection of gene-gene interaction has become increasingly popular over the past decade in genome wide association studies (GWAS). Besides traditional logistic regression analysis for detecting interactions between two markers, new methods have been developed in recent years such as comparing linkage disequilibrium (LD) in case and control groups. All these methods form the building blocks of most screening strategies for disease susceptibility loci in GWAS. In this paper, we are interested in comparing the competing methods and providing practical guidelines for selecting appropriate testing methods for interaction in GWAS. We first review a series of existing statistical methods to detect interactions, and then examine different definitions of interactions to gain insight into the theoretical relationship between the existing testing methods. Lastly, we perform extensive simulations to compare powers of various methods to detect either interaction between two markers at two unlinked loci or the overall association allowing for both interaction and main effects. This investigation reveals informative characteristics of various methods that are helpful to GWAS investigators.

Does choice of outdoor heat metric affect heat-related epidemiologic analyses in the US Medicare population?

Outdoor air temperature is associated with increased morbidity and mortality. Other thermal indices theoretically confer greater physiological relevance by incorporating additional meteorological variables. However, the optimal metric for predicting excess deaths or hospitalizations owing to extreme heat among US Medicare beneficiaries remains unknown. Methods: We calculated daily maximum, minimum, and mean outdoor air temperature (T), heat index (HI), wet-bulb globe temperature (WBGT), and Universal Thermal Climate Index (UTCI) for populous US counties and linked estimates with daily all-cause mortality and heat-related hospitalizations among Medicare beneficiaries (2006-2016). We fit distributed-lag nonlinear models for each metric and compared relative risks (RRs) at the 99th percentile. Results: Across all heat metrics, extreme heat was statistically significantly associated with elevated risks of morbidity and mortality. Associations were more pronounced for maximum daily values versus the corresponding minimum for the same metric. The starkest example was between HImax (RR = 1.14; 95% confidence interval [CI] = 1.12, 1.15) and HImin (RR = 1.10; 95% CI = 1.09, 1.11) for hospitalizations. When comparing RRs across heat metrics, we found no statistically significant differences within the minimum and maximum heat values (i.e., no significant differences between Tmax/HImax/WBGTmax/UTCImax or between Tmin/HImin/WBGTmin/UTCImin). We found similar relationships across the National Climate Assessment regions. Conclusion: Among Medicare beneficiaries in populous US counties, daily maximum and mean values of outdoor heat are associated with greater RRs of heat-related morbidity and all-cause mortality versus minimum values of the same metric. The choice of heat metric (e.g., temperature versus HI) does not appear to substantively affect risk calculations in this population.

Preoperative Use of Methotrexate and the Risk of Early Postoperative Complications in Patients with Inflammatory Bowel Disease.

BACKGROUND: Preoperative immunosuppressive use among patients with Crohn's disease or ulcerative colitis may lead to an increased risk of postoperative complications. There is limited information on the preoperative safety profile of methotrexate (MTX) in inflammatory bowel disease (IBD). METHODS: A retrospective study of patients who underwent abdominal surgery for IBD between 1993 and 2012 was performed and records abstracted, including preoperative use of MTX, azathioprine/6-mercaptopurine, antitumor necrosis factor, and corticosteroids. Early postoperative complications, including death, septic, and nonseptic complications were identified. A meta-analysis was also performed on the use of preoperative MTX in patients with IBD or rheumatoid arthritis. RESULTS: A total of 180 patients with IBD underwent abdominal surgery. A total of 15 patients received MTX either monotherapy or in combination therapy. Total early postoperative complications were identified in 71 (39%) patients, specifically 5 patients on oral MTX. A total of 51 cases (28%) of septic complications and 20 (11%) nonseptic. No significant association between the use of MTX and early postoperative complications was found. The odds ratio (OR) of complications versus no complications associated with MTX was 0.75 (95% CI, 0.25-2.29) and with azathioprine/6-mercaptopurine, OR 1.48 (95% CI, 0.77-2.84). The odds of a septic complication associated with MTX were 0.58 (95% CI, 0.09-3.73), and higher in azathioprine/6-mercaptopurine, OR 3.97 (95% CI, 1.03-15.3). Our meta-analysis also did not reveal an increased risk of postoperative complications in IBD or rheumatoid arthritis on preoperative MTX (OR 0.62, 95% CI, 0.34-1.15). CONCLUSIONS: Preoperative MTX use does not seem to be associated with early postoperative complications in IBD.

The association of psoriasiform rash with anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease: a single academic center case series.

BACKGROUND & AIMS: Anti-tumor necrosis factors (anti-TNF) including infliximab, adalimumab and certolizumab pegol are used to treat Crohn's disease (CD) and ulcerative colitis (UC). Paradoxically, while also indicated for the treatment of psoriasis, anti-TNF therapy has been associated with development of psoriasiform lesions in IBD patients and can compel discontinuation of therapy. We aim to investigate IBD patient, clinical characteristics, and frequency for the development of and outcomes associated with anti-TNF induced psoriasiform rash. METHODS: We identify IBD patients on anti-TNFs with an onset of a psoriasiform rash. Patient characteristics, duration of anti-TNF, concomitant immunosuppressants, lesion distribution, and outcomes of rash are described. RESULTS: Of 1004 IBD patients with exposure to anti-TNF therapy, 27 patients (2.7%) developed psoriasiform lesions. Psoriasiform rash cases stratified by biologic use were 1.3% for infliximab, 4.1% for adalimumab, and 6.4% for certolizumab. Average time on treatment (206.3weeks) and time on treatment until onset of psoriasiform lesions (126.9weeks) was significantly higher in the infliximab group. The adalimumab group had the highest need for treatment discontinuation (60%). The majority (59.3%) of patients were able to maintain on anti-TNFs despite rash onset. Among patients that required discontinuation (40.7%), the majority experienced improvement with a subsequent anti-TNF (66.7%). CONCLUSION: 27 cases of anti-TNF associated psoriasiform lesions are reported. Discontinuation of anti-TNF treatment is unnecessary in the majority. Dermatologic improvement was achieved in the majority with a subsequent anti-TNF, suggesting anti-TNF induced psoriasiform rash is not necessarily a class effect.