Multiple testing for SNP-SNP interactions

Most genetic diseases are complex, i.e. associated to combinations of SNPs rather than individual SNPs. In the last few years, this topic has often been addressed in terms of SNP-SNP interaction patterns given as expressions linked by logical operators. Methods for multiple testing in high-dimensional settings can be applied when many SNPs are considered simultaneously. However, another less well-known multiple testing problem arises within a fixed subset of SNPs when the logic expression is chosen optimally. In this article, we propose a general asymptotic approach for deriving the distribution of the maximally selected chi-square statistic in various situations. We show how this result can be used for testing logic expressions - in particular SNP-SNP interaction patterns - while controlling for multiple comparisons. Simulations show that our method provides multiple testing adjustment when the logic expression is chosen such as to maximize the statistic. Its benefit is demonstrated through an application to a real dataset from a large population-based study considering allergy and asthma in KORA. An implementation of our method is available from the Comprehensive R Archive Network (CRAN) as R package 'SNPmaxsel'

Acupuncture randomized trials (ART) in patients with chronic low back pain and osteoarthritis of the knee - Design and protocols

Background: We report on the study design and protocols of two randomized controlled trials (Acupuncture Randomized Trials = ART) that investigate the efficacy of acupuncture in the treatment of chronic low back pain and osteoarthritis of the knee, respectively. Objective: To investigate whether acupuncture is more efficacious than (a) no treatment or (b) minimal acupuncture in the treatment of low back pain and osteoarthritis. Design: Two randomized, controlled, multicenter trials with three treatment arms and a total follow-up time of 52 weeks. Setting: 30 practitioners and outpatient units in Germany specialized in acupuncture treatment. Patients: 300 patients will be included in each study. In the low back pain trial, patients will be included according to clinical diagnosis. In the osteoarthritis pain trial, patients will be included according to the American College of Rheumatology criteria. Interventions: Patients are randomly assigned to receive either (1) semi-standardized acupuncture (150 patients), (2) minimal acupuncture at non-acupuncture points (75 patients), or (3) no treatment for two months followed by semi-standardized acupuncture (75 patients, waiting list control). Acupuncture treatment consists of 12 sessions per patient over a period of 8 weeks. Main Outcome Measure: The main outcome measure is the difference between baseline and the end of the 8-week treatment period in the following parameters: pain intensity as measured by a visual analogue scale (VAS; 0-100 mm) in the low back pain trial and by the Western Ontario and McMaster Universities Osteoarthritis Score (WOMAC) in the osteoarthritis trial. Outlook: The results of these two studies (available in 2004) will provide health care providers and policy makers with the information needed to make scientifically sound assessments of acupuncture therapy

PDB3: USE OF BOOTSTRAP IN A COST-OF-ILLNESS STUDY TO DERIVE ACCURACY OF ESTIMATES

Farrando, Jordi;Febles, Maria Dolors ;Henrich, Jordi;Tarrasó, Olga ;Fuertes, J.C.;Pérez, S

Neglect of the histological diagnostics of onychomycosis – the best would be so easy

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Noninvasive monitoring of liver fat during treatment with GLP‐1 analogues and SGLT‐2 inhibitors in a real‐world setting

Introduction: Patients with NAFLD have a two‐fold increased risk of diabetes, and conversely, NAFLD affects up to 80% of patients with type 2 diabetes. Due to the co‐occurrence of both diseases and the lack of approved pharmacotherapy for NAFLD, the anti‐steatogenic potential of diabetes‐related drugs is being explored. In this study, we aim to monitor liver fat noninvasively during treatment with SGLT‐2 inhibitors or GLP‐1 analogues in a real‐world setting. Methods: Overall, 39 patients (49% women, age 57.7 ± 10.9 years) with type 2 diabetes and hepatic steatosis (defined by controlled attenuation parameter [CAP] values ≥ 215 dB/m) were observed for 6 months and routinely monitored with respect to hepatic fat contents and liver stiffness (VCTE); body composition (BIA); and blood biochemistry, including liver function tests (LFTs), serum lipids and glucose metabolism markers. Results: Median liver fat contents were significantly (P = .026) reduced by 9% in patients taking either SGLT‐2 (n = 22) or GLP‐1 (n = 17) for 6 months (absolute median CAP decrease: −32 dB/m [−58 to 32 dB/m]). In parallel, serum ALT and γ‐GT activities decreased significantly (P = .002 and P = .049, respectively). These improvements were accompanied by significant (P < .0001) changes to body weight and BMI (−2.5 ± 3.3 kg and −0.9 ± 1.2 kg/m2, respectively) and glucose homeostasis, with significant reductions in HbA1c and fasting plasma glucose (FDG) (both P < .0001). Of note, significant reductions of intrahepatic lipid contents occured in patients receiving SGLT‐2 inhibitors only. Conclusions: In this real‐world observational evaluation of fatty liver monitored noninvasively in patients with type 2 diabetes treated with either SGLT2 or GLP‐1, improvements in measures of hepatic steatosis, glucose and weight parameters were observed after 6 months, with significant reductions of intrahepatic lipid contents seen specifically in the SGLT2 subgroup

Do CBCT scans alter surgical treatment plans? Comparison of preoperative surgical diagnosis using panoramic versus cone-beam CT images

Cone beam CT and/or panoramic images are often required for a successful diagnosis in oral and maxillofacial surgery. The aim of this study was to evaluate if 3D diagnostic imaging information had a significant impact on the decision process in six different classes of surgical indications. Material and methods: Records of all patients who had undergone both panoramic X-ray and CBCT imaging due to surgical indications between January 2008 and December 2012 were examined retrospectively. In February 2013, all surgically relevant diagnoses of both conventional panoramic radiographs and CBCT scans were retrieved from the patient's charts. It was recorded whether (1) 3D imaging presented additional surgically relevant information and (2) if the final decision of surgical therapy had been based on 2D or 3D imaging. Results: A total of 253 consecutive patients with both panoramic radiographs and CBCT analysis were eligible for the study. 3D imaging provided significantly more surgically relevant information in cases of implant dentistry, maxillary sinus diagnosis and in oral and maxillofacial traumatology. However, surgical strategies had not been influenced to any significant extent by 3D imaging. Conclusion: Within the limitations of this study it may be concluded that CBCT imaging results in significantly more surgically relevant information in implant dentistry, maxillary sinus diagnosis and in cases of oral and maxillofacial trauma. However, 3D imaging information did not alter significantly the surgical plan that was based on 2D panoramic radiography. Further studies are necessary to define indications for CBCT in detail

Effects of Arteriovenous Fistula on Blood Pressure in Patients With End-Stage Renal Disease: A Systematic Meta-Analysis

Background Central arteriovenous fistula ( AVF ) creation is under investigation for treatment of severe hypertension. We evaluated the effects of AVF for initiation of hemodialysis on systolic, diastolic, and mean arterial blood pressure in patients with end-stage renal disease. Methods and Results Data search included PubMed, Web of Science, and the Cochrane Library. A systematic review and meta-analysis of peer-reviewed studies reporting the effects of the creation/ligation of an AVF on blood pressure in patients with end-stage renal disease was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis), PRISMA -P (PRISMA for systematic review protocols), and ROBINS-I (Risk of Bias in Non-Randomized Studies) criteria by the Cochrane Bias Methods Group. All studies in which the results could have been biased by hemodialysis were excluded. A total of 14 trials including 412 patients with end-stage renal disease ( AVF creation, n=185; AVF ligation, n=227) fulfilled the criteria and were subsequently analyzed. Average blood pressure in patients with no/closed AVF was 140.5/77.6 mm Hg with a mean arterial blood pressure of 96.1 mm Hg. Following creation of AVF , systolic blood pressure significantly decreased by 8.7 mm Hg ( P<0.001), diastolic blood pressure by 5.9 mm Hg ( P<0.001), and mean arterial blood pressure by 6.6 mm Hg ( P=0.02), whereas after ligation systolic blood pressure increased by 5.2 mm Hg ( P=0.07), diastolic blood pressure by 3.8 mm Hg ( P=0.02), and mean arterial blood pressure by 3.7 mm Hg ( P=0.07) during short- to long-term follow-up. Conclusions Creation of AVF significantly decreases blood pressure in patients with end-stage renal disease, whereas blood pressure tends to increase after ligation. These findings illustrate the hemodynamic consequences of AVF which are under investigation for severe hypertension

Patient factors associated with titration of medical therapy in patients with heart failure with reduced ejection fraction: data from the QUALIFY international registry

Aims: Failure to prescribe key medicines at evidence-based doses is associated with increased mortality and hospitalization forpatients with Heart Failure with reduced Ejection Fraction (HFrEF). We assessed titration patterns of guideline-recommendedHFrEF medicines internationally and explored associations with patient characteristics in the global, prospective, observational,longitudinal registry. Methods and results: Data were collected from September 2013 through December 2014, with 7095 patients from 36 coun-tries [>18 years, previous HF hospitalization within 1–15 months, left ventricular ejection fraction (LVEF)≤40%] enrolled, withdosage data at baseline and up to 18 months from 4368 patients. In 4368 patients (mean age 63 ± 17 years, 75% male)≥100%target doses at baseline: 30.6% (ACEIs), 2.9% (ARBs), 13.9% (BBs), 53.8% (MRAs), 26.2% (ivabradine). Atfinal follow-up,≥100%target doses achieved in more patients for ACEI (34.8%), BB (18.0%), and ivabradine (30.5%) but unchanged for ARBs (3.2%)and MRAs (53.7%). Adjusting for baseline dosage, uptitration during follow-up was more likely with younger age, highersystolic blood pressure, and in absence of chronic kidney disease or diabetes for ACEIs/ARBs; younger age, higher body massindex, higher heart rate, lower LVEF, and absence of coronary artery disease for BBs. For ivabradine, uptitration was morelikely with higher resting heart rate. Conclusions: The international QUALIFY Registry suggests that few patients with HFrEF achieve target doses ofdisease-modifying medication, especially older patients and those with co-morbidity. Quality improvement initiatives are ur-gently required

Markers of cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD: An observational study

In dialysis patients, cholesterol-lowering therapy with statins is less effective than in other high-risk patients. This may be explained by a shift from cholesterol synthesis toward cholesterol absorption. In line, markers of cholesterol absorption-such as campesterol-better predict atherosclerotic cardiovascular events than markers of cholesterol synthesis-such as lathosterol-in dialysis patients. To test the association between markers of cholesterol absorption such as campesterol-and markers of cholesterol synthesis-such as lathosterol-against cardiovascular events in non-dialysis CKD patients. Altogether 251 patients those not on lipid-lowering agents were followed annually for the composite endpoint atherosclerotic cardiovascular disease (ASCVD) and all-cause death. During follow-up of 5.2 ± 2.1 years, 61 participants reached the primary endpoint atherosclerotic cardiovascular disease/all-cause death [ASCVD/D], 47 participants suffered from ASCVD, and 46 participants died. In univariate Cox regression analysis, campesterol/lathosterol ratio did not significantly predict ASCVD/D (HR 0.643; 0.358-1.155; 3rd vs. 1st tertile), all-cause death (HR 1.309; 0.604-2.838; 3rd vs. 1st tertile) nor ASCVD (HR 0.589; 0.311-1.118; 3rd vs. 1st tertile). We did not observe a shift from cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD. Campesterol/lathosterol ratio did not predict future ASCVD or all-cause death in non-dialysis CKD