Familien-basierte Assoziationsanalyse mit Haplotypen : eine Simulationsstudie zum Vergleich statistischer Methoden

Bei der Aufklärung der Ursachen komplexer Krankheiten helfen Assoziationsverfahren genetische Varianten zu finden, die das Krankheitsrisiko beeinflussen. Familien-basierte Methoden haben dabei den Vorteil, nicht anfällig gegen Populationsstratifikation zu sein. Ziel vorliegender Studie ist es, Assoziationsmethoden hinsichtlich des Fehlers 1. Art, der statistischen Power und anderer Eigenschaften zu vergleichen. Im Frühjahr / Sommer 2006 wurden Verfahren, welche auf Assoziation von Haplotypen eng gekoppelter Marker mit binärem Krankheitsmerkmal testen, recherchiert und vier typische Programme in die Analyse einbezogen. Nach verschiedenen Modellen unter der Null- bzw. Alternativhypothese erzeugte ein Simulationsprogramm Familiendaten. Diese wurden von den oben beschriebenen Programmen analysiert und die Ergebnisse wurden zusammengefasst und ausgewertet. Die Tests von FBAT und Famhap sowie die Permutations-basierten Tests von Hotel_Fam sind gültig, d. h. sie halten das Fehlerniveau 1. Art unter der Nullhypothese gut ein. Dagegen sind die asymptotischen Verfahren von Hotel_Fam bzw. Unphased gelegentlich antikonservativ. Die Power der Methoden unterscheidet sich je nach dem Krankheits-Modell, der Marker- sowie der Familienstruktur sehr. Während der permutationsbasierte T2-Test (Hotel_Fam) mit Genotyp-Codierung mit hoher Effizienz single-Marker-Effekte im dominanten oder rezessiven Modell findet, versagt er wie auch andere 'Multi-Marker-Verfahren' bei Haplotyp-Effekten.. Hinsichtlich einer totalen Statistik über alle Markerkombinationen ist das Verfahren nach Zhao im Programm Famhap zum Testniveau 5% vorteilhaft. Auch der Markerkombinations-spezifische 'globale' Haplotyp-Test von FBAT kann durch eine gleichmäßig gute Power überzeugen. Dagegen haben die Unphased-Verfahren sowohl hinsichtlich des Fehlers 1. Art als auch der Power vor allem für kleinere Stichproben sehr unterschiedliche Performance. Weitere Untersuchungen betreffen die Laufzeiten der Programme, die Analyse von Daten mit unvollständigen Genotypen, das Verhalten für unterschiedliche Familientypen und die Verteilung der p-Werte unter der Alternativhypothese. Abgerundet wird die Studie durch die Analyse eines realen Datensatzes. Einerseits wird deutlich, dass die Auswahl einer effektiven Methode zur Aufdeckung potentieller Risikoloci sehr von der konkreten Situation abhängt. Andererseits belegt die Studie einmal mehr, dass von den Programmen ausgegebene p-Werte nur sehr bedingt als Maßzahl der Evidenz für Assoziation interpretiert werden können.Family-based association analysis with haplotypes - a simulation study to compare statistical methods Association methods are established means to unravel genetic variants that cause increased risk of complex diseases. Family-based methods are robust against population stratification. This study is centered on such algorithms for association tests of haplotypes of tightly linked markers with binary traits. A research for such methods in spring / summer 2006 resulted in four programs with typical methods. They were compared with respect of type 1 error under the null hypothesis and power under the alternative. For this purpose family data were simulated according to specific models. The programs were applied on these data and the results were summarized and analysed. The tests of FBAT and Famhap and permutation based tests of Hotel_Fam are valid, viz. they keep the type 1 error level under the null well. In contrast asymptotic methods of Hotel_Fam and Unphased are casually anticonservative. In respect to power there is no very best method. It has been documented that 'multi-marker methods' only work if a single marker is associated with the disease. In this situation the permutation-based T2 test of Hotel_Fam is superior if a dominant or recessive disease model holds. Providing a total statistic over all marker combinations makes the algorithm according to Zhao (Famhap) superior at test size 5%. Aside the marker combination specific 'global' haplotype test (FBAT) convinces by a equable good power. Oppositionally the Unphased methods have varying performance in respect of the type 1 error and power, respective. Further investigations concern the runtimes of the programs, analyses with uncomplete genotype data, the power for different family types and the distribution of P values under the alternative hypothesis. The study is completed by an analysis of a real dataset. On the one hand the choice of an effective method to detect disease susceptibility loci highly depends from the situation. On the other hand the study documents again that P values are not a measure of evidence for association

Anti-gravity treadmill rehabilitation improves gait and muscle atrophy in patients with surgically treated ankle and tibial plateau fractures after one year: A randomised clinical trial

To compare the one-year postoperative outcomes of anti-gravity treadmill rehabilitation with those of standard rehabilitation in patients with ankle or tibial plateau fractures

The Leipzig Prospective Vascular Ultrasound Registry in Radial Artery Catheterization Impact of Sheath Size on Vascular Complications

ObjectivesThis study investigated the impact of sheath size on the rate of radial artery occlusions (RAO) (primary objective) and other access site complications (hemorrhage, pseudoaneurysm, arteriovenous fistula) as secondary objectives after transradial coronary catheterization.BackgroundThe number of vascular access complications in the published data ranges from 5% to 38% after transradial catheterization.MethodsBetween November 2009 and August 2010, 455 patients 65.3 ± 10.9 years of age (62.2% male) with transradial access with 5-F (n = 153) or 6-F (n = 302) arterial sheaths were prospectively recruited. Duplex sonography was obtained in each patient before discharge. Patients with symptomatic RAO were treated with low-molecular-weight heparin (LMWH), and a follow-up was performed.ResultsThe incidence of access site complications was 14.4% with 5-F sheaths compared with 33.1% with 6-F sheaths (p < 0.001). Radial artery occlusion occurred in 13.7% with 5-F sheaths compared with 30.5% with 6-F sheaths (p < 0.001). There was no difference between groups with regard to hemorrhage, pseudoaneurysms, or arteriovenous fistulas. Female sex, larger sheath size, peripheral arterial occlusive disease, and younger age independently predicted RAO in multivariate analysis. In total, 42.5% of patients with RAO were immediately symptomatic; another 7% became symptomatic within a mean of 4 days. Of patients with RAO, 59% were treated with LMWH. The recanalization rates were significantly higher in patients receiving LMWH compared with conventional therapy (55.6% vs. 13.5%, p < 0.001) after a mean of 14 days.ConclusionsThe incidence of RAO by vascular ultrasound was higher than expected from previous data, especially in patients who underwent the procedure with larger sheaths

Combined Coronary CT-Angiography and TAVI-Planning: A Contrast-Neutral Routine Approach for Ruling-Out Significant Coronary Artery Disease

Background: Significant coronary artery disease (CAD) is a common finding in patients undergoing transcatheter aortic valve implantation (TAVI). Assessment of CAD prior to TAVI is recommended by current guidelines and is mainly performed via invasive coronary angiography (ICA). In this study we analyzed the ability of coronary CT-angiography (cCTA) to rule out significant CAD (stenosis ≥ 50%) during routine pre-TAVI evaluation in patients with high pre-test probability for CAD. Methods: In total, 460 consecutive patients undergoing pre-TAVI CT (mean age 79.6 ± 7.4 years) were included. All patients were examined with a retrospectively ECG-gated CT-scan of the heart, followed by a high-pitch-scan of the vascular access route utilizing a single intravenous bolus of 70 mL iodinated contrast medium. Images were evaluated for image quality, calcifications, and significant CAD; CT-examinations in which CAD could not be ruled out were defined as positive (CAD+). Routinely, patients received ICA (388/460; 84.3%; Group A), which was omitted if renal function was impaired and CAD was ruled out on cCTA (Group B). Following TAVI, clinical events were documented during the hospital stay. Results: cCTA was negative for CAD in 40.2% (188/460). Sensitivity, specificity, PPV, and NPV in Group A were 97.8%, 45.2%, 49.6%, and 97.4%, respectively. Median coronary artery calcium score (CAC) was higher in CAD+-patients but did not have predictive value for correct classification of patients with cCTA. There were no significant differences in clinical events between Group A and B. Conclusion: cCTA can be incorporated into pre-TAVI CT-evaluation with no need for additional contrast medium. cCTA may exclude significant CAD in a relatively high percentage of these high-risk patients. Thereby, cCTA may have the potential to reduce the need for ICA and total amount of contrast medium applied, possibly making pre-procedural evaluation for TAVI safer and faster

Is FKBP5 a genetic marker of affective psychosis? A case control study and analysis of disease related traits

BACKGROUND: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an important pathogenic factor in depression. Genetic variants of FKBP5, a protein of the HPA system modulating the glucocorticoid receptor, have been reported to be genetically associated with improved response to medical treatment and an increase of depressive episodes. METHODS: We examined three single nucleotide polymorphisms (SNPs) in FKBP5, rs4713916 in the proposed promoter region, rs1360780 in the second intron and rs3800373 in the 3'-untranslated region (3'-UTR), in a case-control study of Caucasian origin (affective psychosis: n = 248; controls: n = 188) for genetic association and association with disease related traits. RESULTS: Allele and genotype frequencies of rs4713916, rs1360780 and rs3800373 were not significantly different between cases and controls. Two three-locus haplotypes, G-C-T and A-T-G, accounted for 86.2% in controls. Odds ratios were not increased between cases and controls, except the rare haplotype G-C-G (OR 6.81), representing 2.1% of cases and 0.3% of controls. The frequency of rs4713916AG in patients deviated from expected Hardy-Weinberg equilibrium, the genotype AA at rs4713916 in monopolar depression (P = 0.011), and the two-locus haplotype rs1360780T – rs3800373T in the total sample (overall P = 0.045) were nominally associated with longer continuance of disease. CONCLUSION: Our data do not support a significant genetic contribution of FKBP5 polymorphisms and haplotypes to affective psychosis, and the findings are inconclusive regarding their contribution to disease-related traits

Intensive heart rhythm monitoring to decrease ischemic stroke and systemic embolism - the Find-AF 2 study - rationale and design

Background Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, i.e. ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism. Methods Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur. Conclusions The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care

Myoglobin clearance with continuous veno-venous hemodialysis using high cutoff dialyzer versus continuous veno-venous hemodiafiltration using high-flux dialyzer: a prospective randomized controlled trial

Background!#!Myoglobin clearance in acute kidney injury requiring renal replacement therapy is important because myoglobin has direct renal toxic effects. Clinical data comparing different modalities of renal replacement therapy addressing myoglobin clearance are limited. This study aimed to compare two renal replacement modalities regarding myoglobin clearance.!##!Methods!#!In this prospective, randomized, single-blinded, single-center trial, 70 critically ill patients requiring renal replacement therapy were randomized 1:1 into an intervention arm using continuous veno-venous hemodialysis with high cutoff dialyzer and a control arm using continuous veno-venous hemodiafiltration postdilution with high-flux dialyzer. Regional citrate anticoagulation was used in both groups to maintain the extracorporeal circuit. The concentrations of myoglobin, urea, creatinine, β2-microglobulin, interleukin-6 and albumin were measured before and after the dialyzer at 1 h, 6 h, 12 h, 24 h and 48 h after initiating continuous renal replacement therapy.!##!Results!#!Thirty-three patients were allocated to the control arm (CVVHDF with high-flux dialyzer) and 35 patients to the intervention arm (CVVHD with high cutoff dialyzer). Myoglobin clearance, as a primary endpoint, was significantly better in the intervention arm than in the control arm throughout the whole study period. The clearance values for urea and creatinine were higher in the control arm. There was no measurable albumin clearance in both arms. The clearance data for β!##!Conclusions!#!Myoglobin clearance using continuous veno-venous hemodialysis with high cutoff dialyzer and regional citrate anticoagulation is better than that with continuous veno-venous hemodiafiltration with regional citrate anticoagulation.!##!Trial registration!#!German Clinical Trials Registry (DRKS00012407); date of registration 23/05/2017. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&amp;amp;TRIAL_ID=DRKS00012407

Comorbidities, substance abuse, weight and age are independent risk factors for postoperative complications following operation for proximal humerus fractures: a retrospective analysis of 1109 patients

Introduction!#!This study aimed to investigate the influence of epidemiologic parameters on complications that needed operative revision of operatively treated proximal humerus fractures.!##!Methods!#!We performed a retrospective single-center study in a level 1 trauma center. We included all patients with operatively treated proximal humerus fractures from January 1 2005 to December 31 2015. We characterized our cohort and subgroup using descriptive statistics. The primary outcome was postoperative complications. For this purpose, postoperative complications were defined in advance, an operative revision was necessary on a general rule. The secondary outcome was a model of the risk factors for complications created with multiple logistic regression.!##!Results!#!We included 1109 patients. The average age was 67.2 years (± 16.4), and 71.4% of the fractures occurred in women. A total of 644 patients (58.1%) had between one to three comorbidities, and 27.8% had four or more. The fracture morphology was as follows: 3 part 41.8%, 4 part 26.9%, 2 part 24.3%, and dislocation fracture 6.7%. Complications occurred in 150 patients (13.5%). The number of comorbidities [odds ratio (OR) 2.85, p &amp;lt; 0.01], body weight (OR 1.15, p = 0.02), and substance abuse (OR 1.82, p = 0.04) significantly correlated with the risk of complications. We achieved a sensitivity of 48% and a specificity of 74% for the variables body weight, substance abuse, age, and comorbidities CONCLUSION: The epidemiologic parameters, comorbidities, substance abuse, weight, and age are independent risk factors for complications. If these factors are present, one can predict a postoperative complication requiring surgical revision with low sensitivity and moderate specificity. Therefore, concerning the high number of multi-morbid patients with proximal humerus fractures, an increased postoperative complication rate can be expected.!##!Level of evidence!#!Level of evidence IV