A solution to the problem of monotone likelihood in Cox regression

The phenomenon of monotone likelihood is observed in the fitting process of a Cox model if the likelihood converges to a finite value while at least one parameter estimate diverges to +/- infinity. Monotone likelihood primarily occurs in small samples with substantial censoring of survival times and several highly predictive covariates. Previous options to deal with monotone likelihood have been unsatisfactory. The solution we suggest is an adaptation of a procedure by Firth (1993, Biometrika 80, 27-38) originally developed to reduce the bias of maximum likelihood estimates. This procedure produces finite parameter estimates by means of penalized maximum likelihood estimation. Corresponding Wald-type tests and confidence intervals are available, but it is shown that penalized likelihood ratio tests and profile penalized likelihood confidence intervals are often preferable. An empirical study of the suggested procedures confirms satisfactory performance of both estimation and inference. The advantage of the procedure over previous options of analysis is finally exemplified in the analysis of a breast cancer study.     

Analysis of longitudinal marginal structural models

In this article we construct and study estimators of the causal effect of a time-dependent treatment on survival in longitudinal studies. We employ a particular marginal structural model (MSM), proposed by Robins (2000), and follow a general methodology for constructing estimating functions in censored data models. The inverse probability of treatment weighted (IPTW) estimator of Robins et al. (2000) is used as an initial estimator and forms the basis for an improved, one-step estimator that is consistent and asymptotically linear when the treatment mechanism is consistently estimated. We extend these methods to handle informative censoring. The proposed methodology is employed to estimate the causal effect of exercise on mortality in a longitudinal study of seniors in Sonoma County. A simulation study demonstrates the bias of naive estimators in the presence of time-dependent confounders and also shows the efficiency gain of the IPTW estimator, even in the absence such confounding. The efficiency gain of the improved, one-step estimator is demonstrated through simulation.     

真重组率与ELOD值和检验能力的关系

本文讨论了信息配子数为50时,ELOD值与检验能力随着真重组率变化的趋势,结果表明当2个基因座之间的真重组率小于或等于0?15时,连锁分析得到的结果比较可靠。 Abstract:The change of ELOD score and power was studied under the real recombination rates.A total of 50 informative meioses were used in the study as the sample size.The results showed that the linkage analysis was more reliable if the real combination rates between two loci were equal to or smaller than 0.15.     

桂枝芍药知母汤联合甲氨蝶呤对类风湿性关节炎患者中医证候评分、血清炎性因子及免疫球蛋白的影响

摘要 目的：探讨桂枝芍药知母汤联合甲氨蝶呤对类风湿性关节炎（RA）患者血清炎性因子、中医证候评分及免疫球蛋白的影响。方法：选取2018年1月~2019年10月期间我院接收的RA患者136例。根据随机数字表法分为对照组（n=68）和研究组（n=68）。对照组给予甲氨蝶呤治疗，研究组在对照组基础上联合桂枝芍药知母汤治疗。比较两组患者的疗效、中医证候评分、血清炎性因子[肿瘤坏死因子-α（TNF-α）、白介素-17（IL-17）、白介素-1β（IL-1β）]水平、风湿四项检查指标[类风湿因子（RF）、C反应蛋白（CRP）、抗链球菌溶血素"O"(ASO)、血沉（ESR）]水平及免疫球蛋白[免疫球蛋白A（IgA）、免疫球蛋白G（IgG）、免疫球蛋白M（IgM）]水平。结果：研究组治疗2个月后的临床总有效率91.18%（62/68）高于对照组的77.94%（53/68）（P<0.05）。两组治疗2个月后关节肿胀程度、关节屈伸不利程度、畏恶风寒、晨僵证候评分均下降，且研究组低于对照组（P<0.05）。两组治疗2个月后血清TNF-α、IL-1β、IL-17水平均下降，且研究组低于对照组（P<0.05）。两组治疗2个月后IgA、IgM、IgG水平均下降，且研究组低于对照组（P<0.05）。两组治疗2个月后RF、ESR、CRP、ASO水平均下降，且研究组低于对照组（P<0.05）。结论：RA患者在甲氨蝶呤的基础上联合桂枝芍药知母汤治疗，可有效降低患者血清炎性因子、风湿四项检查指标、免疫球蛋白水平，改善患者临床症状，疗效显著。     

A Truncated Proportional Hazards Test

We present two truncated proportional hazards tests. The first, which is applicable to those cases in which the time of action of an agent or treatment is known, was studied in two forms: One uses expected Fisher information and the other observed Fisher information. In this case the expected information statistic, C₁(a₀), had properties superior to the observed information statistic and is recommended. The use of the X² distribution with one degree of freedom for percentiles appears to be satisfactory. When the time of action is unknown, a statistic based on the maximum of the C₁(a) statistics is used. A simulation study gives empirical percentiles for the Max C₁(a) statistic which agree with those given in a study by Muenz, Green and Byar (1977).     

Large oligomeric complex structures can be computationally assembled by efficiently combining docked interfaces

Macromolecular oligomeric assemblies are involved in many biochemical processes of living organisms. The benefits of such assemblies in crowded cellular environments include increased reaction rates, efficient feedback regulation, cooperativity and protective functions. However, an atom‐level structural determination of large assemblies is challenging due to the size of the complex and the difference in binding affinities of the involved proteins. In this study, we propose a novel combinatorial greedy algorithm for assembling large oligomeric complexes from information on the approximate position of interaction interfaces of pairs of monomers in the complex. Prior information on complex symmetry is not required but rather the symmetry is inferred during assembly. We implement an efficient geometric score, the transformation match score, that bypasses the model ranking problems of state‐of‐the‐art scoring functions by scoring the similarity between the inferred dimers of the same monomer simultaneously with different binding partners in a (sub)complex with a set of pregenerated docking poses. We compiled a diverse benchmark set of 308 homo and heteromeric complexes containing 6 to 60 monomers. To explore the applicability of the method, we considered 48 sets of parameters and selected those three sets of parameters, for which the algorithm can correctly reconstruct the maximum number, namely 252 complexes (81.8%) in, at least one of the respective three runs. The crossvalidation coverage, that is, the mean fraction of correctly reconstructed benchmark complexes during crossvalidation, was 78.1%, which demonstrates the ability of the presented method to correctly reconstruct topology of a large variety of biological complexes. Proteins 2015; 83:1887–1899. © 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.     

血清降钙素原在感染性休克患者中的表达及与APACHEⅡ评分的相关性分析

目的:探讨血清降钙素原在感染性休克患者中的表达及与APACHEⅡ评分的相关性分析。方法:选取2012年1月至2013年9月我院收治的58例感染性休克患者,设为感染性休克组,早期采取液体复苏的方法进行救治。另选取同期于我院体检的年龄、性别与之相匹配的52例健康人设为对照组。测定两组不同时间的血清PCT含量,对APACHEⅡ评分进行评定,并进行统计学分析。结果:感染行休克组患者的复苏液体量最少为4332mL,最多为10645mL,平均为(7602.85±1628.47)mL,复苏达标的平均时间为(17.67±3.75)h。感染性休克组患者血清PCT含量治疗后24h为(8.77±4.66)μg/L,明显低于治疗前的(17.78±5.89)μg/L;感染性休克组患者治疗前与治疗后24h血清PCT含量相比于对照组受试者的(0.03±0.01)μg/L均显著提高;感染性休克组患者治疗前与治疗后24hAPACHEⅡ评分分别为(16.68±3.27)分、(10.46±3.18)分,相比于对照组的(7.22±1.15)分均显著提高;感染性休克组患者APACHEⅡ评分治疗后24h明显低于治疗前。差异有统计学意义(P0.05)。感染性休克组治疗前后PCT含量与APACHEⅡ评分均呈一定的正相关(P0.05);PCT含量变化与快速复苏的液体量呈一定的负相关(P0.05);而与APACHEⅡ评分不存在明显的相关性(P0.05)。结论:将血清降钙素原应用于感染性休克患者的诊断及治疗过程中评估病情变化,能够为液体复苏提供有效的指导。血清降钙素原含量与APACHEⅡ评分呈正相关,但其变化与APACHEⅡ评分不存在相关性,而与复苏液体量呈负相关。     

Obesity polymorphisms identified in genome-wide association studies interact with n-3 polyunsaturated fatty acid intake and modify the genetic association with adiposity phenotypes in Yup’ik people

n-3 Polyunsaturated fatty acids (n-3 PUFAs) have anti-obesity effects that may modulate risk of obesity, in part, through interactions with genetic factors. Genome-wide association studies (GWAS) have identified genetic variants associated with body mass index (BMI); however, the extent to which these variants influence adiposity through interactions with n-3 PUFAs remains unknown. We evaluated 10 highly replicated obesity GWAS single nucleotide polymorphisms (SNPs) for individual and cumulative associations with adiposity phenotypes in a cross-sectional sample of Yup’ik people (n = 1,073) and evaluated whether genetic associations with obesity were modulated by n-3 PUFA intake. A genetic risk score (GRS) was calculated by adding the BMI-increasing alleles across all 10 SNPs. Dietary intake of n-3 PUFAs was estimated using nitrogen stable isotope ratio (δ¹⁵N) of red blood cells, and genotype–phenotype analyses were tested in linear models accounting for familial correlations. GRS was positively associated with BMI (p = 0.012), PBF (p = 0.022), ThC (p = 0.025), and waist circumference (p = 0.038). The variance in adiposity phenotypes explained by the GRS included BMI (0.7 %), PBF (0.3 %), ThC (0.7 %), and WC (0.5 %). GRS interactions with n-3 PUFAs modified the association with adiposity and accounted for more than twice the phenotypic variation (~1–2 %), relative to GRS associations alone. Obesity GWAS SNPs contribute to adiposity in this study population of Yup’ik people and interactions with n-3 PUFA intake potentiated the risk of fat accumulation among individuals with high obesity GRS. These data suggest the anti-obesity effects of n-3 PUFAs among Yup’ik people may, in part, be dependent upon an individual’s genetic predisposition to obesity.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-013-0340-z) contains supplementary material, which is available to authorized users.     

Exposure to ELF- magnetic field promotes restoration of sensori-motor functions in adult rats with hemisection of thoracic spinal cord

Clinically effective modalities of treatment for spinal cord injury (SCI) still remain unsatisfactory and are largely invasive in nature. There are reports of accelerated regeneration in injured peripheral nerves by extremely low-frequency pulsed electromagnetic field (ELF-EMF) in the rat. In the present study, the effect of (50 Hz), low-intensity (17.96 μT) magnetic field (MF) exposure of rats after-hemisection of T13 spinal cord (hSCI) was investigated on sensori-motor and locomotor functions. Rats were divided into hSCI (sham-exposed) and hSCI+MF (MF: 2 h/d X 6 weeks) groups. Besides their general conditions, locomotor function by Basso, Beattie, and Brenahan (BBB) score; motor responses to noxious stimuli by threshold of tail flick (TTF), simple vocalization (TSV), tail flick latency (TFL), and neuronal excitability by H-reflex were noted. It is found that, in the hSCI+MF group, a statistically significant improvement over the hSCI control group was noted in BBB score from post-SCI wk2 and TFL and TTF by post-hSCI wk1 and wk3, respectively. Correspondingly, TSV gradually restored by post-hSCI wk5.The threshold of H-reflex was reduced on ipsilateral side vs. contralateral side in hSCI and hSCI+MF group. A complete bladder control was dramatically restored on post-hSCI day4 (vs. day7 of hSCI group) and the survival rate was 100% in the hSCI+MF group (vs. 90% of hSCI group). The results of our study suggest that extremely low-frequency (50 Hz), low-intensity (17.96 μT) MF exposure for 2 h/d x 6wks promotes recovery of sensori-motor behavior including locomotion and bladder control both in terms of temporal pattern and magnitude in hemisection injury of (T13) spinal cord rats.     

Overexpression of PLIN5 in skeletal muscle promotes oxidative gene expression and intramyocellular lipid content without compromising insulin sensitivity

Aims/hypothesis: While lipid deposition in the skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like the skeletal muscle. Here we investigated the effects of PLIN5 overexpression – in comparison with the effects of PLIN2 – on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. Methods: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in the skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. Results: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. Conclusions/interpretation: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in the skeletal muscle promoted expression of a cluster of genes under control of PPARα and PGC1α involved in FA catabolism and mitochondrial oxidation.