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1.
Variance-component methods are popular and flexible analytic tools for elucidating the genetic mechanisms of complex quantitative traits from pedigree data. However, variance-component methods typically assume that the trait of interest follows a multivariate normal distribution within a pedigree. Studies have shown that violation of this normality assumption can lead to biased parameter estimates and inflations in type-I error. This limits the application of variance-component methods to more general trait outcomes, whether continuous or categorical in nature. In this paper, we develop and apply a general variance-component framework for pedigree analysis of continuous and categorical outcomes. We develop appropriate models using generalized-linear mixed model theory and fit such models using approximate maximum-likelihood procedures. Using our proposed method, we demonstrate that one can perform variance-component pedigree analysis on outcomes that follow any exponential-family distribution. Additionally, we also show how one can modify the method to perform pedigree analysis of ordinal outcomes. We also discuss extensions of our variance-component framework to accommodate pedigrees ascertained based on trait outcome. We demonstrate the feasibility of our method using both simulated data and data from a genetic study of ovarian insufficiency.  相似文献   

2.
The level of intake at which methylmercury might result in neurobehavioral or neuro psychological deficits in children has been extensively debated in recent years. The human data base for methylmercury toxicity is very robust, particularly when compared with other environmental substances for which health guidance values have been developed by Federal organizations. However, despite the depth of the data base for methylmercury, some of the key studies have been clouded by the concurrent exposure of the study population to polychlorinated biphenys (PCBs) and other persistent organic pollutants (POPs). In this paper, the authors examine the key points comprising the methylmercury-PCB issue and contrast these with recent reports of concurrent methylmercury/PCB human exposures and laboratory studies. The authors conclude that research published to date concerning the Seychelles and Faroes Island populations suggests that both methylmercury and PCBs are jointly responsible for the effects reported in the Faroes. Further neurobehavioral testing in populations exposed to PCBs alone, as well as with methylmercury alone, is necessary to fully resolve the ongoing debate.  相似文献   

3.

Purpose

To estimate the influence of prolonged radiation treatment time (RTT) on survival outcomes in nasopharyngeal carcinoma after continuous intensity-modulated radiation therapy.

Methods and Materials

Retrospectively review 321 patients with NPC treated between October 2009 and December 2010 and all of them underwent simultaneous accelerated intensity-modulated radiation therapy. The fractionated dose was 2–2.47 Gy/F (median 2.27 Gy), and the total dose for nasopharyngeal region was 64–74 Gy/ 28–33 fractions. The association of prolonged RTT and treatment interruption with PFS, LRFS and DFFS were assessed by univariate analysis and multivariate analysis. Survival analyses were carried out using Kaplan–Meier methodology and the log-rank test was used to assess the difference. The Cox regression proportional hazard model was used for multivariate analyses and evaluating the prognostic parameters for PFS, LRFS and DFFS.

Results

Univariate analysis revealed no significant associations between prolonged RTT and PFS, LRFS, DFFS when dichotomized using various cut-off values (all P>0.05). In multivariate analysis, RTT (range, 36–63 days) as a continuous variable, had no influence on any survival outcome as well (P>0.05). T and N classification were independent prognostic factors for PFS, LRFS and DFFS (all P<0.05, except T classification for LRFS, P = 0.057). Age was an independent prognostic factor for PFS (hazard ratio [HR], 1.033; P = 0.008) and DFFS (HR, 1.032; P = 0.043).

Conclusion

We conclude that no such association between survival outcomes and radiation treatment duration (range: 36–63 days) can be found in the present retrospective study, however, we have to remind that prolongation in treatment should be limited in clinical application and interruptions caused by any reason should be minimized as much as possible.  相似文献   

4.

Background

Individuals may make a rational decision not to engage in healthy behaviours based on their assessment of the benefits of such behaviours to them, compared to other uncontrollable threats to their health. Anticipated survival is one marker of perceived uncontrollable threats to health. We hypothesised that greater anticipated survival: a) is cross-sectionally associated with healthier patterns of behaviours; b) increases the probability that behaviours will be healthier at follow up than at baseline; and c) decreases the probability that behaviours will be ‘less healthy’ at follow than at baseline.

Methods

Data from waves 1 and 5 of the English Longitudinal Survey of Ageing provided 8 years of follow up. Perceptions of uncontrollable threats to health at baseline were measured using anticipated survival. Health behaviours considered were self-reported cigarette smoking, physical activity level, and frequency of alcohol consumption. A wide range of socio-economic, demographic, and health variables were adjusted for.

Results

Greater anticipated survival was cross-sectionally associated with lower likelihood of smoking, and higher physical activity levels, but was not associated with alcohol consumption. Lower anticipated survival was associated with decreased probability of adopting healthier patterns of physical activity, and increased probability of becoming a smoker at follow up. There were no associations between anticipated survival and change in alcohol consumption.

Conclusions

Our hypotheses were partially confirmed, though associations were inconsistent across behaviours and absent for alcohol consumption. Individual assessments of uncontrollable threats to health may be an important determinant of smoking and physical activity.  相似文献   

5.
6.
7.
Cox regression is commonly used to predict the outcome by the time to an event of interest and in addition, identify relevant features for survival analysis in cancer genomics. Due to the high-dimensionality of high-throughput genomic data, existing Cox models trained on any particular dataset usually generalize poorly to other independent datasets. In this paper, we propose a network-based Cox regression model called Net-Cox and applied Net-Cox for a large-scale survival analysis across multiple ovarian cancer datasets. Net-Cox integrates gene network information into the Cox''s proportional hazard model to explore the co-expression or functional relation among high-dimensional gene expression features in the gene network. Net-Cox was applied to analyze three independent gene expression datasets including the TCGA ovarian cancer dataset and two other public ovarian cancer datasets. Net-Cox with the network information from gene co-expression or functional relations identified highly consistent signature genes across the three datasets, and because of the better generalization across the datasets, Net-Cox also consistently improved the accuracy of survival prediction over the Cox models regularized by or . This study focused on analyzing the death and recurrence outcomes in the treatment of ovarian carcinoma to identify signature genes that can more reliably predict the events. The signature genes comprise dense protein-protein interaction subnetworks, enriched by extracellular matrix receptors and modulators or by nuclear signaling components downstream of extracellular signal-regulated kinases. In the laboratory validation of the signature genes, a tumor array experiment by protein staining on an independent patient cohort from Mayo Clinic showed that the protein expression of the signature gene FBN1 is a biomarker significantly associated with the early recurrence after 12 months of the treatment in the ovarian cancer patients who are initially sensitive to chemotherapy. Net-Cox toolbox is available at http://compbio.cs.umn.edu/Net-Cox/.  相似文献   

8.
In longitudinal randomised trials and observational studies within a medical context, a composite outcome—which is a function of several individual patient-specific outcomes—may be felt to best represent the outcome of interest. As in other contexts, missing data on patient outcome, due to patient drop-out or for other reasons, may pose a problem. Multiple imputation is a widely used method for handling missing data, but its use for composite outcomes has been seldom discussed. Whilst standard multiple imputation methodology can be used directly for the composite outcome, the distribution of a composite outcome may be of a complicated form and perhaps not amenable to statistical modelling. We compare direct multiple imputation of a composite outcome with separate imputation of the components of a composite outcome. We consider two imputation approaches. One approach involves modelling each component of a composite outcome using standard likelihood-based models. The other approach is to use linear increments methods. A linear increments approach can provide an appealing alternative as assumptions concerning both the missingness structure within the data and the imputation models are different from the standard likelihood-based approach. We compare both approaches using simulation studies and data from a randomised trial on early rheumatoid arthritis patients. Results suggest that both approaches are comparable and that for each, separate imputation offers some improvement on the direct imputation of a composite outcome.  相似文献   

9.
Northern hemisphere elementary circulation mechanisms, defined with the Dzerdzeevski classification and published on a daily basis from 1899–2012, are analysed with statistical methods as continuous categorical time series. Classification consists of 41 elementary circulation mechanisms (ECM), which are assigned to calendar days. Empirical marginal probabilities of each ECM were determined. Seasonality and the periodicity effect were investigated with moving dispersion filters and randomisation procedure on the ECM categories as well as with the time analyses of the ECM mode. The time series were determined as being non-stationary with strong time-dependent trends. During the investigated period, periodicity interchanges with periods when no seasonality is present. In the time series structure, the strongest division is visible at the milestone of 1986, showing that the atmospheric circulation pattern reflected in the ECM has significantly changed. This change is result of the change in the frequency of ECM categories; before 1986, the appearance of ECM was more diverse, and afterwards fewer ECMs appear. The statistical approach applied to the categorical climatic time series opens up new potential insight into climate variability and change studies that have to be performed in the future.  相似文献   

10.
Two methods of testing multivariate hypotheses in an IXJXK contingency table are presented. In one case, use is made of the trace of the matrix of sum of squares and sum of products while in the other, determinants of the matrices are used to construct test statistics. Asymptotic equivalence of the methods is shown.  相似文献   

11.
In the analysis of two-period crossover designs, one frequently must consider the case of a categorical response with binary as a special case. These circumstances are considered in this paper and the proposed method—an extension of GART'S tests for the binary case—is similar to that of PIKE, CASAGRANDE and SMITH for the analysis of pair-matched case-control studies. The results are illustrated with a numerical example.  相似文献   

12.
In many clinical studies that involve follow-up, it is common to observe one or more sequences of longitudinal measurements, as well as one or more time to event outcomes. A competing risks situation arises when the probability of occurrence of one event is altered/hindered by another time to event. Recently, there has been much attention paid to the joint analysis of a single longitudinal response and a single time to event outcome, when the missing data mechanism in the longitudinal process is non-ignorable. We, in this paper, propose an extension where multiple longitudinal responses are jointly modeled with competing risks (multiple time to events). Our shared parameter joint model consists of a system of multiphase non-linear mixed effects sub-models for the multiple longitudinal responses, and a system of cause-specific non-proportional hazards frailty sub-models for competing risks, with associations among multiple longitudinal responses and competing risks modeled using latent parameters. The joint model is applied to a data set of patients who are on mechanical circulatory support and are awaiting heart transplant, using readily available software. While on the mechanical circulatory support, patient liver and renal functions may worsen and these in turn may influence one of the two possible competing outcomes: (i) death before transplant; (ii) transplant. In one application, we propose a system of multiphase cause-specific non-proportional hazard sub-model where frailty can be time varying. Performance under different scenarios was assessed using simulation studies. By using the proposed joint modeling of the multiphase sub-models, one can identify: (i) non-linear trends in multiple longitudinal outcomes; (ii) time-varying hazards and cumulative incidence functions of the competing risks; (iii) identify risk factors for the both types of outcomes, where the effect may or may not change with time; and (iv) assess the association between multiple longitudinal and competing risks outcomes, where the association may or may not change with time.  相似文献   

13.

Background

Randomized Controlled Trials almost invariably utilize the hazard ratio calculated with a Cox proportional hazard model as a treatment efficacy measure. Despite the widespread adoption of HRs, these provide a limited understanding of the treatment effect and may even provide a biased estimate when the assumption of proportional hazards in the Cox model is not verified by the trial data. Additional treatment effect measures on the survival probability or the time scale may be used to supplement HRs but a framework for the simultaneous generation of these measures is lacking.

Methods

By splitting follow-up time at the nodes of a Gauss Lobatto numerical quadrature rule, techniques for Poisson Generalized Additive Models (PGAM) can be adopted for flexible hazard modeling. Straightforward simulation post-estimation transforms PGAM estimates for the log hazard into estimates of the survival function. These in turn were used to calculate relative and absolute risks or even differences in restricted mean survival time between treatment arms. We illustrate our approach with extensive simulations and in two trials: IPASS (in which the proportionality of hazards was violated) and HEMO a long duration study conducted under evolving standards of care on a heterogeneous patient population.

Findings

PGAM can generate estimates of the survival function and the hazard ratio that are essentially identical to those obtained by Kaplan Meier curve analysis and the Cox model. PGAMs can simultaneously provide multiple measures of treatment efficacy after a single data pass. Furthermore, supported unadjusted (overall treatment effect) but also subgroup and adjusted analyses, while incorporating multiple time scales and accounting for non-proportional hazards in survival data.

Conclusions

By augmenting the HR conventionally reported, PGAMs have the potential to support the inferential goals of multiple stakeholders involved in the evaluation and appraisal of clinical trial results under proportional and non-proportional hazards.  相似文献   

14.
This article presents semiparametric joint models to analyze longitudinal data with recurrent events (e.g. multiple tumors, repeated hospital admissions) and a terminal event such as death. A broad class of transformation models for the cumulative intensity of the recurrent events and the cumulative hazard of the terminal event is considered, which includes the proportional hazards model and the proportional odds model as special cases. We propose to estimate all the parameters using the nonparametric maximum likelihood estimators (NPMLE). We provide the simple and efficient EM algorithms to implement the proposed inference procedure. Asymptotic properties of the estimators are shown to be asymptotically normal and semiparametrically efficient. Finally, we evaluate the performance of the method through extensive simulation studies and a real-data application.  相似文献   

15.
16.

Background

Associations between Vitamin D3 [25(OH)D], vitamin D binding protein (VDBP) and chronic obstructive pulmonary disease (COPD) are previously reported. We aimed to further investigate these associations on longitudinal outcomes.

Methods

426 COPD patients from western Norway, GOLD stage II-IV, aged 40–76, were followed every six-month from 2006 through 2009 with spirometry, bioelectrical impedance measurements and registration of exacerbation frequency. Serum 25(OH)D and VDBP levels were determined at study-entry by high-performance liquid chromatography coupled with mass spectrometry and enzyme immunoassays respectively. Yearly change in lung function and body composition was assessed by generalized estimating equations (GEE), yearly exacerbation rate by negative binomial regression models, and 5 years all-cause mortality by Cox proportional-hazard regression.

Results

1/3 of the patients had vitamin D deficiency (<20ng/mL) and a greater decline in both FEV1 and FVC, compared to patients with normal levels; for FEV1 this difference only reached statistical significance in the 28 patients with the lowest levels (<10ng/mL, p = 0.01). Neither 25(OH)D nor VDBP levels predicted exacerbation rate, change in fat free mass index or risk of death.

Conclusion

Severe vitamin D deficiency may affect decline in lung function parameters in COPD. Neither 25(OH)D nor VDBP levels did otherwise predict markers of disease progression.  相似文献   

17.

Background

Pedigree studies of complex heritable diseases often feature nominal or ordinal phenotypic measurements and missing genetic marker or phenotype data.

Methodology

We have developed a Bayesian method for Linkage analysis of Ordinal and Categorical traits (LOCate) that can analyze complex genealogical structure for family groups and incorporate missing data. LOCate uses a Gibbs sampling approach to assess linkage, incorporating a simulated tempering algorithm for fast mixing. While our treatment is Bayesian, we develop a LOD (log of odds) score estimator for assessing linkage from Gibbs sampling that is highly accurate for simulated data. LOCate is applicable to linkage analysis for ordinal or nominal traits, a versatility which we demonstrate by analyzing simulated data with a nominal trait, on which LOCate outperforms LOT, an existing method which is designed for ordinal traits. We additionally demonstrate our method''s versatility by analyzing a candidate locus (D2S1788) for panic disorder in humans, in a dataset with a large amount of missing data, which LOT was unable to handle.

Conclusion

LOCate''s accuracy and applicability to both ordinal and nominal traits will prove useful to researchers interested in mapping loci for categorical traits.  相似文献   

18.
A simple method for searching for periods in biological series is proposed. Because it is based on an auto-comparison of the observations within a series we call it the concordance method. It requires few theoritical assumptions. In fact, even the ever present stationarity condition is not used. The method is compared with competing methods based on the khi-square periodogram. It is shown that the concordance method is much better for analyzing multimodal and noisy series. Rhythms presenting simultaneously circadian and ultradian components can also be analyzed with this method.  相似文献   

19.
BackgroundPediatric uptake and outcomes in antiretroviral treatment (ART) programmes have lagged behind adult programmes. We describe outcomes from a population-based pediatric ART cohort in rural southern Malawi.MethodsData were analyzed on children who initiated ART from October/2003 –September/2011. Demographics and diagnoses were described and survival analyses conducted to assess the impact of age, presenting features at enrolment, and drug selection.ResultsThe cohort consisted of 2203 children <15 years of age. Age at entry was <1 year for 219 (10%), 1–1.9 years for 343 (16%), 2–4.9 years for 584 (27%), and 5–15 years for 1057 (48%) patients. Initial clinical diagnoses of tuberculosis and wasting were documented for 409 (19%) and 523 (24%) patients, respectively. Median follow-up time was 1.5 years (range 0–8 years), with 3900 patient-years of follow-up. Over the period of observation, 134 patients (6%) died, 1324 (60%) remained in the cohort, 345 (16%) transferred out, and 387 (18%) defaulted. Infants <1 year of age accounted for 19% of deaths, with a 2.7-fold adjusted mortality hazard ratio relative to 5–15 year olds; median time to death was also shorter for infants (60 days) than older children (108 days). Survival analysis demonstrated younger age at ART initiation, more advanced HIV stage, and presence of tuberculosis to each be associated with shorter survival time. Among children <5 years, severe wasting (weight-for-height z-score </ = -3.0) was also associated with reduced survival.ConclusionsCumulative incidence of mortality was 5.2%, 7.1% and 7.7% after 1, 3, and 5 years, respectively, with disproportionate mortality in infants <1 year of age and those presenting with tuberculosis. These findings reinforce the urgent need for early diagnosis and treatment in this population, but also demonstrate that provision of pediatric care in a rural setting can yield outcomes comparable to more resourced urban settings of poor countries.  相似文献   

20.
A simple method for searching for periods in biological series is proposed. Because it is based on an auto-comparison of the observations within a series we call it the concordance method. It requires few theoritical assumptions. In fact, even the ever present stationarity condition is not used. The method is compared with competing methods based on the khi-square periodogram. It is shown that the concordance method is much better for analyzing multimodal and noisy series. Rhythms presenting simultaneously circadian and ultradian components can also be analyzed with this method.  相似文献   

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