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PubMed2026

Symptom assessment and health-related quality of life in children with lower urinary tract dysfunction: A retrospective cross-sectional study.

INTRODUCTION: Lower urinary tract dysfunction (LUTD) significantly impacts children's health-related quality of life (HRQoL), but key determinants of this impairment remain incompletely understood within a patient-centered framework. METHODS: This retrospective cross-sectional study enrolled 272 children with LUTD. Clinical symptoms were assessed using the Dysfunctional Voiding Scoring System (DVSS) and the Overactive Bladder Symptom Score (OABSS), and HRQoL via the Pediatric Quality of Life Inventory (PedsQL™) 4.0 Generic Core Scales. RESULTS: The mean total PedsQL score was 83.66 ± 16.07, with the School Functioning domain being the most impaired (73.75 ± 20.94). Univariate analysis identified older age (≥11 years), daytime urinary leakage, overactive bladder (OAB) symptoms, and abnormal DVSS scores as factors associated with reduced HRQoL (all P < 0.05); multivariate regression further confirmed only older age and abnormal DVSS were independent influencing factors (both P < 0.001). A significant negative correlation existed between the total DVSS score and the total PedsQL score (r = -0.390, P < 0.01), indicating that greater symptom severity predicts poorer overall HRQoL. CONCLUSION: This study indicates that in children with LUTD, the severity of voiding dysfunction (quantified by DVSS) is inversely correlated with HRQoL. Voiding dysfunction impairs multiple domains of daily functioning, including physical well-being, emotional adjustment, social interaction, and school performance. Shifting from a symptom-focused to a patient-centered care model and integrating routine HRQoL assessment into standard clinical management can optimize clinical practice for pediatric LUTD.

Humans↗

PubMed2005

Immunoglobulin mimicry by Hepatitis C Virus envelope protein E2.

Hepatitis C virus (HCV) establishes persistent infection in the majority of infected individuals. The currently accepted hypothesis of immune evasion by antigenic variation in hypervariable region 1 (HVR1) of glycoprotein E2 does not however, explain the lack of subsequent immune recognition. Here, we show that the N-terminal region of E2 is antigenically and structurally similar to human immunoglobulin (Ig) variable domains. E2 is recognized by anti-human IgG antibodies and also possesses common amino acid (aa) sequence features of the conserved v-gene framework regions of human Ig light chains in particular but also heavy chains and T cell receptors. Using a position specific scoring system, the degree of similarity of HVR1 to Ig types correlated with immune escape and persistence in humans and experimentally infected chimpanzees. We propose a unique role for threshold levels of Ig molecular mimicry in HCV biology that not only advances our concept of viral immune escape and persistent infection but also provides insight into host-dependent disease patterns.

Amino Acid Sequence↗

PubMed1998

Testing for differences in multiple quality of life dimensions: generating hypotheses from the experience of hospital staff.

In clinical trials with a quality of life (QoL) component, it is usual to monitor several QoL dimensions at several points in time. Multiple significance tests without formal hypotheses are problematic. It is not always feasible to specify a priori hypotheses for all variables. Can such studies be used to generate hypotheses for testing in later research only? We developed a method which can allow for formal hypothesis testing on a data set collected without a priori hypotheses in the protocol. We surveyed experienced physicians and nurses treating patients, to obtain independent expectations about differences in QoL dimensions. These 'staff expectations' will be used in the analysis of QoL data collected from breast cancer patients taking part in three randomized trials of adjuvant therapy. We propose frameworks for the informal and formal use of the experience of the staff in testing for group differences in patients' QoL scores. The method described here is anticipated to be useful for QoL studies in general, even when a priori hypotheses were specified before the studies were initiated.

Bayes Theorem↗

PubMed1995

Differential relationships of objective and projective dependency scores to self-reports of interpersonal life events in college student subjects.

Eighty-three undergraduate subjects (58 women and 25 men) participated in a prospective study in which they (a) completed widely used objective and projective measures of dependency, and then (b) provided monthly reports of the frequency and impact of various types of life events during a 1-semester (3-month) period. As expected, subjects' projective dependency scores predicted their frequency estimates and impact ratings of interpersonal life events but were unrelated to frequency estimates and impact ratings of other types of life events (e.g., achievement-related, legal). Objective dependency scores were unrelated to all life event frequency estimates and impact ratings. Findings are discussed in the context of recent theoretical frameworks that distinguish implicit dependency needs (which are assessed via projective measures) from self-attributed dependency needs (which are assessed via self-report tests). The importance of the type of dependency measure used in studies of the dependency-life events relationship is emphasized.

Journal Article↗

PubMed2005

Item response theory and the measurement of clinical change.

An instrument's sensitivity to detect individual-level change is an important consideration for both psychometric and clinical researchers. In this article, we develop a cognitive problems measure and evaluate its sensitivity to detect change from an item response theory (IRT) perspective. After illustrating assumption checking and model fit assessment, we detail 4 features of IRT modeling: (a) the scale information curve and its relation to the bandwidth of measurement precision, (b) the scale response curve and how it is used to link the latent trait metric with the raw score metric, (c) content-based versus norm-based score referencing, and (d) the level of measurement of the latent trait scale. We conclude that IRT offers an informative, alternative framework for understanding an instrument's psychometric properties and recommend that IRT analyses be considered prior to investigations of change, growth, or the effectiveness of clinical interventions.

Adult↗

PubMed2026

Beyond Exons: Linking Noncoding Heritability and Polygenicity across Complex Human Traits and Disorders.

The genetic architecture of complex traits spans a continuum of polygenicity, yet it remains unclear how differences in polygenicity relate to the functional localization of SNP heritability across the genome. We use a MiXeR-based framework to partition heritability across exonic, intronic, and intergenic regions for 34 traits and introduce a likelihood-based annotation contribution score that quantifies annotation-specific impact on heritability. Exons explain a minority of heritability, and their contribution decreases with increasing polygenicity, from an average of 22% in less polygenic somatic diseases and biomarkers to 13% in highly polygenic psychiatric and cognitive phenotypes. Intergenic fractions show the opposite trend, whereas intronic fractions remain relatively stable. Analysis of a broader set of functional annotations reveals systematic differences along the polygenicity axis: highly polygenic traits show stronger contributions from comparative genomics and variant-effect scores, whereas less polygenic traits show stronger contributions in promoter, transcription, and chromatin annotations. Together, these results indicate that the functional partitioning of heritability systematically varies with polygenicity, pointing to a shift from gene-proximal regulatory architectures to architectures shaped by numerous dispersed regulatory effects as a key determinant of differences in polygenicity across traits.

Journal Article↗

PubMed1991

Nonparametric tests of association between survival time and continuously measured covariates: the logit-rank and associated procedures.

O'Brien's logit-rank procedure (1978, Biometrics 34, 243-250) is shown to arise as a score test based on the partial likelihood for a proportional hazards model provided the covariate structure is suitably defined. Within this framework the asymptotic properties claimed by O'Brien can be readily deduced and can be seen to be valid under a more general model of censoring than that considered in his paper. More important, perhaps, it is now possible to make a more natural and interpretable generalization to the multiple regression problem than that suggested by O'Brien as a means of accounting for the effects of nuisance covariates. This can be achieved either by modelling or stratification. The proportional hazards framework is also helpful in that it enables us to recognize the logit-rank procedure as being one member of a class of contending procedures. One consequence of this is that the relative efficiencies of any two procedures can be readily evaluated using the results of Lagakos (1988, Biometrika 75, 156-160). Our own evaluations suggest that, for non-time-dependent covariates, a simplification of the logit-rank procedure, leading to considerable reduction in computational complexity, is to be preferred to the procedure originally outlined by O'Brien.

Biometry↗

PubMed1986

Recognition and frequency judgments in young and elderly adults.

Three experiments examined frequency judgments and recognition memory in young and elderly adults. Subjects were presented a long list of words at either a 5-s rate (Experiments 1 & 3) or a 1-s rate (Experiment 2), after which frequency-judgment and recognition memory tasks were administered. Either an absolute (Experiments 1 & 2) or a relative (Experiment 3) frequency-judgment task was used. The recognition test, which involved repeated tests of some items, involved either one incorrect item paired with each correct item (Experiments 1 & 2), or four incorrect items (Experiment 3). Age-related differences in frequency judgments, for the more frequently presented items, were found in all three experiments. For the recognition scores, the predicted interaction between age and successive tests was found only in Experiment 3. The results were interpreted within the framework of age-related differences in elaborative encoding and in distractibility to irrelevant stimuli.

Adolescent↗

PubMed2026

Evolving Role of Immunotherapy in Advanced Esophageal Squamous Cell Carcinoma: Are Programmed Death-Ligand 1 (PD-L1) Cutoffs Still Relevant?

Immune checkpoint inhibitors have transformed the management of advanced esophageal squamous cell carcinoma (ESCC) across first-line, second-line, and perioperative settings. Programmed death-ligand 1 (PD-L1) expression has served as the principal biomarker guiding patient selection for these agents, yet it is measured inconsistently across trials and antibody platforms, and its predictive value has come under renewed scrutiny as follow-up data have matured. This review synthesizes the pivotal randomized trials that established anti-programmed cell death protein-1 therapy in ESCC, critically appraises the pooled and patient-level meta-analyses that have re-examined outcomes across biomarker subgroups, and situates recent regulatory reassessment of PD-L1 thresholds within this broader evidence base. Assay heterogeneity between scoring systems, discordance across antibody clones, and the biological distinction between PD-L1 as a prognostic versus a predictive marker are examined as sources of continued uncertainty. The review concludes by considering emerging genomic and microenvironmental biomarkers that may eventually complement or refine PD-L1-based patient selection, and offers a framework for interpreting a single expression threshold as an approximate, assay-dependent stratifier rather than a precise biological boundary.

combined positive score↗

PubMed2006

Rationalizing rationing in health care: experience of two primary care trusts.

BACKGROUND: Priority setting, or rationing, in healthcare is an unavoidable consequence of competing demands on the resources available. This is a description of the experience of the two Primary Care Trusts in using an explicit scoring tool to prioritize proposals submitted for new funding within the local health economy. METHODS: A Priorities Forum Panel was established, comprising representatives from the local NHS trusts. The Panel reviewed and scored new funding proposals and then ranked them for priority funding. RESULTS: Over 100 proposals were submitted (total cost: approximately 44 million pounds). Sixty-six proposals were scored (total cost: over 26 million pounds). Around 5 million pounds was available for funding, resulting in few of the top-scoring proposals being supported. The proposals which were linked to the implementation of National Institute for Health and Clinical Excellence (NICE) guidance were generally given a lower priority compared with those likely to relieve local pressures and facilitate the implementation of specific National Service Framework criteria. CONCLUSIONS: Funding of the locally driven priorities took precedence over some of the nationally driven priorities, such as funding of specific NICE guidance. The shortfall in resources did not allow for the funding of a significant number of high-scoring proposals.

Financing, Government↗

PubMed2025

vcfgl: a flexible genotype likelihood simulator for VCF/BCF files.

MOTIVATION: Accurate quantification of genotype uncertainty is pivotal in ensuring the reliability of genetic inferences drawn from NGS data. Genotype uncertainty is typically modeled using Genotype Likelihoods (GLs), which can help propagate measures of statistical uncertainty in base calls to downstream analyses. However, the effects of errors and biases in the estimation of GLs, introduced by biases in the original base call quality scores or the discretization of quality scores, as well as the choice of the GL model, remain under-explored. RESULTS: We present vcfgl, a versatile tool for simulating genotype likelihoods associated with simulated read data. It offers a framework for researchers to simulate and investigate the uncertainties and biases associated with the quantification of uncertainty, thereby facilitating a deeper understanding of their impacts on downstream analytical methods. Through simulations, we demonstrate the utility of vcfgl in benchmarking GL-based methods. The program can calculate GLs using various widely used genotype likelihood models and can simulate the errors in quality scores using a Beta distribution. It is compatible with modern simulators such as msprime and SLiM, and can output data in pileup, Variant Call Format (VCF)/BCF, and genomic VCF file formats, supporting a wide range of applications. The vcfgl program is freely available as an efficient and user-friendly software written in C/C++. AVAILABILITY AND IMPLEMENTATION: vcfgl is freely available at https://github.com/isinaltinkaya/vcfgl.

Software↗

PubMed2005

Design and analysis of in vitro experiments for combination chemotherapy.

A method is proposed for the evaluation of in vitro experiments for combination chemotherapy, a new and growing area of cancer research. We first describe and review a popular graphical device called an isobologram. We then propose a statistical framework, a simple experimental design, and a statistical test for use with this widely accepted methodology. The test we propose is a score test based on the linear logistic regression model.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Biomarker discovery in microarray gene expression data with Gaussian processes.

MOTIVATION: In clinical practice, pathological phenotypes are often labelled with ordinal scales rather than binary, e.g. the Gleason grading system for tumour cell differentiation. However, in the literature of microarray analysis, these ordinal labels have been rarely treated in a principled way. This paper describes a gene selection algorithm based on Gaussian processes to discover consistent gene expression patterns associated with ordinal clinical phenotypes. The technique of automatic relevance determination is applied to represent the significance level of the genes in a Bayesian inference framework. RESULTS: The usefulness of the proposed algorithm for ordinal labels is demonstrated by the gene expression signature associated with the Gleason score for prostate cancer data. Our results demonstrate how multi-gene markers that may be initially developed with a diagnostic or prognostic application in mind are also useful as an investigative tool to reveal associations between specific molecular and cellular events and features of tumour physiology. Our algorithm can also be applied to microarray data with binary labels with results comparable to other methods in the literature.

Algorithms↗

PubMed2005

Using factor analysis to evaluate checklist items.

BACKGROUND: Relatively little research has been published examining the use of factor analytic techniques to improve the psychometric qualities of performance assessments. The purpose of the current investigation is to illustrate the potential use of structural equation modeling (SEM) with scores from a standardized patient examination. METHOD: Checklist items for a single case were examined to compare two models within a SEM framework: a single, underlying "data gathering" construct and a two-factor model consisting of medical history interviewing and physical examination maneuvers. RESULTS: The chi2 statistics obtained were statistically significant for both the single factor (chi2=1645.8, p<.001) and the two-factor model, (chi2=1373.1; p<.001), indicating marginal model-data fit. A difference statistic was calculated (chi2=320.9; p<.001), suggesting that the two-factor model has better fit. CONCLUSIONS: The parameters estimated by each model could be used to evaluate checklist item performance. The results of this investigation illustrate the utility of this method in the analysis of checklist item data.

Clinical Competence↗

PubMed2000

RHO--radiation hybrid ordering.

Radiation hybrid (RH) mapping is a somatic cell technique that is used for ordering markers along a chromosome and estimating the physical distances between them. With the advent of this mapping technique, analyzing the experimental data is becoming a challenging and demanding computational task. In this paper we present the software package RHO (radiation hybrid ordering). The package implements a number of heuristics that attempt to order genomic markers along a chromosome, given as input the results of an RH experiment. The heuristics are based on reducing an appropriate optimization problem to the traveling salesman problem (TSP). The reduced optimization problem is either the nonparametric obligate chromosome breaks (OCBs) or the parametric maximum likelihood estimation (MLE). We tested our package on both simulated and publicly available RH data. For synthetic RH data, the reconstructed markers' permutation is very close to the original permutation, even with fairly high error rates. For real data we used the framework markers' data from the Whitehead Institute maps. For most of the chromosomes (18 out of 23), there is a perfect agreement or nearly perfect agreement (reversal of chromosome arm or arms) between our maps and the Whitehead framework maps. For the remaining five chromosomes, our maps improve on the Whitehead framework maps with respect to both optimization criteria, having higher likelihood and fewer breakpoints. For three chromosomes, the results differ significantly (lod score >1.75), with chromosome 2 having the largest improvement (lod score 3.776).

Algorithms↗

PubMed1999

Proximal and distal correlates of maternal control style.

Control, as an aspect of maternal interaction, has been found to be an important component to optimal child development. Maternal control style is defined as a mother's tendency to be controlling or supportive of her child's autonomy. The relationship between two types of maternal characteristics, proximal and distal, and maternal control style was investigated in a sample of 184 mothers and their 4-year-old children. Global ratings of videotaped data of two problem-solving tasks were made on a 5-point scale. An optimal maternal control style was associated with higher levels of the distal maternal characteristics of maternal education, age, occupation, and higher levels of the proximal characteristics of maternal responsivity and involvement. A hierarchical regression model explaining 26% of the variance in maternal control style scores supports the importance of both types of maternal characteristics. The results are discussed in relation to the methodology and the theoretical framework of role.

Adult↗

PubMed2006

Protein-ligand binding affinity predictions by implicit solvent simulations: a tool for lead optimization?

Continuum electrostatics is combined with rigorous free-energy calculations in an effort to deliver a reliable and efficient method for in silico lead optimization. The methodology is tested by calculation of the relative binding free energies of a set of inhibitors of neuraminidase, cyclooxygenase2, and cyclin-dependent kinase 2. The calculated free energies are compared to the results obtained with explicit solvent simulations and empirical scoring functions. For cyclooxygenase2, deficiencies in the continuum electrostatics theory are identified and corrected with a modified simulation protocol. For neuraminidase, it is shown that a continuum representation of the solvent leads to markedly different protein-ligand interactions compared to the explicit solvent simulations, and a reconciliation of the two protocols is problematic. Cyclin-dependent kinase 2 proves more challenging, and none of the methods employed in this study yield high quality predictions. Despite the differences observed, for these systems, the use of an implicit solvent framework to predict the ranking of congeneric inhibitors to a protein is shown to be faster, as accurate or more accurate than the explicit solvent protocol, and superior to empirical scoring schemes.

Cyclin-Dependent Kinase 2↗

PubMed2005

A unique collaboration of female medical providers within the United States Armed Forces: rehabilitation of a marine with post-concussive vestibulopathy.

Uncle Sam's loyal nieces have come a long way from the days of World War I. The development of occupational and physical therapy was heavily influenced by an early relationship with medical specialists during the First World War. This relationship can be considered largely responsible for the eventual acceptance (by the Armed Forces) of women working in this area. Over the past decade active duty women have seen many changes in opportunities to serve and are now stationed aboard aircraft carriers, performing roles previously considered for male personnel. We report a case study of the medical care provided by both military and civilian women working for the United States Armed Forces. Initial assessment was conducted in a battalion aid station of a United States Marine Corp base and the subject was then referred to a military medical center with highly technical vestibular assessment and rehabilitation services. The subject's case represents a unique collaboration of women therapists, enabling a Marines' access to timely and accurate assessment, treatment and ultimately, successful return to active duty. This case study is one of many examples of the acceptance and successful integration of women as providers of medical care within the Military's medical framework.

Adult↗