Estimation of the infection attack rate of mumps in an outbreak among college students using paired serology.

Mumps virus is a highly transmissible pathogen that is effectively controlled in countries with high vaccination coverage. Nevertheless, outbreaks have occurred worldwide over the past decades in vaccinated populations. Here we analyse an outbreak of mumps virus genotype G among college students in the Netherlands over the period 2009-2012 using paired serological data. To identify infections in the presence of preexisting antibodies we compared mumps specific serum IgG concentrations in two consecutive samples (n=746), whereby the first sample was taken when students started their study prior to the outbreaks, and the second sample was taken 2-5 years later. We fit a binary mixture model to the data. The two mixing distributions represent uninfected and infected classes. Throughout we assume that the infection probability increases with the ratio of antibody concentrations of the second to first sample. The estimated infection attack rate in this study is higher than reported earlier (0.095 versus 0.042). The analyses yield probabilistic classifications of participants, which are mostly quite precise owing to the high intraclass correlation of samples in uninfected participants (0.85, 95%CrI: 0.82-0.87). The estimated probability of infection increases with decreasing antibody concentration in the pre-outbreak sample, such that the probability of infection is 0.12 (95%CrI: 0.10-0.13) for the lowest quartile of the pre-outbreak samples and 0.056 (95%CrI: 0.044-0.068) for the highest quartile. We discuss the implications of these insights for the design of booster vaccination strategies.

Painful differences between different pain scale assessments: The outcome of assessed pain is a matter of the choices of scale and statistics.

OBJECTIVES: Perceived pain is a multi-factorial subjective variable, commonly measured by numeric rating scales, verbal descriptive scales (VDS), or by a position on an analogue line (VAS). A major question is whether an individual's VAS and VDS pain assessments, on the same occasion, could be comparable. The aim was to compare continuous and discretized VAS pain data with verbal descriptive pain datasets from the Oswestry Disability Index (ODI) and the European Quality of Life Scale (EQ-5D) in paired pain datasets. METHODS: The measurement level of data from any type of scale assessments is ordinal, having rank-invariant properties only. Non-parametric statistical methods were used. Two ways of discretizing the VAS-line to VAS-intervals to fit the number of the comparing VDS-categories were used: the commonly used (equidistant VAS,VDS)-pairs and the (unbiased VAS,VDS)-pairs of pain data. The comparability of the (VAS,VDS)-pairs of data of perceived pain was studied by the bivariate ranking approach. Hence, each pair will be regarded as ordered, disordered, or tied with respect to the other pairs of data. The percentage agreement, PA, the measures of disorder, D, and of order consistency, MA, were calculated. Total interchangeability requires PA = 1 and MA = 1. RESULTS: The wide range of overlapping of (VAS,VDS)-pairs indicated that the continuous VAS data were not comparable to any of the VDS pain datasets. The percentage of agreement, PA; in the (equidistant VAS,ODI) and (equidistant VAS, EQ-5D) pairs were 38 and 49%, and the order consistency, MA, was 0.70 and 0.80, respectively. Corresponding results for the (unbiased VAS,VDS)-pairs of pain data were PA: 54 and 100%, and MA: 0.77 and 1.0. CONCLUSION: Our results confirmed that perceived pain is the individual's subjective experience, and possible scale-interchangeability is only study-specific. The pain experience is not possible to be measured univocally, but is possible for the individual to rate on a scale.

Continuity corrected score confidence interval for the difference in proportions in paired data.

For paired binary data, the hybrid method and the score method are often recommended for use to calculate the confidence interval for risk difference. These asymptotic intervals do not control the coverage probability. We propose to develop a new score interval with continuity correction to further improve the performance of the existing intervals. The traditional correction value may be too large which leads to a wide interval. For that reason, we propose three different correction values to identify the optimal correction interval with balanced coverage probability and interval width. From simulation studies, we find that a small correction value for the score interval has good performance. In addition, we derive the non-iterative solutions for the developed continuity correction score intervals.

Using bilateral data in controls and patients with bilateral and unilateral pathology requires increased scrutiny.

In many aspects of human research, capturing multiple measures from the same participant is common due to the symmetric nature of the human body (e.g., two eyes, ten fingers, two legs, etc.). This has established a concerning paradox in biomedical and clinical research. When the same condition exist bilaterally (controls or bilateral pathology), researchers often blindly include both (or multiple) measures into the statistical analysis. This assumes that measures between the two sides are statistically independent (uncorrelated). However, there are certain inherent factors within an individual (e.g., age, sex, physical activity, gait pattern, tissue characteristics, hormonal status, pain thresholds, etc.) that would point to a statistical dependence between bilateral measures. Conversely, in unilateral pathology, it is common practice to use the contralateral side as the comparator. This assumes the exact opposite, that sans pathology, bilateral measures are perfectly correlated without bias. Both of these assumptions can lead to errors in the study conclusions. Few studies have explored the statistical dependence between multiple measures from the same participant. Thus, the purpose of this perspective is to explore the statistical considerations associated with analyzing multiple measures from the same participant and provide recommendations for navigating the use of multiple, non-temporal, data points from the same participant. To give context for these recommendations, an example dataset involving patellofemoral kinematics is provided. Due to the prevalent use of bilateral data in the current literature and the resulting potential for invalid study conclusions, we recommend that future research use caution when using multiple measures from the same participant and apply proper statistical analysis (e.g., generalized estimating equations) when these measures are not independent. If the contralateral limb is used as a comparator in unilateral pathology, strong evidence must exist that the underlying pathology has not altered the measures of interest in this contralateral limb.

Weighted mean difference statistics for paired data in the presence of missing values.

Missing data is a common issue in many biomedical studies. Under a paired design, some subjects may have missing values in either one or both of the conditions due to loss of follow-up, insufficient biological samples, etc. Such partially paired data complicate statistical comparison of the distribution of the variable of interest between the two conditions. In this article, we propose a general class of test statistics based on the difference in weighted sample means without imposing any distributional or model assumption. An optimal weight is derived from this class of tests. Simulation studies show that our proposed test with the optimal weight performs well and outperforms existing methods in practical situations. Two cancer biomarker studies are provided for illustration.

New Confidence Intervals for Relative Risk of Two Correlated Proportions.

Biomedical studies, such as clinical trials, often require the comparison of measurements from two correlated tests in which each unit of observation is associated with a binary outcome of interest via relative risk. The associated confidence interval is crucial because it provides an appreciation of the spectrum of possible values, allowing for a more robust interpretation of relative risk. Of the available confidence interval methods for relative risk, the asymptotic score interval is the most widely recommended for practical use. We propose a modified score interval for relative risk and we also extend an existing nonparametric U-statistic-based confidence interval to relative risk. In addition, we theoretically prove that the original asymptotic score interval is equivalent to the constrained maximum likelihood-based interval proposed by Nam and Blackwelder. Two clinically relevant oncology trials are used to demonstrate the real-world performance of our methods. The finite sample properties of the new approaches, the current standard of practice, and other alternatives are studied via extensive simulation studies. We show that, as the strength of correlation increases, when the sample size is not too large the new score-based intervals outperform the existing intervals in terms of coverage probability. Moreover, our results indicate that the new nonparametric interval provides the coverage that most consistently meets or exceeds the nominal coverage probability.

Analyzing partially paired data: when can the unpaired portion(s) be safely ignored?

Partially paired data, either with incompleteness in one or both arms, are common in practice. For testing equality of means of two arms, practitioners often use only the portion of data with complete pairs and perform paired tests. Although such tests (referred as 'naive paired tests') are legitimate, their powers might be low as only partial data are utilized. The recently proposed 'P-value pooling methods', based on combining P-values from two tests, use all data, have reasonable type-I error control and good power property. While it is generally believed that 'P-value pooling methods' are superior to 'naive paired tests' in terms of power as the former use more data than the latter, no detailed power comparison has been done. This paper aims to compare powers of 'naive paired tests' and 'P-value pooling methods' analytically and our findings are counterintuitive, i.e. the 'P-value pooling methods' do not always outperform the naive paired tests in terms of power. Based on these results, we present guidance on how to select the best test for testing equality of means with partially paired data.

Robust statistical inference for matched win statistics.

As alternatives to the time-to-first-event analysis of composite endpoints, the win statistics, that is, the net benefit, the win ratio, and the win odds have been proposed to assess treatment effects, using a hierarchy of prioritized component outcomes based on clinical relevance or severity. Whether we are using paired organs of a human body or pair-matching patients by risk profiles or propensity scores, we can leverage the level of granularity of matched win statistics to assess the treatment effect. However, inference for the matched win statistics (net benefit, win ratio, and win odds)-quantities related to proportions-is either not available or unsatisfactory, especially in samples of small to moderate size or when the proportion of wins (or losses) is near 0 or 1. In this paper, we present methods to address these limitations. First, we introduce a different statistic to test for the null hypothesis of no treatment effect and provided a sample size formula. Then, we use the method of variance estimates recovery to derive reliable, boundary-respecting confidence intervals for the matched net benefit, win ratio, and win odds. Finally, a simulation study demonstrates the performance of the proposed methods. We illustrate the proposed methods with two data examples.

Constraining PERMANOVA and LDM to within-set comparisons by projection improves the efficiency of analyses of matched sets of microbiome data.

BACKGROUND: Matched-set data arise frequently in microbiome studies. For example, we may collect pre- and post-treatment samples from a set of individuals, or use important confounding variables to match data from case participants to one or more control participants. Thus, there is a need for statistical methods for data comprised of matched sets, to test hypotheses against traits of interest (e.g., clinical outcomes or environmental factors) at the community level and/or the operational taxonomic unit (OTU) level. Optimally, these methods should accommodate complex data such as those with unequal sample sizes across sets, confounders varying within sets, and continuous traits of interest. METHODS: PERMANOVA is a commonly used distance-based method for testing hypotheses at the community level. We have also developed the linear decomposition model (LDM) that unifies the community-level and OTU-level tests into one framework. Here we present a new strategy that can be used with both PERMANOVA and the LDM for analyzing matched-set data. We propose to include an indicator variable for each set as covariates, so as to constrain comparisons between samples within a set, and also permute traits within each set, which can account for exchangeable sample correlations. The flexible nature of PERMANOVA and the LDM allows discrete or continuous traits or interactions to be tested, within-set confounders to be adjusted, and unbalanced data to be fully exploited. RESULTS: Our simulations indicate that our proposed strategy outperformed alternative strategies, including the commonly used one that utilizes restricted permutation only, in a wide range of scenarios. Using simulation, we also explored optimal designs for matched-set studies. The flexibility of PERMANOVA and the LDM for a variety of matched-set microbiome data is illustrated by the analysis of data from two real studies. CONCLUSIONS: Including set indicator variables and permuting within sets when analyzing matched-set data with PERMANOVA or the LDM is a strategy that performs well and is capable of handling the complex data structures that frequently occur in microbiome studies. Video Abstract.

SEaCorAl: Identifying and contrasting the regulation-correlation bias in RNA-Seq paired expression data of patient groups.

The Cancer Genome Atlas database offers the possibility of analyzing genome-wide expression RNA-Seq cancer data using paired counts, that is, studies where expression data are collected in pairs of normal and cancer cells, by taking samples from the same individual. Correlation of gene expression profiles is the most common analysis to study co-expression groups, which is used to find biological interpretation of -omics big data. The aim of the paper is threefold: firstly we show for the first time, the presence of a "regulation-correlation bias" in RNA-Seq paired expression data, that is an artifactual link between the expression status (up- or down-regulation) of a gene pair and the sign of the corresponding correlation coefficient. Secondly, we provide a statistical model able to theoretically explain the reasons for the presence of such a bias. Thirdly, we present a bias-removal algorithm, called SEaCorAl, able to effectively reduce bias effects and improve the biological significance of correlation analysis. Validation of the SEaCorAl algorithm is performed by showing a significant increase in the ability to detect biologically meaningful associations of positive correlations and a significant increase of the modularity of the resulting unbiased correlation network.

Evaluation of knowledge graph embedding approaches for drug-drug interaction prediction in realistic settings.

BACKGROUND: Current approaches to identifying drug-drug interactions (DDIs), include safety studies during drug development and post-marketing surveillance after approval, offer important opportunities to identify potential safety issues, but are unable to provide complete set of all possible DDIs. Thus, the drug discovery researchers and healthcare professionals might not be fully aware of potentially dangerous DDIs. Predicting potential drug-drug interaction helps reduce unanticipated drug interactions and drug development costs and optimizes the drug design process. Methods for prediction of DDIs have the tendency to report high accuracy but still have little impact on translational research due to systematic biases induced by networked/paired data. In this work, we aimed to present realistic evaluation settings to predict DDIs using knowledge graph embeddings. We propose a simple disjoint cross-validation scheme to evaluate drug-drug interaction predictions for the scenarios where the drugs have no known DDIs. RESULTS: We designed different evaluation settings to accurately assess the performance for predicting DDIs. The settings for disjoint cross-validation produced lower performance scores, as expected, but still were good at predicting the drug interactions. We have applied Logistic Regression, Naive Bayes and Random Forest on DrugBank knowledge graph with the 10-fold traditional cross validation using RDF2Vec, TransE and TransD. RDF2Vec with Skip-Gram generally surpasses other embedding methods. We also tested RDF2Vec on various drug knowledge graphs such as DrugBank, PharmGKB and KEGG to predict unknown drug-drug interactions. The performance was not enhanced significantly when an integrated knowledge graph including these three datasets was used. CONCLUSION: We showed that the knowledge embeddings are powerful predictors and comparable to current state-of-the-art methods for inferring new DDIs. We addressed the evaluation biases by introducing drug-wise and pairwise disjoint test classes. Although the performance scores for drug-wise and pairwise disjoint seem to be low, the results can be considered to be realistic in predicting the interactions for drugs with limited interaction information.

A sequential density-based empirical likelihood ratio test for treatment effects.

In health-related experiments, treatment effects can be identified using paired data that consist of pre- and posttreatment measurements. In this framework, sequential testing strategies are widely accepted statistical tools in practice. Since performances of parametric sequential testing procedures vitally depend on the validity of the parametric assumptions regarding underlying data distributions, we focus on distribution-free mechanisms for sequentially evaluating treatment effects. In fixed sample size designs, the density-based empirical likelihood (DBEL) methods provide powerful nonparametric approximations to optimal Neyman-Pearson-type statistics. In this article, we extend the DBEL methodology to develop a novel sequential DBEL testing procedure for detecting treatment effects based on paired data. The asymptotic consistency of the proposed test is shown. An extensive Monte Carlo study confirms that the proposed test outperforms the conventional sequential Wilcoxon signed-rank test across a variety of alternatives. The excellent applicability of the proposed method is exemplified using the ventilator-associated pneumonia study that evaluates the effect of Chlorhexidine Gluconate treatment in reducing oral colonization by pathogens in ventilated patients.

A Review of Matched-pairs Feature Selection Methods for Gene Expression Data Analysis.

With the rapid accumulation of gene expression data from various technologies, e.g., microarray, RNA-sequencing (RNA-seq), and single-cell RNA-seq, it is necessary to carry out dimensional reduction and feature (signature genes) selection in support of making sense out of such high dimensional data. These computational methods significantly facilitate further data analysis and interpretation, such as gene function enrichment analysis, cancer biomarker detection, and drug targeting identification in precision medicine. Although numerous methods have been developed for feature selection in bioinformatics, it is still a challenge to choose the appropriate methods for a specific problem and seek for the most reasonable ranking features. Meanwhile, the paired gene expression data under matched case-control design (MCCD) is becoming increasingly popular, which has often been used in multi-omics integration studies and may increase feature selection efficiency by offsetting similar distributions of confounding features. The appropriate feature selection methods specifically designed for the paired data, which is named as matched-pairs feature selection (MPFS), however, have not been maturely developed in parallel. In this review, we compare the performance of 10 feature-selection methods (eight MPFS methods and two traditional unpaired methods) on two real datasets by applied three classification methods, and analyze the algorithm complexity of these methods through the running of their programs. This review aims to induce and comprehensively present the MPFS in such a way that readers can easily understand its characteristics and get a clue in selecting the appropriate methods for their analyses.

Positive Value of a Women's Junior Faculty Mentoring Program: A Mentor-Mentee Analysis.

BACKGROUND: Recently appointed women faculty in academic medicine face many challenges during their careers and can become overwhelmed managing their multiple faculty roles as teacher, scholar, and clinician, in addition to their roles in personal life. Although a mentor can be invaluable in assisting a woman junior faculty member to adjust to faculty life and providing critical career guidance, not all medical institutions have faculty mentoring programs. We created a mentoring program specifically for our women junior faculty to address this issue at our own institution. MATERIALS AND METHODS: To assess the value of this program, we conducted a novel mentor-mentee paired-data analysis of annual surveys collected from 2010 to 2015. Of the 470 responses received, 83 were from unique mentees and 61 from unique mentors. RESULTS: Career development, research, and promotion were the top topics discussed among the mentoring pairs, followed by discussions of institutional resources and administration/service. There was high congruency among the mentoring pairs that they thought these discussions, as well as other conversations about mentee professional development and well-being, had been helpful. However in some instances, mentors felt they had not been helpful to their mentee, whereas their mentees felt otherwise; this finding speaks to the value and importance of mentees providing positive feedback to their mentors. Overall, both mentees and mentors thought that the mentees had significantly benefited from the mentorship. Unexpected outcomes of these relationships included promotion, grant applications/awards, articles, presentations, and professional memberships. The use of a Mentee Needs Assessment Form to individualize the mentoring relationship for each mentee may explain the high overall satisfaction and participant recommendations of the program. CONCLUSIONS: Our findings demonstrate the value in establishing mentoring programs specifically for women faculty, especially in environments in which other mentoring opportunities do not exist.

A novel nonparametric confidence interval for differences of proportions for correlated binary data.

Various confidence interval estimators have been developed for differences in proportions resulted from correlated binary data. However, the width of the mostly recommended Tango's score confidence interval tends to be wide, and the computing burden of exact methods recommended for small-sample data is intensive. The recently proposed rank-based nonparametric method by treating proportion as special areas under receiver operating characteristic provided a new way to construct the confidence interval for proportion difference on paired data, while the complex computation limits its application in practice. In this article, we develop a new nonparametric method utilizing the U-statistics approach for comparing two or more correlated areas under receiver operating characteristics. The new confidence interval has a simple analytic form with a new estimate of the degrees of freedom of n - 1. It demonstrates good coverage properties and has shorter confidence interval widths than that of Tango. This new confidence interval with the new estimate of degrees of freedom also leads to coverage probabilities that are an improvement on the rank-based nonparametric confidence interval. Comparing with the approximate exact unconditional method, the nonparametric confidence interval demonstrates good coverage properties even in small samples, and yet they are very easy to implement computationally. This nonparametric procedure is evaluated using simulation studies and illustrated with three real examples. The simplified nonparametric confidence interval is an appealing choice in practice for its ease of use and good performance.

Sample size determination for a matched-pairs study with incomplete data using exact approach.

This research was motivated by a clinical trial design for a cognitive study. The pilot study was a matched-pairs design where some data are missing, specifically the missing data coming at the end of the study. Existing approaches to determine sample size are all based on asymptotic approaches (e.g., the generalized estimating equation (GEE) approach). When the sample size in a clinical trial is small to medium, these asymptotic approaches may not be appropriate for use due to the unsatisfactory Type I and II error rates. For this reason, we consider the exact unconditional approach to compute the sample size for a matched-pairs study with incomplete data. Recommendations are made for each possible missingness pattern by comparing the exact sample sizes based on three commonly used test statistics, with the existing sample size calculation based on the GEE approach. An example from a real surgeon-reviewers study is used to illustrate the application of the exact sample size calculation in study designs.

The Differences and Similarities Between Two-Sample T-Test and Paired T-Test.

In clinical research, comparisons of the results from experimental and control groups are often encountered. The two-sample t-test (also called independent samples t-test) and the paired t-test are probably the most widely used tests in statistics for the comparison of mean values between two samples. However, confusion exists with regard to the use of the two test methods, resulting in their inappropriate use. In this paper, we discuss the differences and similarities between these two t-tests. Three examples are used to illustrate the calculation procedures of the two-sample t-test and paired t-test.

Methods for generating paired competing risks data.

BACKGROUND AND OBJECTIVES: Clustered competing risks data arise often in genetic studies, multicenter investigations, and matched-pairs studies. In the last two decades, major advances in competing risks theory had been made. Many new statistical methods need to be evaluated via simulation studies. Some mechanisms for simulating clustered competing risks data have been considered in the literature. However, most of them produce data where the strength of the dependence between individuals within a cluster is not clear. In this article, we aim to examine various techniques for generating bivariate competing risks data. METHODS: Theoretical framework for simulating dependent competing risks data using latent failure time approach, multistate models, and shared frailty models is described. The steps needed to implement each method are outlined. Properties of each technique are discussed and standard measures of association are provided in order to assess the degree of dependence in simulated paired competing risks data. RESULTS AND CONCLUSIONS: In addition to describing a variety of techniques to generate dependent competing risks data, the cross-hazard ratios from multiple scenarios for each method are computed. The cross-hazard ratios provide a means to compare the level of dependence of the generated data across methods. This acts as a guide for researchers to select an approach and the parameters needed to achieve the desired degree of dependence for their simulation studies.

Bioinformatic Studies to Predict MicroRNAs with the Potential of Uncoupling RECK Expression from Epithelial-Mesenchymal Transition in Cancer Cells.

RECK is downregulated in many tumors, and forced RECK expression in tumor cells often results in suppression of malignant phenotypes. Recent findings suggest that RECK is upregulated after epithelial-mesenchymal transition (EMT) in normal epithelium-derived cells but not in cancer cells. Since several microRNAs (miRs) are known to target RECK mRNA, we hypothesized that certain miR(s) may be involved in this suppression of RECK upregulation after EMT in cancer cells. To test this hypothesis, we used three approaches: (1) text mining to find miRs relevant to EMT in cancer cells, (2) predicting miR targets using four algorithms, and (3) comparing miR-seq data and RECK mRNA data using a novel non-parametric method. These approaches identified the miR-183-96-182 cluster as a strong candidate. We also looked for transcription factors and signaling molecules that may promote cancer EMT, miR-183-96-182 upregulation, and RECK downregulation. Here we describe our methods, findings, and a testable hypothesis on how RECK expression could be regulated in cancer cells after EMT.

Adjusted inference procedures for the interobserver agreement in twin studies.

We propose adjusted inference procedures for evaluating the agreement/disagreement of two raters in a clustered setting involving twins or paired body parts. These procedures include the construction of a confidence interval for the kappa statistic, a related test of statistical significance and a formula that facilitates sample size estimation. The results of a simulation study suggest that a simple adjustment using an estimated design effect will provide valid inferences. The methods proposed are illustrated using an example from the literature.