Regression-based estimation of the false negative fraction when multiple negatives are unverified

Summary.  The paper describes a method of estimating the false negative fraction of a multiple-screening test when individuals who test negatively on all K tests do not have their true disease status verified. The method proposed makes no explicit assumptions about the underlying heterogeneity of the population or about serial correlation of test results within an individual. Rather, it is based on estimating false negative fractions conditionally on observed diagnostic histories and extrapolating the observed patterns in these empirical frequencies by using logistic regression. The method is illustrated on, and motivated by, data on a multiple-screening test for bowel cancer.     

An application of multinomial logistic regression to estimating performance of a multiple-screening test with incomplete verification

Summary.  The paper describes a method of estimating the performance of a multiple-screening test where those who test negatively do not have their true disease status determined. The methodology is motivated by a data set on 49927 subjects who were given K =6 binary tests for bowel cancer. A complicating factor is that individuals may have polyps in the bowel, a condition that the screening test is not designed to detect but which may be worth diagnosing. The methodology is based on a multinomial logit model for Pr( S | R ₆), the probability distribution of patient status S (healthy, polyps or diseased) conditional on the results R ₆ from six binary tests. An advantage of the methodology described is that the modelling is data driven. In particular, we require no assumptions about correlation within subjects, the relative sensitivity of the K tests or the conditional independence of the tests. The model leads to simple estimates of the trade-off between different errors as the number of tests is varied, presented graphically by using receiver operating characteristic curves. Finally, the model allows us to estimate better protocols for assigning subjects to the disease group, as well as the gains in accuracy from these protocols.     

Testing for the presence of disease by pooling samples

Screening of pooled urine samples was suggested during the Second World War as a method of detecting syphilis in US soldiers. Recently, pooling has been used in screening blood for Human Immunodeficiency Virus (HIV) antibody to help curb the further spread of the deadly virus. Pooling reduces the cost and also reduces the rates of false‐negative results in samples that are not disease‐free, a factor that has led to pooling not being adopted as an efficient procedure for screening HIV. This paper generalizes a common pooling strategy with retesting, and discusses its characteristics. Furthermore, it suggests a new testing strategy with retesting.     

A test for detecting etiologic heterogeneity in epidemiological studies

Current statistical methods for analyzing epidemiological data with disease subtype information allow us to acquire knowledge not only for risk factor-disease subtype association but also, on a more profound account, heterogeneity in these associations by multiple disease characteristics (so-called etiologic heterogeneity of the disease). Current interest, particularly in cancer epidemiology, lies in obtaining a valid p-value for testing the hypothesis whether a particular cancer is etiologically heterogeneous. We consider the two-stage logistic regression model along with pseudo-conditional likelihood estimation method and design a testing strategy based on Rao's score test. An extensive Monte Carlo simulation study is carried out, false discovery rate and statistical power of the suggested test are investigated. Simulation results indicate that applying the proposed testing strategy, even a small degree of true etiologic heterogeneity can be recovered with a large statistical power from the sampled data. The strategy is then applied on a breast cancer data set to illustrate its use in practice where there are multiple risk factors and multiple disease characteristics of simultaneous concern.     

Testing exogeneity in overidentified models

Summary In this paper we analyse the consequences of model overidentification on testing exogeneity, when maximum likelihood techniques for estimation and inference are used. This situation is viewed as a particular case of the more general problem of considering how restrictions on nuisance parameters could help in making inference on the parameters of interest. At first a general model is considered. A suitable likelihood function factorization is used which allows a simple derivation of the information matrix and others tools useful for building up joint tests of exogeneity and overidentifying restrictions both of Wald and Lagrange Multiplier type. The asymptotic local power of the exogeneity test in the justidentified model is compared with that in the overidentified one, when we assume that the latter is the true model. Then the pseudo-likelihood framework is used to derive the consequences of working with a model where overidentifying restrictions are erroneously imposed. The inconsistency introduced by imposing false restrictions is analysed and the consequences of the misspecification on the exogeneity test are carefully examined.     

SCREENING FOR BREAST CANCER

It is widely recognized that early detection of malignant cancer is associated with increased survival prospects. If regular examinations are given, then in the case of breast cancer, there is a high chance of locating lesions before they would normally be found by the patient. Such examinations are called screenings and may involve several detection modalities. The two main parameters in the design of a screening program are the frequency of examination and the sensitivity of the detection modality. Models are developed in this paper to examine the effect of screening on the sue of tumors at the time of detection. They are then used to assess the effect of the frequency and sensitivity of the screening program on the non-recurrence rate for breast cancer. As a result of the modelling, various recommendations on screening design are given.     

A classification updating procedure motivated by high-content screening data

The current paradigm for the identification of candidate drugs within the pharmaceutical industry typically involves the use of high-throughput screens. High-content screening (HCS) is the term given to the process of using an imaging platform to screen large numbers of compounds for some desirable biological activity. Classification methods have important applications in HCS experiments, where they are used to predict which compounds have the potential to be developed into new drugs. In this paper, a new classification method is proposed for batches of compounds where the rule is updated sequentially using information from the classification of previous batches. This methodology accounts for the possibility that the training data are not a representative sample of the test data and that the underlying group distributions may change as new compounds are analysed. This technique is illustrated on an example data set using linear discriminant analysis, k-nearest neighbour and random forest classifiers. Random forests are shown to be superior to the other classifiers and are further improved by the additional updating algorithm in terms of an increase in the number of true positives as well as a decrease in the number of false positives.     

MAXIMUM LIKELIHOOD ESTIMATION FOR A POISSON RATE PARAMETER WITH MISCLASSIFIED COUNTS

This paper proposes a Poisson‐based model that uses both error‐free data and error‐prone data subject to misclassification in the form of false‐negative and false‐positive counts. It derives maximum likelihood estimators (MLEs) for the Poisson rate parameter and the two misclassification parameters — the false‐negative parameter and the false‐positive parameter. It also derives expressions for the information matrix and the asymptotic variances of the MLE for the rate parameter, the MLE for the false‐positive parameter, and the MLE for the false‐negative parameter. Using these expressions the paper analyses the value of the fallible data. It studies characteristics of the new double‐sampling rate estimator via a simulation experiment and applies the new MLE estimators and confidence intervals to a real dataset.     

Feature screening for case‐cohort studies with failure time outcome

Case‐cohort design has been demonstrated to be an economical and efficient approach in large cohort studies when the measurement of some covariates on all individuals is expensive. Various methods have been proposed for case‐cohort data when the dimension of covariates is smaller than sample size. However, limited work has been done for high‐dimensional case‐cohort data which are frequently collected in large epidemiological studies. In this paper, we propose a variable screening method for ultrahigh‐dimensional case‐cohort data under the framework of proportional model, which allows the covariate dimension increases with sample size at exponential rate. Our procedure enjoys the sure screening property and the ranking consistency under some mild regularity conditions. We further extend this method to an iterative version to handle the scenarios where some covariates are jointly important but are marginally unrelated or weakly correlated to the response. The finite sample performance of the proposed procedure is evaluated via both simulation studies and an application to a real data from the breast cancer study.     

Repeated screening with inspection error and no false positive results with application to pharmaceutical pill production

Summary.  Repeated screening is a 100% sampling inspection of a batch of items followed by removal of the defective items and further iterations of inspection and removal. The reason for repeating the inspection is that the detection of a defective item happens with probability p <1. A missed defective item is a false negative result. The no false positive result is contemplated in this paper, which is motivated by a problem coming from the production of pharmaceutical pills. Bayesian posterior distributions for the quality of the lot are obtained for the case of both p known and p unknown. Batch rejection and batch acceptance control limits for the number of defective items at subsequent iterations can then be calculated. Theoretical connections to the problem of estimating the number-of-trials parameter of a binomial distribution are drawn.     

Detecting multiple change points in piecewise constant hazard functions

The National Cancer Institute (NCI) suggests a sudden reduction in prostate cancer mortality rates, likely due to highly successful treatments and screening methods for early diagnosis. We are interested in understanding the impact of medical breakthroughs, treatments, or interventions, on the survival experience for a population. For this purpose, estimating the underlying hazard function, with possible time change points, would be of substantial interest, as it will provide a general picture of the survival trend and when this trend is disrupted. Increasing attention has been given to testing the assumption of a constant failure rate against a failure rate that changes at a single point in time. We expand the set of alternatives to allow for the consideration of multiple change-points, and propose a model selection algorithm using sequential testing for the piecewise constant hazard model. These methods are data driven and allow us to estimate not only the number of change points in the hazard function but where those changes occur. Such an analysis allows for better understanding of how changing medical practice affects the survival experience for a patient population. We test for change points in prostate cancer mortality rates using the NCI Surveillance, Epidemiology, and End Results dataset.     

TESTING FOR MOVING AVERAGE REGRESSION DISTURBANCES

This paper considers a locally optimal procedure for testing for first order moving average disturbances in the linear regression model. For this hypothesis testing problem, the Durbin-Watson test is shown to be approximately locally best invariant while the new test is most powerful invariant in a given neighbourhood of the alternative hypothesis. Two versions of the test procedure are recommended for general use; one for problems involving positively correlated disturbances and one for negatively correlated disturbances. An empirical comparison of powers shows the clear superiority of the recommended tests over the Durbin-Watson test. Selected bounds for the tests' significance points are tabulated.     

Assessing accuracy of a continuous screening test in the presence of verification bias

Summary.  In studies to assess the accuracy of a screening test, often definitive disease assessment is too invasive or expensive to be ascertained on all the study subjects. Although it may be more ethical or cost effective to ascertain the true disease status with a higher rate in study subjects where the screening test or additional information is suggestive of disease, estimates of accuracy can be biased in a study with such a design. This bias is known as verification bias. Verification bias correction methods that accommodate screening tests with binary or ordinal responses have been developed; however, no verification bias correction methods exist for tests with continuous results. We propose and compare imputation and reweighting bias-corrected estimators of true and false positive rates, receiver operating characteristic curves and area under the receiver operating characteristic curve for continuous tests. Distribution theory and simulation studies are used to compare the proposed estimators with respect to bias, relative efficiency and robustness to model misspecification. The bias correction estimators proposed are applied to data from a study of screening tests for neonatal hearing loss.     

A NONPARAMETRIC MIXED‐EFFECTS MODEL FOR CANCER MORTALITY

There are several ways to handle within‐subject correlations with a longitudinal discrete outcome, such as mortality. The most frequently used models are either marginal or random‐effects types. This paper deals with a random‐effects‐based approach. We propose a nonparametric regression model having time‐varying mixed effects for longitudinal cancer mortality data. The time‐varying mixed effects in the proposed model are estimated by combining kernel‐smoothing techniques and a growth‐curve model. As an illustration based on real data, we apply the proposed method to a set of prefecture‐specific data on mortality from large‐bowel cancer in Japan.     

Pooled Panel Unit Root Tests and the Effect of Past Initialization

This paper analyzes the role of initialization when testing for a unit root in panel data, an issue that has received surprisingly little attention in the literature. In fact, most studies assume that the initial value is either zero or bounded. As a response to this, the current paper considers a model in which the initialization is in the past, which is shown to have several distinctive features that makes it attractive, even in comparison to the common time series practice of making the initial value a draw from its unconditional distribution under the stationary alternative. The results have implications not only for theory, but also for applied work. In particular, and in contrast to the time series case, in panels the effect of the initialization need not be negative but can actually lead to improved test performance.     

A new class of mixture models for differential gene expression in DNA microarray data

One of the fundamental issues in analyzing microarray data is to determine which genes are expressed and which ones are not for a given group of subjects. In datasets where many genes are expressed and many are not expressed (i.e., underexpressed), a bimodal distribution for the gene expression levels often results, where one mode of the distribution represents the expressed genes and the other mode represents the underexpressed genes. To model this bimodality, we propose a new class of mixture models that utilize a random threshold value for accommodating bimodality in the gene expression distribution. Theoretical properties of the proposed model are carefully examined. We use this new model to examine the problem of differential gene expression between two groups of subjects, develop prior distributions, and derive a new criterion for determining which genes are differentially expressed between the two groups. Prior elicitation is carried out using empirical Bayes methodology in order to estimate the threshold value as well as elicit the hyperparameters for the two component mixture model. The new gene selection criterion is demonstrated via several simulations to have excellent false positive rate and false negative rate properties. A gastric cancer dataset is used to motivate and illustrate the proposed methodology.     

Detecting excessive similarity in answers on multiple choice exams

This paper provides a simple and robust method for detecting cheating. Unlike some methods, non-cheating behaviour and not cheating behaviour is modelled because this requires the fewest assumptions. The main concern is the prevention of false accusations. The model is suitable for screening large classes and the results are simple to interpret. Simulation and the Bonferroni inequality are used to prevent false accusation due to 'data dredging'. The model has received considerable application in practice and has been verified through the adjacent seating method.     

Efficient Stratified Testing Procedure for a False Discovery Rate

The false discovery rate (FDR) has become a popular error measure in the large-scale simultaneous testing. When data are collected from heterogenous sources and form grouped hypotheses testing, it may be beneficial to use the distinct feature of groups to conduct the multiple hypotheses testing. We propose a stratified testing procedure that uses different FDR levels according to the stratification features based on p-values. Our proposed method is easy to implement in practice. Simulations studies show that the proposed method produces more efficient testing results. The stratified testing procedure minimizes the overall false negative rate (FNR) level, while controlling the overall FDR. An example from a type II diabetes mice study further illustrates the practical advantages of this new approach.     

Operating characteristics and extensions of the false discovery rate procedure

Summary. We investigate the operating characteristics of the Benjamini–Hochberg false discovery rate procedure for multiple testing. This is a distribution-free method that controls the expected fraction of falsely rejected null hypotheses among those rejected. The paper provides a framework for understanding more about this procedure. We first study the asymptotic properties of the `deciding point' D that determines the critical p -value. From this, we obtain explicit asymptotic expressions for a particular risk function. We introduce the dual notion of false non-rejections and we consider a risk function that combines the false discovery rate and false non-rejections. We also consider the optimal procedure with respect to a measure of conditional risk.     

GROUPING CORRECTIONS FOR SEQUENTIAL TESTS

When testing sequentially with grouped data, we may or may not adjust the test statistic to allow for the grouping. If the test statistic is not adjusted, the whole power curve will be altered by the grouping, while if the statistic is adjusted, the power curve is altered, but the probability levels or errors of the first and second kind, being distribution-free, are unchanged. It is shown, even for very coarse grouping of the data, that the power curve is only slightly affected by using the unadjusted statistic for tests on the mean or the variance of a normal distribution. For certain other distributions, however, in particular the negative exponential distribution, this procedure breaks down completely if the group width exceeds a certain value.