On optimal biomarker cutoffs accounting for misclassification costs in diagnostic trilemmas with applications to pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most deadly cancer and currently there is strong clinical interest in novel biomarkers that contribute to its early detection. Assessing appropriately the accuracy of such biomarkers is a crucial issue and often one needs to take into account that many assays include biospecimens of individuals coming from three groups: healthy, chronic pancreatitis, and PDAC. The ROC surface is an appropriate tool for assessing the overall accuracy of a marker employed under such trichotomous settings. A decision/classification rule is often based on the so-called Youden index and its three-dimensional generalization. However, both the clinical and the statistical literature have not paid the necessary attention to the underlying false classification (FC) rates that are of equal or even greater importance. In this article we provide a framework to make inferences around all classification rates as well as comparisons. We explore the trinormal model, flexible models based on power transformations, and robust non-parametric alternatives. We provide a full framework for the construction of confidence intervals, regions, and spaces for joint inferences or for clinically meaningful points of interest. We further discuss the implications of costs related to different FCs. We evaluate our approaches through extensive simulations and illustrate them using data from a recent PDAC study conducted at the MD Anderson Cancer Center.

An Isotonic Partial Credit Model for Ordering Subjects on the Basis of Their Sum Scores.

In practice, the sum of the item scores is often used as a basis for comparing subjects. For items that have more than two ordered score categories, only the partial credit model (PCM) and special cases of this model imply that the subjects are stochastically ordered on the common latent variable. However, the PCM is very restrictive with respect to the constraints that it imposes on the data. In this paper, sufficient conditions for the stochastic ordering of subjects by their sum score are obtained. These conditions define the isotonic (nonparametric) PCM model. The isotonic PCM is more flexible than the PCM, which makes it useful for a wider variety of tests. Also, observable properties of the isotonic PCM are derived in the form of inequality constraints. It is shown how to obtain estimates of the score distribution under these constraints by using the Gibbs sampling algorithm. A small simulation study shows that the Bayesian p-values based on the log-likelihood ratio statistic can be used to assess the fit of the isotonic PCM to the data, where model-data fit can be taken as a justification of the use of the sum score to order subjects.

Incomplete Tests of Conditional Association for the Assessment of Model Assumptions.

Many of the models that have been proposed for response data share the assumptions that define the monotone homogeneity (MH) model. Observable properties that are implied by the MH model allow for these assumptions to be tested. For binary response data, the most restrictive of these properties is called conditional association (CA). All the other properties considered can be considered incomplete tests of CA that alleviate the practical limitations encountered when assessing the MH model assumptions using CA. It is found that the assessment of the MH model assumptions with an incomplete test of CA, rather than CA, is generally associated with a substantial loss of information. We also look at the sensitivity of the observable properties to model violation and discuss the implications of the results. It is argued that more research is required about the extent to which the assumptions and the model specifications influence the inferences made from response data.

The optimal power puzzle: scrutiny of the monotone likelihood ratio assumption in multiple testing.

In single hypothesis testing, power is a non-decreasing function of type I error rate; hence it is desirable to test at the nominal level exactly to achieve optimal power. The puzzle lies in the fact that for multiple testing, under the false discovery rate paradigm, such a monotonic relationship may not hold. In particular, exact false discovery rate control may lead to a less powerful testing procedure if a test statistic fails to fulfil the monotone likelihood ratio condition. In this article, we identify different scenarios wherein the condition fails and give caveats for conducting multiple testing in practical settings.