Optimal classification and generalized prevalence estimates for diagnostic settings with more than two classes (preprint)

An accurate multiclass classification strategy is crucial to interpreting antibody tests. However, traditional methods based on confidence intervals or receiver operating characteristics lack clear extensions to settings with more than two classes. We address this problem by developing a multiclass classification based on probabilistic modeling and optimal decision theory that minimizes the convex combination of false classification rates. The classification process is challenging when the relative fraction of the population in each class, or generalized prevalence, is unknown. Thus, we also develop a method for estimating the generalized prevalence of test data that is independent of classification. We validate our approach on serological data with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) na\"ive, previously infected, and vaccinated classes. Synthetic data are used to demonstrate that (i) prevalence estimates are unbiased and converge to true values and (ii) our procedure applies to arbitrary measurement dimensions. In contrast to the binary problem, the multiclass setting offers wide-reaching utility as the most general framework and provides new insight into prevalence estimation best practices.

Modeling in higher dimensions to improve diagnostic testing accuracy: theory and examples for multiplex saliva-based SARS-CoV-2 antibody assays (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the importance and challenges of correctly interpreting antibody test results. Identification of positive and negative samples requires a classification strategy with low error rates, which is hard to achieve when the corresponding measurement values overlap. Additional uncertainty arises when classification schemes fail to account for complicated structure in data. We address these problems through a mathematical framework that combines high dimensional data modeling and optimal decision theory. Specifically, we show that appropriately increasing the dimension of data better separates positive and negative populations and reveals nuanced structure that can be described in terms of mathematical models. We combine these models with optimal decision theory to yield a classification scheme that better separates positive and negative samples relative to traditional methods such as confidence intervals (CIs) and receiver operating characteristics. We validate the usefulness of this approach in the context of a multiplex salivary SARS-CoV-2 immunoglobulin G assay dataset. This example illustrates how our analysis: (i) improves the assay accuracy (e.g. lowers classification errors by up to 42 % compared to CI methods); (ii) reduces the number of indeterminate samples when an inconclusive class is permissible (e.g. by 40 % compared to the original analysis of the example multiplex dataset); and (iii) decreases the number of antigens needed to classify samples. Our work showcases the power of mathematical modeling in diagnostic classification and highlights a method that can be adopted broadly in public health and clinical settings.

Improving Baseline Subtraction for Increased Sensitivity of Quantitative PCR Measurements (preprint)

Motivated by the current COVID-19 health-crisis, we examine the task of baseline subtraction for quantitative polymerase chain-reaction (qPCR) measurements. In particular, we present an algorithm that leverages information obtained from non-template and/or DNA extraction-control experiments to remove systematic bias from amplification curves. We recast this problem in terms of mathematical optimization, i.e. by finding the amount of control signal that, when subtracted from an amplification curve, minimizes background noise. We demonstrate that this approach can yield a decade improvement in sensitivity relative to standard approaches, especially for data exhibiting late-cycle amplification. Critically, this increased sensitivity and accuracy promises more effective screening of viral DNA and a reduction in the rate of false-negatives in diagnostic settings.