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Longitudinal observational data on patients can be used to investigate causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for estimating such effects by controlling for the time-dependent confounding that typically occurs. The most commonly used is marginal structural models (MSM) estimated using inverse probability of treatment weights (IPTW) (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, and involves creating a sequence of "trials" from new time origins and comparing treatment initiators and non-initiators. Individuals are censored when they deviate from their treatment assignment at the start of each "trial" (initiator or noninitiator), which is accounted for using inverse probability of censoring weights. The analysis uses data combined across trials. We show that the sequential trials approach can estimate the parameters of a particular MSM. The causal estimand that we focus on is the marginal risk difference between the sustained treatment strategies of "always treat" vs "never treat." We compare how the sequential trials approach and MSM-IPTW estimate this estimand, and discuss their assumptions and how data are used differently. The performance of the two approaches is compared in a simulation study. The sequential trials approach, which tends to involve less extreme weights than MSM-IPTW, results in greater efficiency for estimating the marginal risk difference at most follow-up times, but this can, in certain scenarios, be reversed at later time points and relies on modelling assumptions. We apply the methods to longitudinal observational data from the UK Cystic Fibrosis Registry to estimate the effect of dornase alfa on survival.

Variable selection is an important step to end up with good prediction models. LASSO regression models are one of the most commonly used methods for this purpose, for which cross-validation is the most widely applied validation technique to choose the tuning parameter . Validation techniques in a complex survey framework are closely related to “replicate weights”. However, to our knowledge, they have never been used in a LASSO regression context. Applying LASSO regression models to complex survey data could be challenging. The goal of this paper is twofold. On the one hand, we analyze the performance of replicate weights methods to select the tuning parameter for fitting LASSO regression models to complex survey data. On the other hand, we propose new replicate weights methods for the same purpose. In particular, we propose a new design-based cross-validation method as a combination of the traditional cross-validation and replicate weights. The performance of all these methods has been analyzed and compared by means of an extensive simulation study to the traditional cross-validation technique to select the tuning parameter for LASSO regression models. The results suggest a considerable improvement when the new proposal design-based cross-validation is used instead of the traditional cross-validation. This work was financially supported in part by grants from the Departamento de Educación, Política Lingüística y Cultura del Gobierno Vasco IT1456-22 and by the Ministry of Science and Innovation through BCAM Severo Ochoa accreditation CEX2021-001142-S/MICIN/AEI/10.13039/501100011033 and through project PID2020-115882RB-I00/AEI/10.13039/501100011033 funded by Agencia Estatal de Investigación and acronym “S3M1P4R” and also by the Basque Government through the BERC 2022-2025 program. The work of AI was supported by grant PIF18/213. Open Access funding is provided by the University of the Basque Country.

Accurate and efficient detection of ovarian cancer at early stages is critical to ensure proper treatments for patients. Among the first-line modalities investigated in studies of early diagnosis are features distilled from protein mass spectra. This method, however, considers only a specific subset of spectral responses and ignores the interplay among protein expression levels, which can also contain diagnostic information. We propose a new modality that automatically searches protein mass spectra for discriminatory features by considering the self-similar nature of the spectra. Self-similarity is assessed by taking a wavelet decomposition of protein mass spectra and estimating the rate of level-wise decay in the energies of the resulting wavelet coefficients. Level-wise energies are estimated in a robust manner using distance variance, and rates are estimated locally via a rolling window approach. This results in a collection of rates that can be used to characterize the interplay among proteins, which can be indicative of cancer presence. Discriminatory descriptors are then selected from these evolutionary rates and used as classifying features. The proposed wavelet-based features are used in conjunction with features proposed in the existing literature for early stage diagnosis of ovarian cancer using two datasets published by the American National Cancer Institute. Including the wavelet-based features from the new modality results in improvements in diagnostic performance for early-stage ovarian cancer detection. This demonstrates the ability of the proposed modality to characterize new ovarian cancer diagnostic information., Comment: Pages 18, 8 figures

The increased availability of ultrahigh-dimensional biomarker data and the high demand of identifying biomarkers importantly related to survival outcomes made feature screening methods commonplace in the analysis of cancer genome data. When survival outcomes include endpoints of overall survival (OS) and time-to-progression (TTP), a high concordance is typically found in both endpoints in cancer studies, namely, patients' OS would most likely be extended when tumour progression is delayed. Existing screening procedures are often performed on a single survival endpoint only and may result in biased selection of features for OS in ignorance of disease progression. We propose a novel feature screening method by incorporating information of TTP into the selection of important biomarker predictors for more accurate inference of OS subsequent to disease progression. The proposal is based on the rank of correlation between individual features and the conditional distribution of OS given observations of TTP. It is advantageous for its flexible model nature, which requires no marginal model assumption for each endpoint, and its minimal computational cost for implementation. Theoretical results show its ranking consistency, sure screening and false rate control properties. Simulation results demonstrate that the proposed screener leads to more accurate feature selection than the method without considering the prior observations of disease progression. An application to breast cancer genome data illustrates its practical utility and facilitates disease classification using selected biomarker predictors. Ministry of Education (MOE) Xiang’s research was partially supported by the Singapore Ministry of Education Academic Research Fund Tier 1 Grant (RG98/20) and Tier 2 Grant (MOE-T2EP20121-0004), and Peng’s research was partially supported by the National Key R&D Program of China (Nos. 2021YFA1000100 and 2021YFA1000101) and the National Natural Science Foundation of China (NSFC grant no. 92046005).

Age-period-cohort (APC) models are frequently used in a variety of health and demographic-related outcomes. Fitting and interpreting APC models to data in equal intervals (equal age and period widths) is nontrivial due to the structural link between the three temporal effects (given two, the third can always be found) causing the well-known identification problem. The usual method for resolving the structural link identification problem is to base a model on identifiable quantities. It is common to find health and demographic data in unequal intervals, this creates further identification problems on top of the structural link. We highlight the new issues by showing that curvatures which were identifiable for equal intervals are no longer identifiable for unequal data. Furthermore, through extensive simulation studies, we show how previous methods for unequal APC models are not always appropriate due to their sensitivity to the choice of functions used to approximate the true temporal functions. We propose a new method for modeling unequal APC data using penalized smoothing splines. Our proposal effectively resolves the curvature identification issue that arises and is robust to the choice of the approximating function. To demonstrate the effectiveness of our proposal, we conclude with an application to UK all-cause mortality data from the Human mortality database.

SummaryProtein microarrays are a promising technology that measure protein levels in serum or plasma samples. Due to the high technical variability of these assays and high variation in protein levels across serum samples in any population, directly answering biological questions of interest using protein microarray measurements is challenging. Using within-array ranks of protein levels for analysis can mitigate the impact of between-sample variation on downstream analysis. Although ranks are sensitive to pre-processing steps, ranking methods that accommodate uncertainty provide robust and loss-function optimal ranks. Such ranking methods require Bayesian modeling that produces full posterior distributions for parameters of interest. Bayesian models that produce such outputs have been developed for other assays, for example DNA microarrays, but those modeling assumptions are not appropriate for protein microarrays. We develop and evaluate a Bayesian model to extract a full posterior distribution of normalized fluorescent signals and associated ranks for protein microarrays, and show that it fits well to data from two studies that use protein microrarrays from different manufacturing processes. We validate the model via simulation and demonstrate the downstream impact of using estimates from this model to obtain optimal ranks.

We present several related methods for creating confidence intervals to assess disease prevalence in variety of survey sampling settings. These include simple random samples with imperfect tests, weighted sampling with perfect tests, and weighted sampling with imperfect tests, with the first two settings considered special cases of the third. Our methods use survey results and measurements of test sensitivity and specificity to construct melded confidence intervals. We demonstrate that our methods appear to guarantee coverage in simulated settings, while competing methods are shown to achieve much lower than nominal coverage. We apply our method to a seroprevalence survey of SARS-CoV-2 in undiagnosed adults in the United States between May and July 2020., Comment: 45 pages, 35 figures