arXiv subjects

Sarah C. Lotspeich

Publications and source records attributed to Sarah C. Lotspeich.

16 recordsLinked to original sources

arXiv2026

Symmetric Vaccine Efficacy

Traditional measures of vaccine efficacy (VE) are inherently asymmetric, constrained above by $1$ but unbounded below. As a result, VE estimates and corresponding confidence intervals can extend far below zero, making interpretation difficult and potentially obscuring whether the apparent effect reflects true harm or simply statistical uncertainty. The proposed symmetric vaccine efficacy (SVE) is a bounded and interpretable alternative to VE that maintains desirable statistical properties while resolving these asymmetries. SVE is defined as a symmetric transformation of infection risks, with possible values within $[-1, 1]$, providing a common scale for both beneficial and harmful vaccine effects. This paper describes the relationship between SVE and traditional VE, considers inference about SVE, and illustrates the utility of the proposed measure by reanalyzing data from a randomized trial of a candidate HIV vaccine. Open-source tools for computing estimates of SVE and corresponding confidence intervals are available in R through the sve package.

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arXiv2026

Predicting Hospitalization from a Whole-Person Health Score with Incomplete Electronic Health Records Data: A Case Study

Embedding a standardized whole-person health measure in electronic health records (EHR) could be instrumental to preventative care. The allostatic load index (ALI), calculated from ten component stressors across three body systems, offers a promising snapshot of holistic health. The ALI can be calculated from EHR data, but many components are missing, since not all patients undergo all tests. Using statistical modeling and machine learning, EHR data for $1000$ patients from a large academic health system were used to predict in-patient hospitalization (as a count or binary) from ALI, controlling for age and sex. Various methods were evaluated to fill in information gaps for patients' missing ALI components, including summary measures combining components or using them separately. Performance was measured using receiver operating characteristic (ROC) curves and corresponding areas under the ROC curve (AUC). Count modeling of hospitalization did not improve upon binary, and logistic regression beat random forest. Overall, summary measures performed similarly, with the complete-case proportion (i.e., the proportion of non-missing components that were "unhealthy") performing best (AUC $= 0.64$) but by $\leq 0.01$. When using components separately, the pattern submodel approach most accurately predicted hospitalization (AUC $= 0.73$) in sample, but did not cross-validate as well (AUC $= 0.63$). All summary measures performed similarly. However, when including the ALI components separately, tailoring models to subsets of patients with the same missing data pattern performed best. Next steps include EHR implementation to enable prediction and support clinician decision-making at scale.

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arXiv2026

Two-phase validation sampling via principal components to improve efficiency in multi-model estimation from error-prone biomedical databases

Two-phase sampling offers a cost-effective way to validate error-prone covariate measurements in biomedical databases. Inexpensive or easy-to-obtain information is collected for the entire study in Phase I. Then, a subset of patients undergoes cost-intensive validation (e.g., expert chart review) to collect more accurate data in Phase II. When balancing primary and secondary analyses, competing models and priorities can result in poorly defined objectives for the most informative Phase II sampling criterion. Extreme tail sampling (ETS), wherein patients with the smallest and largest values of a particular quantity (like a covariate or residual) are selected, can offer great statistical efficiency in two-phase studies when focusing on a single analytic objective by targeting observations with the biggest contributions to the Fisher information. We propose an intuitive, easy-to-use approach that extends ETS to balance and prioritize explaining the largest amount of variability across multiple models of interest. Using principal components analysis, we succinctly summarize the inherent variability of all models' error-prone exposures. Then, we sample patients with the most extreme values of the first principal component for validation. Through extensive simulations and an application to the National Health and Nutrition Examination Survey (NHANES), the proposed strategy offered simultaneous efficiency gains across multiple models of interest. Its advantages persisted across various real-world scenarios, including correlated or heterogeneous measurement error. When designing a validation study, concentrating on a single model may be short-sighted. Strategically allocating resources more broadly balances multiple analytical goals simultaneously. Employing dimension reduction before sampling will allow this strategy to scale up well to big-data applications with many error-prone exposures.

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arXiv2026

Correcting for Missing Data When Evaluating Surrogate Markers in a Clinical Trial

Evaluating treatment effects is critical in clinical trials but sometimes involves lengthy, invasive, or costly follow-up procedures. In these cases, surrogate markers, which provide intermediate measures of the long-term treatment effect, allow clinicians to obtain results faster and more efficiently than would have otherwise been possible. Prior to adoption, it is vital that the utility of surrogate markers (i.e., their ability to capture the treatment effect on the primary outcome) is statistically validated. Many frameworks for evaluating surrogate markers have been proposed, but they do not account for missing data. Instead, they rely on complete cases (the subset of patients without missing data), which can be inefficient and biased. To improve on this, we propose methods to accommodate missing data in nonparametric and parametric surrogate evaluation via inverse probability weighting (IPW) and semiparametric maximum likelihood estimation (SMLE). Through simulation studies, we demonstrate that the proposed methods remain unbiased under a broader range of missing data mechanisms than complete case analysis and can help retain the statistical precision of the full trial. We illustrate their practical utility through an application to a diabetes clinical trial. Moreover, our missing data corrections have complementary strengths with respect to computational ease, robustness, and statistical efficiency. All methods are implemented in the MissSurrogate R package.

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arXiv2026

Accounting for Heavy Censoring in Evaluating the Risk Stratification Abilities of Existing Models for Time to Diagnosis of Huntington Disease

Huntington disease (HD) is a neurodegenerative disease with progressively worsening symptoms. Accurately modeling time to HD diagnosis is essential for clinical trial design. Langbehn's model, the CAG-Age Product (CAP) model, the Prognostic Index Normed (PIN) model, and the Multivariate Risk Score (MRS) model have all been proposed for this task. However, these models may yield conflicting predictions and few studies have systematically compared their performance. Further, those that have could be misleading due to testing the models on the same data used to train them and failing to account for high rates of right censoring (80%+) in performance metrics. We discuss the theoretical foundations of these models, offering intuitive comparisons about their practical feasibility. We externally validate their risk stratification abilities using data from the ENROLL-HD study and two censoring-appropriate performance metrics, guiding model selection for HD clinical trial design. As these models were developed in HD studies that ended more than a decade ago, we compared their predictive performance using published parameters versus updated ones (re-estimated using ENROLL-HD). We show how these models can be used to estimate sample sizes for an HD clinical trial. Based on either metric and using published or updated parameters, the MRS model, which incorporates the most covariates, performed best. However, the simpler PIN model offered similarly good performance while requiring fewer variables, many of which would require patients to undergo additional tests. In illustrating an HD clinical trial design, we defined an optimal threshold based on model performance metrics to determine which patients are more likely to be diagnosed. Sample size calculations using an optimal threshold based on metrics that did not account for censoring, as in previous studies, are shown to lead to underpowered trials.

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arXiv2025

Linking Potentially Misclassified Healthy Food Access to Diabetes Prevalence

Access to healthy food is key to maintaining a healthy lifestyle and can be quantified by the distance to the nearest grocery store. However, calculating this distance forces a trade-off between cost and correctness. Accurate route-based distances following passable roads are cost-prohibitive, while simple straight-line distances ignoring infrastructure and natural barriers are accessible yet error-prone. Categorizing low-access neighborhoods based on these straight-line distances induces misclassification and introduces bias into standard regression models estimating the relationship between disease prevalence and access. Yet, fully observing the more accurate, route-based food access measure is often impossible, which induces a missing data problem. We combat bias and address missingness with a new maximum likelihood estimator for Poisson regression with a binary, misclassified exposure (access to healthy food within some threshold), where the misclassification may depend on additional error-free covariates. In simulations, we show the consequence of ignoring the misclassification (bias) and how the proposed estimator corrects for bias while preserving more statistical efficiency than the complete case analysis (i.e., deleting observations with missing data). Finally, we apply our estimator to model the relationship between census tract diabetes prevalence and access to healthy food in northwestern North Carolina.

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arXiv2025

On Using Large Language Models to Enhance Clinically-Driven Missing Data Recovery Algorithms in Electronic Health Records

Objective: Electronic health records (EHR) data are prone to missingness and errors. Previously, we devised an "enriched" chart review protocol where a "roadmap" of auxiliary diagnoses (anchors) was used to recover missing values in EHR data (e.g., a diagnosis of impaired glycemic control might imply that a missing hemoglobin A1c value would be considered unhealthy). Still, chart reviews are expensive and time-intensive, which limits the number of patients whose data can be reviewed. Now, we investigate the accuracy and scalability of a roadmap-driven algorithm, based on ICD-10 codes (International Classification of Diseases, 10th revision), to mimic expert chart reviews and recover missing values. Materials and Methods: In addition to the clinicians' original roadmap from our previous work, we consider new versions that were iteratively refined using large language models (LLM) in conjunction with clinical expertise to expand the list of auxiliary diagnoses. Using chart reviews for 100 patients from the EHR at an extensive learning health system, we examine algorithm performance with different roadmaps. Using the larger study of $1000$ patients, we applied the final algorithm, which used a roadmap with clinician-approved additions from the LLM. Results: The algorithm recovered as much, if not more, missing data as the expert chart reviewers, depending on the roadmap. Discussion: Clinically-driven algorithms (enhanced by LLM) can recover missing EHR data with similar accuracy to chart reviews and can feasibly be applied to large samples. Extending them to monitor other dimensions of data quality (e.g., plausability) is a promising future direction.

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arXiv2025

Overcoming data challenges through enriched validation and targeted sampling to measure whole-person health in electronic health records

The allostatic load index (ALI) is a 10-component measure of whole-person health. Data from electronic health records (EHR) present a huge opportunity to operationalize the ALI in learning health systems; however, these data are prone to missingness and errors. Validation (e.g., through chart reviews) provides better-quality data, but realistically, only a subset of patients' data can be validated, and most protocols do not recover missing data. Using a representative sample of 1000 patients from the EHR at an extensive learning health system (100 of whom could be validated), we propose methods to design, conduct, and analyze statistically efficient and robust studies of ALI and healthcare utilization. Employing semiparametric maximum likelihood estimation, we robustly incorporate all available patient information into statistical models. Using targeted design strategies, we examine ways to select the most informative patients for validation. Incorporating clinical expertise, we devise a novel validation protocol to promote EHR data quality and completeness. Chart reviews uncovered few errors (99% matched source documents) and recovered some missing data through auxiliary information in patients' charts. On average, validation increased the number of non-missing ALI components per patient from 6 to 7. Through simulations based on preliminary data, residual sampling was identified as the most informative strategy for completing our validation study. Incorporating validation data, statistical models indicated that worse whole-person health (higher ALI) was associated with higher odds of engaging in the healthcare system, adjusting for age.

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arXiv2025

Improved computational efficiency and stability when imputing censored covariates: Analytic and numerical approaches

Imputation is a popular approach to handling censored, missing, and error-prone covariates -- all coarsened data types for which the true values are unknown. However, there are nuances to imputing these different data types based on the mechanism dominating the unobserved values and other available information. For example, in prospective studies, the time to a disease diagnosis will be incompletely observed if only some patients are diagnosed by the end of the follow-up. Some will be randomly right-censored, and patients' disease-free follow-up times must be incorporated into their imputed values. Assuming noninformative censoring, censored values are replaced with their conditional means, which are calculated by estimating the conditional survival function of the censored covariate and then integrating over it. Semiparametric approaches are common, which estimate the survival with a Cox model and then the integral with the trapezoidal rule. While these approaches offer robustness, they come at the cost of computational efficiency and stability in numerically approximating an improper integral. After modeling the survival function parametrically, we derive analytic solutions for conditional mean imputed values under many common distributions. We define stabilized calculations for other distributions. Parametric imputation using various distributions and calculations is implemented in the R package, speedyCMI.

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arXiv2025

Combining straight-line and map-based distances to investigate the connection between proximity to healthy foods and disease

Healthy foods are essential for a healthy life, but accessing healthy food can be more challenging for some people than others. This disparity in food access may lead to disparities in well-being, potentially with disproportionate rates of diseases in communities that face more challenges in accessing healthy food (i.e., low-access communities). Identifying low-access, high-risk communities for targeted interventions is a public health priority, but current methods to quantify food access rely on distance measures that are either computationally simple (like the length of the shortest straight-line route) or accurate (like the length of the shortest map-based driving route), but not both. We propose a multiple imputation approach to combine these distance measures, allowing researchers to harness the computational ease of one with the accuracy of the other. The approach incorporates straight-line distances for all neighborhoods and map-based distances for just a subset, offering comparable estimates to the "gold standard" model using map-based distances for all neighborhoods and improved efficiency over the "complete case" model using map-based distances for just the subset. Through the adoption of a measurement error framework, information from the straight-line distances can be leveraged to compute informative placeholders (i.e., impute) for any neighborhoods without map-based distances. Using simulations and data for the Piedmont Triad region of North Carolina, we quantify and compare the associations between two health outcomes (diabetes and obesity) and neighborhood-level access to healthy foods. The imputation procedure also makes it possible to predict the full landscape of food access in an area without requiring map-based measurements for all neighborhoods.

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arXiv2024

The `Why' behind including `Y' in your imputation model

Missing data is a common challenge when analyzing epidemiological data, and imputation is often used to address this issue. Here, we investigate the scenario where a covariate used in an analysis has missingness and will be imputed. There are recommendations to include the outcome from the analysis model in the imputation model for missing covariates, but it is not necessarily clear if this recommendation always holds and why this is sometimes true. We examine deterministic imputation (i.e., single imputation with fixed values) and stochastic imputation (i.e., single or multiple imputation with random values) methods and their implications for estimating the relationship between the imputed covariate and the outcome. We mathematically demonstrate that including the outcome variable in imputation models is not just a recommendation but a requirement to achieve unbiased results when using stochastic imputation methods. Moreover, we dispel common misconceptions about deterministic imputation models and demonstrate why the outcome should not be included in these models. This paper aims to bridge the gap between imputation in theory and in practice, providing mathematical derivations to explain common statistical recommendations. We offer a better understanding of the considerations involved in imputing missing covariates and emphasize when it is necessary to include the outcome variable in the imputation model.

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arXiv2023

Extrapolation before imputation reduces bias when imputing censored covariates

Modeling symptom progression to identify informative subjects for a new Huntington's disease clinical trial is problematic since time to diagnosis, a key covariate, can be heavily censored. Imputation is an appealing strategy where censored covariates are replaced with their conditional means, but existing methods saw over 200% bias under heavy censoring. Calculating these conditional means well requires estimating and then integrating over the survival function of the censored covariate from the censored value to infinity. To estimate the survival function flexibly, existing methods use the semiparametric Cox model with Breslow's estimator, leaving the integrand for the conditional means (the estimated survival function) undefined beyond the observed data. The integral is then estimated up to the largest observed covariate value, and this approximation can cut off the tail of the survival function and lead to severe bias, particularly under heavy censoring. We propose a hybrid approach that splices together the semiparametric survival estimator with a parametric extension, making it possible to approximate the integral up to infinity. In simulation studies, our proposed approach of extrapolation then imputation substantially reduces the bias seen with existing imputation methods, even when the parametric extension was misspecified. We further demonstrate how imputing with corrected conditional means helps to prioritize patients for future clinical trials.

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arXiv2023

Quantifying the HIV reservoir with dilution assays and deep viral sequencing

People living with HIV on antiretroviral therapy often have undetectable virus levels by standard assays, but "latent" HIV still persists in viral reservoirs. Eliminating these reservoirs is the goal of HIV cure research. The quantitative viral outgrowth assay (QVOA) is commonly used to estimate the reservoir size, i.e., the infectious units per million (IUPM) of HIV-persistent resting CD4+ T cells. A new variation of the QVOA, the Ultra Deep Sequencing Assay of the outgrowth virus (UDSA), was recently developed that further quantifies the number of viral lineages within a subset of infected wells. Performing the UDSA on a subset of wells provides additional information that can improve IUPM estimation. This paper considers statistical inference about the IUPM from combined dilution assay (QVOA) and deep viral sequencing (UDSA) data, even when some deep sequencing data are missing. Methods are proposed to accommodate assays with wells sequenced at multiple dilution levels and with imperfect sensitivity and specificity, and a novel bias-corrected estimator is included for small samples. The proposed methods are evaluated in a simulation study, applied to data from the University of North Carolina HIV Cure Center, and implemented in the open-source R package SLDeepAssay.

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arXiv2023

Mission Imputable: Correcting for Berkson Error When Imputing a Censored Covariate

To select outcomes for clinical trials testing experimental therapies for Huntington disease, a fatal neurodegenerative disorder, analysts model how potential outcomes change over time. Yet, subjects with Huntington disease are often observed at different levels of disease progression. To account for these differences, analysts include time to clinical diagnosis as a covariate when modeling potential outcomes, but this covariate is often censored. One popular solution is imputation, whereby we impute censored values using predictions from a model of the censored covariate given other data, then analyze the imputed dataset. However, when this imputation model is misspecified, our outcome model estimates can be biased. To address this problem, we developed a novel method, dubbed "ACE imputation." First, we model imputed values as error-prone versions of the true covariate values. Then, we correct for these errors using semiparametric theory. Specifically, we derive an outcome model estimator that is consistent, even when the censored covariate is imputed using a misspecified imputation model. Simulation results show that ACE imputation remains empirically unbiased even if the imputation model is misspecified, unlike multiple imputation which yields >100% bias. Applying our method to a Huntington disease study pinpoints outcomes for clinical trials aimed at slowing disease progression.

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arXiv2022

Optimal Multi-Wave Validation of Secondary Use Data with Outcome and Exposure Misclassification

The growing availability of observational databases like electronic health records (EHR) provides unprecedented opportunities for secondary use of such data in biomedical research. However, these data can be error-prone and need to be validated before use. It is usually unrealistic to validate the whole database due to resource constraints. A cost-effective alternative is to implement a two-phase design that validates a subset of patient records that are enriched for information about the research question of interest. Herein, we consider odds ratio estimation under differential outcome and exposure misclassification. We propose optimal designs that minimize the variance of the maximum likelihood odds ratio estimator. We develop a novel adaptive grid search algorithm that can locate the optimal design in a computationally feasible and numerically accurate manner. Because the optimal design requires specification of unknown parameters at the outset and thus is unattainable without prior information, we introduce a multi-wave sampling strategy to approximate it in practice. We demonstrate the efficiency gains of the proposed designs over existing ones through extensive simulations and two large observational studies. We provide an R package and Shiny app to facilitate the use of the optimal designs.

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arXiv2021

Correcting Conditional Mean Imputation for Censored Covariates and Improving Usability

Analysts are often confronted with censoring, wherein some variables are not observed at their true value, but rather at a value that is known to fall above or below that truth. While much attention has been given to the analysis of censored outcomes, contemporary focus has shifted to censored covariates, as well. Missing data is often overcome using multiple imputation, which leverages the entire dataset by replacing missing values with informed placeholders, and this method can be modified for censored data by also incorporating partial information from censored values. One such modification involves replacing censored covariates with their conditional means given other fully observed information, such as the censored value or additional covariates. So-called conditional mean imputation approaches were proposed for censored covariates in Atem et al. [2017], Atem et al.[2019a], and Atem et al. [2019b]. These methods are robust to additional parametric assumptions on the censored covariate and utilize all available data, which is appealing. As we worked to implement these methods, however, we discovered that these three manuscripts provide nonequivalent formulas and, in fact, none is the correct formula for the conditional mean. Herein, we derive the correct form of the conditional mean and demonstrate the impact of the incorrect formulas on the imputed values and statistical inference. Under several settings considered, using an incorrect formula is seen to seriously bias parameter estimation in simple linear regression. Lastly, we provide user-friendly R software, the imputeCensoRd package, to enable future researchers to tackle censored covariates in their data.

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