Sepsis-trained macrophages promote antitumoral tissue-resident T cells.

Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.

Latent pathway-based Bayesian models to identify intervenable factors of racial disparities in breast cancer stage at diagnosis.

PURPOSE: We built Bayesian Network (BN) models to explain roles of different patient-specific factors affecting racial differences in breast cancer stage at diagnosis, and to identify healthcare related factors that can be intervened to reduce racial health disparities. METHODS: We studied women age 67-74 with initial diagnosis of breast cancer during 2006-2014 in the National Cancer Institute's SEER-Medicare dataset. Our models included four measured variables (tumor grade, hormone receptor status, screening utilization and biopsy delay) expressed through two latent pathways-a tumor biology path, and health-care access/utilization path. We used various Bayesian model assessment tools to evaluate these two latent pathways as well as each of the four measured variables in explaining racial disparities in stage-at-diagnosis. RESULTS: Among 3,010 Black non-Hispanic (NH) and 30,310 White NH breast cancer patients, respectively 70.2% vs 76.9% were initially diagnosed at local stage, 25.3% vs 20.3% with regional stage, and 4.56% vs 2.80% with distant stage-at-diagnosis. Overall, BN performed approximately 4.7 times better than Classification And Regression Tree (CART) (Breiman L, Friedman JH, Stone CJ, Olshen RA. Classification and regression trees. CRC press; 1984) in predicting stage-at-diagnosis. The utilization of screening mammography is the most prominent contributor to the accuracy of the BN model. Hormone receptor (HR) status and tumor grade are useful for explaining racial disparity in stage-at diagnosis, while log-delay in biopsy impeded good prediction. CONCLUSIONS: Mammography utilization had a significant effect on racial differences in breast cancer stage-at-diagnosis, while tumor biology factors had less impact. Biopsy delay also aided in predicting local and regional stages-at-diagnosis for Black NH women but not for white NH women.

A cluster of broadly neutralizing IgG against BK polyomavirus in a repertoire dominated by IgM.

The BK polyomavirus (BKPyV) is an opportunistic pathogen, which is only pathogenic in immunosuppressed individuals, such as kidney transplant recipients, in whom BKPyV can cause significant morbidity. To identify broadly neutralizing antibodies against this virus, we used fluorescence-labeled BKPyV virus-like particles to sort BKPyV-specific B cells from the PBMC of KTx recipients, then single-cell RNAseq to obtain paired heavy- and light-chain antibody sequences from 2,106 sorted B cells. The BKPyV-specific repertoire was highly diverse in terms of both V-gene usage and clonotype diversity and included most of the IgM B cells, including many with extensive somatic hypermutation. In two patients where sufficient data were available, IgM B cells in the BKPyV-specific dataset had significant differences in V-gene usage compared with IgG B cells from the same patient. CDR3 sequence-based clustering allowed us to identify and characterize three broadly neutralizing "41F17-like" clonotypes that were predominantly IgG, suggesting that some specific BKPyV capsid epitopes are preferentially targeted by IgG.

CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy.

Tumors exploit numerous immune checkpoints, including those deployed by myeloid cells to curtail antitumor immunity. Here, we show that the C-type lectin receptor CLEC-1 expressed by myeloid cells senses dead cells killed by programmed necrosis. Moreover, we identified Tripartite Motif Containing 21 (TRIM21) as an endogenous ligand overexpressed in various cancers. We observed that the combination of CLEC-1 blockade with chemotherapy prolonged mouse survival in tumor models. Loss of CLEC-1 reduced the accumulation of immunosuppressive myeloid cells in tumors and invigorated the activation state of dendritic cells (DCs), thereby increasing T cell responses. Mechanistically, we found that the absence of CLEC-1 increased the cross-presentation of dead cell-associated antigens by conventional type-1 DCs. We identified antihuman CLEC-1 antagonist antibodies able to enhance antitumor immunity in CLEC-1 humanized mice. Together, our results demonstrate that CLEC-1 acts as an immune checkpoint in myeloid cells and support CLEC-1 as a novel target for cancer immunotherapy.

Median regression models for clustered, interval-censored survival data - An application to prostate surgery study.

Genitourinary surgeons and oncologists are particularly interested in whether a robotic surgery improves times to Prostate Specific Antigen (PSA) recurrence compared to a non-robotic surgery for removing the cancerous prostate. Time to PSA recurrence is an example of a survival time that is typically interval-censored between two consecutive clinical inspections with opposite test results. In addition, success of medical devices and technologies often depends on factors such as experience and skill level of the medical service providers, thus leading to clustering of these survival times. For analyzing the effects of surgery types and other covariates on median of clustered interval-censored time to post-surgery PSA recurrence, we present three competing novel models and associated frequentist and Bayesian analyses. The first model is based on a transform-both-sides of survival time with Gaussian random effects to account for the within-cluster association. Our second model assumes an approximate marginal Laplace distribution for the transformed log-survival times with a Gaussian copula to accommodate clustering. Our third model is a special case of the second model with Laplace distribution for the marginal log-survival times and Gaussian copula for the within-cluster association. Simulation studies establish the second model to be highly robust against extreme observations while estimating median regression coefficients. We provide a comprehensive comparison among these three competing models based on the model properties and the computational ease of their Frequentist and Bayesian analysis. We also illustrate the practical implementations and uses of these methods via analysis of a simulated clustered interval-censored data-set similar in design to a post-surgery PSA recurrence study.

Rural-Urban Differences in Breast Cancer Stage at Diagnosis.

Purpose: To analyze the extent to which rural-urban differences in breast cancer stage at diagnosis are explained by factors including age, race, tumor grade, receptor status, and insurance status. Methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 database, analysis was performed using data from women aged 50-74 diagnosed with breast cancer between the years 2013 and 2016. Patient rurality of residence was coded according to SEER's Rural-Urban Continuum Code 2013: Large Urban (RUCC 1), Small Urban (RUCC 2,3), and Rural (RUCC 4,5,6,7,8,9). Stage at diagnosis was coded according to SEER's Combined Summary Stage 2000 (2004+) criteria: Localized (0,1), Regional (2,3,4,5), and Distant (7). Descriptive statistics were analyzed, and variations were tested for across rural-urban categories using Kruskall-Wallis and Kendall's tau-b tests. Additionally, odds ratios (ORs) and 95% confidence intervals for the three ordinal levels of rural-urban residence were calculated while adjusting for other independent variables using ordinal logistic regression. Results: The rural residence category showed the largest proportion of women diagnosed with distant stage breast cancer. Additionally, we determined that patients with residence in both large and small urban areas had statistically significantly lower odds of higher stage diagnosis compared to rural patients even after controlling for age, race, tumor grade, receptor status, and insurance status. Conclusions: Rural women with breast cancer show small but statistically significant disparities in stage-at-diagnosis. Further research is needed to understand local area variation in these disparities across a wide range of rural communities, and to identify the most effective interventions to eliminate these disparities.

Semiparametric analysis of clustered interval-censored survival data using soft Bayesian additive regression trees (SBART).

Popular parametric and semiparametric hazards regression models for clustered survival data are inappropriate and inadequate when the unknown effects of different covariates and clustering are complex. This calls for a flexible modeling framework to yield efficient survival prediction. Moreover, for some survival studies involving time to occurrence of some asymptomatic events, survival times are typically interval censored between consecutive clinical inspections. In this article, we propose a robust semiparametric model for clustered interval-censored survival data under a paradigm of Bayesian ensemble learning, called soft Bayesian additive regression trees or SBART (Linero and Yang, 2018), which combines multiple sparse (soft) decision trees to attain excellent predictive accuracy. We develop a novel semiparametric hazards regression model by modeling the hazard function as a product of a parametric baseline hazard function and a nonparametric component that uses SBART to incorporate clustering, unknown functional forms of the main effects, and interaction effects of various covariates. In addition to being applicable for left-censored, right-censored, and interval-censored survival data, our methodology is implemented using a data augmentation scheme which allows for existing Bayesian backfitting algorithms to be used. We illustrate the practical implementation and advantages of our method via simulation studies and an analysis of a prostate cancer surgery study where dependence on the experience and skill level of the physicians leads to clustering of survival times. We conclude by discussing our method's applicability in studies involving high-dimensional data with complex underlying associations.

Naïve Bayesian network-based contribution analysis of tumor biology and healthcare factors to racial disparity in breast cancer stage-at-diagnosis.

BACKGROUND: Variation in breast cancer stage at initial diagnosis (including racial disparities) is driven both by tumor biology and healthcare factors. METHODS: We studied women age 67-74 with initial diagnosis of breast cancer from 2006 through 2014 in the SEER-Medicare database. We extracted variables related to tumor biology (histologic grade and hormone receptor status) and healthcare factors (screening mammography [SM] utilization and time delay from mammography to diagnostic biopsy). We used naïve Bayesian networks (NBNs) to illustrate the relationships among patient-specific factors and stage-at-diagnosis for African American (AA) and white patients separately. After identifying and controlling confounders, we conducted counterfactual inference through the NBN, resulting in an unbiased evaluation of the causal effects of individual factors on the expected utility of stage-at-diagnosis. An NBN-based decomposition mechanism was developed to evaluate the contributions of each patient-specific factor to an actual racial disparity in stage-at-diagnosis. 2000 bootstrap samples from our training patients were used to compute the 95% confidence intervals (CIs) of these contributions. RESULTS: Using a causal-effect contribution analysis, the relative contributions of each patient-specific factor to the actual racial disparity in stage-at-diagnosis were as follows: tumor grade, 45.1% (95% CI: 44.5%, 45.8%); hormone receptor status, 5.0% (4.5%, 5.4%); mammography utilization, 23.1% (22.4%, 24.0%); and biopsy delay 26.8% (26.1%, 27.3%). CONCLUSION: The modifiable mechanisms of mammography utilization and biopsy delay drive about 49.9% of racial difference in stage-at-diagnosis, potentially guiding more targeted interventions to eliminate cancer outcome disparities. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13755-021-00165-5.

Efficient Computation of Reduced Regression Models.

We consider settings where it is of interest to fit and assess regression submodels that arise as various explanatory variables are excluded from a larger regression model. The larger model is referred to as the full model; the submodels are the reduced models. We show that a computationally efficient approximation to the regression estimates under any reduced model can be obtained from a simple weighted least squares (WLS) approach based on the estimated regression parameters and covariance matrix from the full model. This WLS approach can be considered an extension to unbiased estimating equations of a first-order Taylor series approach proposed by Lawless and Singhal. Using data from the 2010 Nationwide Inpatient Sample (NIS), a 20% weighted, stratified, cluster sample of approximately 8 million hospital stays from approximately 1000 hospitals, we illustrate the WLS approach when fitting interval censored regression models to estimate the effect of type of surgery (robotic versus nonrobotic surgery) on hospital length-of-stay while adjusting for three sets of covariates: patient-level characteristics, hospital characteristics, and zip-code level characteristics. Ordinarily, standard fitting of the reduced models to the NIS data takes approximately 10 hours; using the proposed WLS approach, the reduced models take seconds to fit.

ParSel: Parallel Selection of Micro-RNAs for Survival Classification in Cancers.

It is known that tumor micro-RNAs (miRNA) can define patient survival and treatment response. We present a framework to identify miRNAs which are predictive of cancer survival. The framework attempts to rank the miRNAs by exploring their collaborative role in gene regulation. Our approach tests a significantly large number of combinatorial cases leveraging parallel computation. We carefully avoided parametric assumptions involved in evaluations of miRNA expressions but used rigorous statistical computation to assign an importance score to a miRNA. Experimental results on three cancer types namely, KIRC, OV and GBM verify that the top ranked miRNAs obtained using the proposed framework produce better classification accuracy as compared to some best practice variable selection methods. Some of these top ranked miRNA are also known to be associated with related diseases.

Bias-corrected estimates for logistic regression models for complex surveys with application to the United States' Nationwide Inpatient Sample.

For complex surveys with a binary outcome, logistic regression is widely used to model the outcome as a function of covariates. Complex survey sampling designs are typically stratified cluster samples, but consistent and asymptotically unbiased estimates of the logistic regression parameters can be obtained using weighted estimating equations (WEEs) under the naive assumption that subjects within a cluster are independent. Despite the relatively large samples typical of many complex surveys, with rare outcomes, many interaction terms, or analysis of subgroups, the logistic regression parameters estimates from WEE can be markedly biased, just as with independent samples. In this paper, we propose bias-corrected WEEs for complex survey data. The proposed method is motivated by a study of postoperative complications in laparoscopic cystectomy, using data from the 2009 United States' Nationwide Inpatient Sample complex survey of hospitals.

Tests for equivalence of two survival functions: Alternative to the tests under proportional hazards.

For either the equivalence trial or the non-inferiority trial with survivor outcomes from two treatment groups, the most popular testing procedure is the extension (e.g., Wellek, A log-rank test for equivalence of two survivor functions, Biometrics, 1993; 49: 877-881) of log-rank based test under proportional hazards model. We show that the actual type I error rate for the popular procedure of Wellek is higher than the intended nominal rate when survival responses from two treatment arms satisfy the proportional odds survival model. When the true model is proportional odds survival model, we show that the hypothesis of equivalence of two survival functions can be formulated as a statistical hypothesis involving only the survival odds ratio parameter. We further show that our new equivalence test, formulation, and related procedures are applicable even in the presence of additional covariates beyond treatment arms, and the associated equivalence test procedures have correct type I error rates under the proportional hazards model as well as the proportional odds survival model. These results show that use of our test will be a safer statistical practice for equivalence trials of survival responses than the commonly used log-rank based tests.

Approximate median regression for complex survey data with skewed response.

The ready availability of public-use data from various large national complex surveys has immense potential for the assessment of population characteristics using regression models. Complex surveys can be used to identify risk factors for important diseases such as cancer. Existing statistical methods based on estimating equations and/or utilizing resampling methods are often not valid with survey data due to complex survey design features. That is, stratification, multistage sampling, and weighting. In this article, we accommodate these design features in the analysis of highly skewed response variables arising from large complex surveys. Specifically, we propose a double-transform-both-sides (DTBS)'based estimating equations approach to estimate the median regression parameters of the highly skewed response; the DTBS approach applies the same Box-Cox type transformation twice to both the outcome and regression function. The usual sandwich variance estimate can be used in our approach, whereas a resampling approach would be needed for a pseudo-likelihood based on minimizing absolute deviations (MAD). Furthermore, the approach is relatively robust to the true underlying distribution, and has much smaller mean square error than a MAD approach. The method is motivated by an analysis of laboratory data on urinary iodine (UI) concentration from the National Health and Nutrition Examination Survey.

Using the jackknife for estimation in log link Bernoulli regression models.

Bernoulli (or binomial) regression using a generalized linear model with a log link function, where the exponentiated regression parameters have interpretation as relative risks, is often more appropriate than logistic regression for prospective studies with common outcomes. In particular, many researchers regard relative risks to be more intuitively interpretable than odds ratios. However, for the log link, when the outcome is very prevalent, the likelihood may not have a unique maximum. To circumvent this problem, a 'COPY method' has been proposed, which is equivalent to creating for each subject an additional observation with the same covariates except the response variable has the outcome values interchanged (1's changed to 0's and 0's changed to 1's). The original response is given weight close to 1, while the new observation is given a positive weight close to 0; this approach always leads to convergence of the maximum likelihood algorithm, except for problems with convergence due to multicollinearity among covariates. Even though this method produces a unique maximum, when the outcome is very prevalent, and/or the sample size is relatively small, the COPY method can yield biased estimates. Here, we propose using the jackknife as a bias-reduction approach for the COPY method. The proposed method is motivated by a study of patients undergoing colorectal cancer surgery.

Simple methods of determining confidence intervals for functions of estimates in published results.

Often, the reader of a published paper is interested in a comparison of parameters that has not been presented. It is not possible to make inferences beyond point estimation since the standard error for the contrast of the estimated parameters depends upon the (unreported) correlation. This study explores approaches to obtain valid confidence intervals when the correlation [Formula: see text] is unknown. We illustrate three proposed approaches using data from the National Health Interview Survey. The three approaches include the Bonferroni method and the standard confidence interval assuming [Formula: see text] (most conservative) or [Formula: see text] (when the correlation is known to be non-negative). The Bonferroni approach is found to be the most conservative. For the difference in two estimated parameter, the standard confidence interval assuming [Formula: see text] yields a 95% confidence interval that is approximately 12.5% narrower than the Bonferroni confidence interval; when the correlation is known to be positive, the standard 95% confidence interval assuming [Formula: see text] is approximately 38% narrower than the Bonferroni. In summary, this article demonstrates simple methods to determine confidence intervals for unreported comparisons. We suggest use of the standard confidence interval assuming [Formula: see text] if no information is available or [Formula: see text] if the correlation is known to be non-negative.

Almost efficient estimation of relative risk regression.

Relative risks (RRs) are often considered the preferred measures of association in prospective studies, especially when the binary outcome of interest is common. In particular, many researchers regard RRs to be more intuitively interpretable than odds ratios. Although RR regression is a special case of generalized linear models, specifically with a log link function for the binomial (or Bernoulli) outcome, the resulting log-binomial regression does not respect the natural parameter constraints. Because log-binomial regression does not ensure that predicted probabilities are mapped to the [0,1] range, maximum likelihood (ML) estimation is often subject to numerical instability that leads to convergence problems. To circumvent these problems, a number of alternative approaches for estimating RR regression parameters have been proposed. One approach that has been widely studied is the use of Poisson regression estimating equations. The estimating equations for Poisson regression yield consistent, albeit inefficient, estimators of the RR regression parameters. We consider the relative efficiency of the Poisson regression estimator and develop an alternative, almost efficient estimator for the RR regression parameters. The proposed method uses near-optimal weights based on a Maclaurin series (Taylor series expanded around zero) approximation to the true Bernoulli or binomial weight function. This yields an almost efficient estimator while avoiding convergence problems. We examine the asymptotic relative efficiency of the proposed estimator for an increase in the number of terms in the series. Using simulations, we demonstrate the potential for convergence problems with standard ML estimation of the log-binomial regression model and illustrate how this is overcome using the proposed estimator. We apply the proposed estimator to a study of predictors of pre-operative use of beta blockers among patients undergoing colorectal surgery after diagnosis of colon cancer.

Bias correction for the proportional odds logistic regression model with application to a study of surgical complications.

The proportional odds logistic regression model is widely used for relating an ordinal outcome to a set of covariates. When the number of outcome categories is relatively large, the sample size is relatively small, and/or certain outcome categories are rare, maximum likelihood can yield biased estimates of the regression parameters. Firth (1993) and Kosmidis and Firth (2009) proposed a procedure to remove the leading term in the asymptotic bias of the maximum likelihood estimator. Their approach is most easily implemented for univariate outcomes. In this paper, we derive a bias correction that exploits the proportionality between Poisson and multinomial likelihoods for multinomial regression models. Specifically, we describe a bias correction for the proportional odds logistic regression model, based on the likelihood from a collection of independent Poisson random variables whose means are constrained to sum to 1, that is straightforward to implement. The proposed method is motivated by a study of predictors of post-operative complications in patients undergoing colon or rectal surgery (Gawande et al., 2007).

Bayesian analysis of recurrent event with dependent termination: an application to a heart transplant study.

For a heart transplant patient, the risk of graft rejection and risk of death are likely to be associated. Two fully specified Bayesian models for recurrent events with dependent termination are applied to investigate the potential relationships between these two types of risk as well as association with risk factors. We particularly focus on the choice of priors, selection of the appropriate prediction model, and prediction methods for these two types of risk for an individual patient. Our prediction tools can be easily implemented and helpful to physicians for setting heart transplant patients' biopsy schedule.

Semiparametric Bayesian survival analysis using models with log-linear median.

We present a novel semiparametric survival model with a log-linear median regression function. As a useful alternative to existing semiparametric models, our large model class has many important practical advantages, including interpretation of the regression parameters via the median and the ability to address heteroscedasticity. We demonstrate that our modeling technique facilitates the ease of prior elicitation and computation for both parametric and semiparametric Bayesian analysis of survival data. We illustrate the advantages of our modeling, as well as model diagnostics, via a reanalysis of a small-cell lung cancer study. Results of our simulation study provide further support for our model in practice.

Analysis of cure rate survival data under proportional odds model.

Due to significant progress in cancer treatments and management in survival studies involving time to relapse (or death), we often need survival models with cured fraction to account for the subjects enjoying prolonged survival. Our article presents a new proportional odds survival models with a cured fraction using a special hierarchical structure of the latent factors activating cure. This new model has same important differences with classical proportional odds survival models and existing cure-rate survival models. We demonstrate the implementation of Bayesian data analysis using our model with data from the SEER (Surveillance Epidemiology and End Results) database of the National Cancer Institute. Particularly aimed at survival data with cured fraction, we present a novel Bayes method for model comparisons and assessments, and demonstrate our new tool's superior performance and advantages over competing tools.