Case-cohort Design Research Articles

Abstract 5241: Association of polygenic risk scores with breast cancer risk among women with benign breast disease

Abstract Over one million biopsies are performed annually in the U.S. to evaluate suspicious breast lesions. Most biopsies lead to a diagnosis of benign breast disease (BBD) and these women have a 1.5- to fourfold increase in subsequent breast cancer (BC) risk compared with the general population. A polygenic risk score (PRS) including 313 common variants was developed to predict BC risk in the general population and has improved performance when added to existing BC prediction models. However, the value of PRS in risk prediction models among women with BBD has not been evaluated. To evaluate the role of the established PRS, BBD, and BC risk, we pooled data from 15,194 white women (6,706 BC cases and 8,488 controls) participating in five Breast Cancer Association Consortium case-control studies. BC risk associations were evaluated by self-reported BBD history and combinations of PRS expressed in tertiles using odds ratios (OR), considering the lowest category of PRS among women without BBD as the referent. Associations were also assessed in an independent case-cohort study (831 BC cases and 1,845 controls) using hazard ratios (HR). Among the case-control studies, the PRS was strongly associated with BC risk (OR=2.50 per standard deviation increase), and associations were similar in women with (OR=2.60) and without a history of BBD (OR=2.44, p-interaction=0.23). Women with BBD have a higher risk of BC than those without BBD within each level of PRS. Compared to women without BBD and in the lowest PRS category, those with BBD and PRS in the highest tertile had 5-fold increased odds of BC (OR = 5.38; 95% CI 4.73-6.13). Associations were similar in an independent case-cohort study. These findings indicate that BBD history and PRS are independent contributors to BC risk, and consideration of both simultaneously could improve breast cancer risk prediction. Future studies are needed to integrate PRS with other risk measures to refine absolute BC risk prediction among BBD patients. Associations of BC risk with combinations of PRS (tertiles) and history of BBD in five case-control studies and a case-cohort study from the Breast Cancer Association Consortium. Case-control studies Case-cohort study PRS score range History of BBD n BC cases n controls OR (95% CI)1 n BC cases n controls HR (95% CI)2 Tertile 1 (≤ -0.57) No 1009 2692 1.00 (Ref) 117 584 1.00 (Ref) Yes 508 902 1.54 (1.35-1.76) 69 163 2.05 (1.45-2.89) Tertile 2 (-0.58, -0.03) No 1469 2001 1.97 (1.78-2.17) 181 475 1.93 (1.48-2.51) Yes 760 798 2.65 (2.34-3.01) 108 170 2.99 (2.18-4.09) Tertile 3 (≥ -0.02) No 1910 1551 3.32 (3.01-3.67) 214 336 3.28 (2.52-4.26) Yes 1050 544 5.38 (4.73-6.13) 142 117 4.83 4.25-8.02) 1.Logistic regression analysis, adjusted for study site/genomic platform and age at enrollment. OR, odds ratio; CI, confidence interval.2.Cox proportional hazards regression analysis, accounting for the case-cohort study design and adjusted for age at enrollment. HR, hazard ratio; CI, confidence interval. Citation Format: Stacey J. Winham, Mark Sherman, Robert Vierkant, Bryan McCauley, Christopher Scott, Mia Gaudet, Melissa Troester, Sandhya Pruthi, Derek Radisky, Amy Degnim, Kristan Aronson, Rachel Murphy, Pascal Guenel, Therese Truong, Jenny Chang-Claude, Heiko Becher, Montserrat Garcia-Closas, Stephen Chanock, Thomas Ahearn, Xiaohong Yang, Doug Easton, Manjeet Bolla, Celine Vachon, Breast Cancer Association Consortium. Association of polygenic risk scores with breast cancer risk among women with benign breast disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5241.

A semi-parametric weighted likelihood approach for regression analysis of bivariate interval-censored outcomes from case-cohort studies.

The case-cohort design was developed to reduce costs when disease incidence is low and covariates are difficult to obtain. However, most of the existing methods are for right-censored data and there exists only limited research on interval-censored data, especially on regression analysis of bivariate interval-censored data. Interval-censored failure time data frequently occur in many areas and a large literature on their analyses has been established. In this paper, we discuss the situation of bivariate interval-censored data arising from case-cohort studies. For the problem, a class of semiparametric transformation frailty models is presented and for inference, a sieve weighted likelihood approach is developed. The large sample properties, including the consistency of the proposed estimators and the asymptotic normality of the regression parameter estimators, are established. Moreover, a simulation is conducted to assess the finite sample performance of the proposed method and suggests that it performs well in practice.

Abstract MP11: Ultra-Processed Food Consumption and Cardiovascular Disease in the European Prospective Investigation Into Cancer and Nutrition Study

Introduction: Diets containing many ultra-processed foods (UPF) are linked to unfavourable health. UPF are defined by the NOVA classification as industrial food and drinks made from substances not used in domestic culinary preparations, such as hydrogenated fats, modified starches, and other food additives. There is evidence suggesting a link between UPF consumption and cardiovascular disease (CVD) incidence, but this association has not been tested in a large European cohort. Using data from the pan-European Prospective Investigation into Cancer and nutrition (EPIC) study, we assessed the hypothesis that higher consumption of UPF is associated with an increased risk of incident fatal and non-fatal CHD and stroke in the EPIC-Heart cohort. Methods: Case-cohort design nested in the EPIC cohort including 36,415 adults from Denmark, Germany, Italy, the Netherlands, Spain, Sweden, and the UK. Socio-demographic, lifestyle factors and usual dietary intake were assessed at time of recruitment (1992 - 2000) using country-specific validated questionnaires. Consumption of UPF was expressed in percentage of grams per day. CVD cases ascertainment varied across EPIC centres and included hospital admissions, linkage to registers, self-report and mortality data. Proportion of missing values ranged from 0.95% for smoking status to 14.2% for history of diabetes. We performed multiple imputation on all covariates with missing values. Cox proportional hazard models with age as the underlying time variable stratified by sex, centre and age were used to test the longitudinal association between UPF consumption and coronary heart disease (CHD) and stroke incidence adjusted for confounders. We applied prentice weights to our cox proportional hazard models to account for the case-cohort design. Results: The mean contribution of UPF to the overall diet in grams was 14.2% in men and 12.8% in women. After a median follow-up time of 9.7 years, it was documented 11,973 non-fatal and 2,281 fatal CHD events, and 6,765 non-fatal and 899 fatal stroke events. In models adjusted for education, smoking, physical activity, body mass index, height, diabetes, high blood pressure, alcohol, energy, and sodium intake, and the Mediterranean diet score, each 10% increase in the consumption of grams from UPF was associated with an increased risk of non-fatal CHD (HR 1.13, 95%CI 1.02 - 1.26), fatal CHD (HR 1.33, 95%CI 1.09 - 1.62) and fatal stroke (HR 1.40, 95%CI 1.07 - 1.85), but not with non-fatal stroke (HR 1.11, 95%CI 0.98 - 1.24). Complete-case analysis showed similar results. Conclusion: In this large prospective cross-European study we found that higher proportion of UPF in the diet was associated with an increased risk of non-fatal CHD and fatal CHD and stroke. These findings corroborate other large-scale cohort studies indicating that the increasing consumption of ultra-processed intake may contribute to higher CVD incidence.

ERG Status at the Margin Is Associated With Biochemical Recurrence After Radical Prostatectomy With Positive Surgical Margins

Positive surgical margins at radical prostatectomy are associated with an increased risk of biochemical recurrence (BCR). However, there is considerable variability in outcomes, suggesting that molecular biomarkers—when assessed specifically at the margin tumor tissue—may be useful to stratify prognosis in this group. We used a case-cohort design for the outcome of BCR, selecting 215 patients from a cohort of 813 patients undergoing prostatectomy treated at the Johns Hopkins from 2008 to 2017 with positive margins and available clinical data. Tissue microarrays were created from the tumor adjacent to the positive margin and stained for PTEN, ERG, and Ki-67. Cases were scored dichotomously (PTEN and ERG) or by the Ki-67 staining index using previously validated protocols. The analysis used Cox proportional hazards models weighted for the case-cohort design. Overall, 20% (37/185) of evaluable cases had PTEN loss and 38% (71/185) had ERG expression, and the median Ki-67 expression was 0.42%. In multivariable analysis adjusting for the CAPRA-S score, adjuvant radiation, and grade group at the positive margin, ERG-positive tumors were associated with a higher risk of BCR compared to those that were ERGnegative (hazard ratio [HR], 2.4; 95% CI, 1.2-4.9; P = .012) regardless of PTEN status at the margin, and adding ERG to clinicopathologic variables increased the concordance index from 0.827 to 0.847. PTEN loss was associated with an increased risk of BCR on univariable analysis (HR, 3.19; 95% CI, 1.72-5.92; P = .0002), but this association did not remain after adjusting for clinicopathologic variables (HR, 1.06; 95% CI, 0.49-2.29; P = .890). Thus, in the setting of prostate tumors with positive surgical margins after prostatectomy, ERG-positive tumors with or without PTEN loss at the positive margin are associated with a significantly higher risk of BCR after adjusting for clinicopathologic variables. If validated, ERG status may be helpful in decision-making surrounding adjuvant therapy after prostatectomy.

Increases in Plasma Tryptophan Are Inversely Associated with Incident Cardiovascular Disease in the Prevención con Dieta Mediterránea (PREDIMED) Study

Background: During development of cardiovascular disease (CVD), interferon-γ-mediated inflammation accelerates degradation of tryptophan into downstream metabolites. A Mediterranean diet (MedDiet) consisting of a high intake of extra-virgin olive oil (EVOO), nuts, fruits, vegetables, and cereals has been demonstrated to lower the risk of CVD. The longitudinal relation between tryptophan and its downstream metabolites and CVD in the context of a MedDiet is unstudied.Objective: We sought to investigate the relation between metabolites in the tryptophan-kynurenine pathway and CVD in the context of a MedDiet pattern.Methods: We used a case-cohort design nested in the Prevención con Dieta Mediterránea randomized controlled trial. There were 231 CVD cases (stroke, myocardial infarction, cardiovascular death) among 985 participants over a median of 4.7 y of follow-up [mean ± SD age: 67.6 ± 6.1 y; 53.7% women; mean ± SD body mass index (in kg/m2): 29.7 ± 3.7]. We assessed plasma tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid concentrations at baseline and after 1 y of intervention with a MedDiet. We combined these metabolites in a kynurenine risk score (KRS) by weighting each metabolite by the adjusted coefficient of its associations with CVD. Cox models were used in the primary analysis.Results: Increases in tryptophan after 1 y were associated with a lower risk of composite CVD (HR per SD: 0.79; 95% CI: 0.63, 0.98). The baseline kynurenic acid concentration was associated with a higher risk of myocardial infarction and coronary artery disease death but not stroke. A higher KRS was more strongly associated with CVD in the control group than in the 2 intervention groups (P-interaction = 0.003). Adjustment for changes in plasma tryptophan attenuated the inverse association between MedDiet+EVOO and CVD.Conclusions: An increase in the plasma tryptophan concentration was significantly associated with a decreased risk of CVD. A MedDiet may counteract the deleterious effects of a high kynurenine risk score.

Preterm Prelabor Rupture of Membranes Linked to Vaginal Bacteriome of Pregnant Females in the Early Second Trimester: a Case-Cohort Design.

Preterm prelabor rupture of membranes (PPROM) is a major cause of spontaneous preterm birth (sPTB), one of the greatest challenges facing obstetrics with complicated pathogenesis. This case-cohort study investigated the association between vaginal bacteriome of singleton pregnant females in the early second trimester and PPROM. The study included 35,255 and 180 pregnant females with PPROM as cases and term-birth without prelabor rupture of membranes (TWPROM) and term prelabor rupture of membranes (TPROM) pregnant females as controls, respectively. Using 16S rRNA sequencing, the vaginal microbiome traits were analyzed. Females with PPROM had higher alpha and beta diversity (P < 0.05) than TWPROM and TPROM. The presence of L. mulieris was associated with a decreased risk of PPROM (adjusted odds ratio [aOR] = 0.35; 95% confidence interval [CI]: 0.17-0.72) compared with TWPROM. Meanwhile, the presence of Megasphaera genus (aOR = 2.27; 95% CI: 1.09-4.70), Faecalibacterium genus (aOR = 3.29; 95% CI: 1.52-7.13), Bifidobacterium genus (aOR = 3.26; 95% CI: 1.47-7.24), Xanthomonadales genus (aOR = 2.76; 95% CI: 1.27-6.01), Gammaproteobacteria class (aOR = 2.36; 95% CI: 1.09-5.14), and Alphaproteobacteria class (aOR = 2.45; 95% CI: 1.14-5.26) was associated with an increased risk of PPROM compared with TWPROM. Our results indicated that the risk of PPROM can decrease with vaginal L. mulieris but increase with high alpha or beta diversity, and several vaginal bacteria in pregnant females may be involved in the occurrence of PPROM.

Lipolysis and gestational diabetes mellitus onset: a case-cohort genome-wide association study in Chinese

BackgroundGenetic knowledge of gestational diabetes mellitus (GDM) in Chinese women is quite limited. This study aimed to identify the risk factors and mechanism of GDM at the genetic level in a Chinese population.MethodsWe conducted a genome-wide association study (GWAS) based on single nucleotide polymorphism (SNP) array genotyping (ASA-CHIA Bead chip, Illumina) and a case-cohort study design. Variants including SNPs, copy number variants (CNVs), and insertions-deletions (InDels) were called from genotyping data. A total of 2232 pregnant women were enrolled in their first/second trimester between February 2018 and December 2020 from Anqing Municipal Hospital in Anhui Province, China. The GWAS included 193 GDM patients and 819 subjects without a diabetes diagnosis, and risk ratios (RRs) and their 95% confidence intervals (CIs) were estimated by a regression-based method conditional on the population structure. The calling and quality control of genotyping data were performed following published guidelines. CNVs were merged into CNV regions (CNVR) to simplify analyses. To interpret the GWAS results, gene mapping and overexpression analyses (ORAs) were further performed to prioritize the candidate genes and related biological mechanisms.ResultsWe identified 14 CNVRs (false discovery rate corrected P values < 0.05) and two suggestively significant SNPs (P value < 0.00001) associated with GDM, and a total of 19 candidate genes were mapped. Ten genes were significantly enriched in gene sets related to lipase (triglyceride lipase and lipoprotein lipase) activity (LIPF, LIPK, LIPN, and LIPJ genes), oxidoreductase activity (TPH1 and TPH2 genes), and cellular components beta-catenin destruction complex (APC and GSK3B genes), Wnt signalosome (APC and GSK3B genes), and lateral element in the Gene Ontology resource (BRCA1 and SYCP2 genes) by two ORA methods (adjusted P values < 0.05).ConclusionsGenes related to lipolysis, redox reaction, and proliferation of islet β-cells are associated with GDM in Chinese women. Energy metabolism, particularly lipolysis, may play an important role in GDM aetiology and pathology, which needs further molecular studies to verify.

A case-cohort study of the association between adiponectin and mortality in EPIC–Heidelberg: NT-proBNP may explain the adiponectin paradox

Background and aimsNT-proBNP has been hypothesized as a possible explanation for the paradoxical association between adiponectin and cardiovascular and all-cause mortality. We examined the heterogeneities by NT-proBNP, sex, BMI, smoking status, hypertension and diabetes status in the association between adiponectin and cardiovascular disease risk and mortality. Methods and resultsWe used a case-cohort design nested within the EPIC-Heidelberg cohort, including 1387 incident cases of myocardial infarction or stroke, 582 deaths from cardiovascular causes and 2352 total deaths. We estimated hazard ratios for the association between 1SD increase in log-transformed total adiponectin levels and cardiovascular disease risk, cardiovascular mortality and mortality using Prentice-weighted Cox-proportional hazard models and assessed heterogeneity of the associations across strata of covariates. Overall, adiponectin was significantly associated with all-cause mortality [HR = 1.09, 95% CI: 1.03–1.16, p = 0.004]. The association with cardiovascular mortality did not reach statistical significance [1.10 (0.99–1.37), p = 0.073]. There was significant heterogeneity by NT-proBNP in the association between total adiponectin and all-cause mortality (phet = 0.019) such that significant increase in hazards of mortality were restricted to participants in the highest tertile of NT-proBNP. Among these participants, adiponectin showed a dose-response relationship with total mortality such that; compared to participants in the lowest quintile, those in the third, fourth and fifth were at 1.22 (0.87–1.70), 1.50 (1.07–2.11), and 1.59 (1.15–2.21) higher hazards of mortality respectively. ConclusionsSignificant association between adiponectin and mortality was only observed in the context of high NT-proBNP. Our findings provide further support for hypothesis that NT-proBNP may explain the adiponectin paradox.

Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial

In the PREVENT-19 phase 3 trial of the NVX-CoV2373 vaccine (NCT04611802), anti-spike binding IgG concentration (spike IgG), anti-RBD binding IgG concentration (RBD IgG), and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks post-dose two are assessed as correlates of risk and as correlates of protection against COVID-19. Analyses are conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases. All markers are inversely associated with COVID-19 risk and directly associated with vaccine efficacy. In vaccine recipients with nAb ID50 titers of 50, 100, and 7230 international units (IU50)/ml, vaccine efficacy estimates are 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), and 96.8% (88.3%, 99.3%). The results support potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use.

Additive subdistribution hazards regression for competing risks data in case-cohort studies.

In survival data analysis, a competing risk is an event whose occurrence precludes or alters the chance of the occurrence of the primary event of interest. In large cohort studies with long-term follow-up, there are often competing risks. Further, if the event of interest is rare in such large studies, the case-cohort study design is widely used to reduce the cost and achieve the same efficiency as a cohort study. The conventional additive hazards modeling for competing risks data in case-cohort studies involves the cause-specific hazard function, under which direct assessment of covariate effects on the cumulative incidence function, or the subdistribution, is not possible. In this paper, we consider an additive hazard model for the subdistribution of a competing risk in case-cohort studies. We propose estimating equationsbased on inverse probability weighting methods for the estimation of the model parameters. Consistency and asymptotic normality of the proposed estimators are established. The performance of the proposed methods in finite samples is examined through simulation studies and the proposed approach is applied to a case-cohort dataset from the SisterStudy.

Male origin microchimerism and brain cancer: a case-cohort study.

Despite considerable research effort, causes of brain cancer are largely unknown. Male brain cancer predominance and reduced brain cancer risk with increasing parity among women, however, support a favourable role of pregnancy. We set out to determine whether fetal-origin microchimerism, namely the presence and long-term persistence of fetal cells, likely obtained via natural trafficking across the placenta during pregnancy, associates with reduced risk of brain cancer in women. Using a case-cohort design, we sampled 505 middle-aged women randomly at baseline in the Diet, Cancer and Health cohort (controls), and 73 women with incident brain cancer diagnosed during follow-up in the Danish Cancer Registry (cases). Male origin microchimerism was determined by presence of Y chromosome sequences in female blood samples. Data were analysed using weighted proportional Hazards regression, yielding Hazard Ratios with 95% confidence intervals. Compared with male origin microchimerism negative women, positive women had half the risk of developing brain cancer (Hazard Ratio = 0.50 [0.33-0.77]). Sensitivity analyses support that our findings are unlikely due to bias or chance. Here, for the first time, we demonstrate half the risk of brain cancer in male origin microchimerism positive compared with negative women. Our findings resemble those of previous studies of male origin microchimerism and other female cancers.

Abstract C020: Neutrophil-mediated stromal-tumor IL-6/STAT-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study

Abstract Background: Partial/complete pathologic response following neoadjuvant chemotherapy (NAC) in pancreatic cancer (PDAC) patients undergoing pancreatectomy is associated with improved survival. We sought to determine whether neutrophil-to-lymphocyte ratio (NLR) dynamics predict pathologic response following chemotherapy in PDAC, and if manipulating NLR impacts chemosensitivity in preclinical models and uncovers potential mechanistic underpinnings underlying these effects. Methods: Pathologic response in PDAC patients (n=94) undergoing NAC and pancreatectomy (7/2015-12/2019) was dichotomized as partial/complete or poor/absent (case-cohort design). Bootstrap-validated multivariable models assessed associations between pre-chemotherapy NLR (%neutrophils÷%lymphocytes) or NLR dynamics during chemotherapy (ΔNLR=pre-surgery—pre-chemotherapy NLR) and pathologic response, disease-free survival (DFS), and overall survival (OS). To preclinically model effects of NLR attenuation on chemosensitivity, C57BL/6 mice (n=8-10/arm) were orthotopically injected with KrasG12D/+;Trp53fl/+;PdxCre(KPC) cells and randomized to vehicle, NLR-attenuating anti-Ly6G, gemcitabine/paclitaxel, or gemcitabine/paclitaxel+anti-Ly6G treatments. Results: In 94 PDAC patients undergoing NAC (median:4 months), pre-chemotherapy NLR (P&amp;lt;0.001) and ΔNLR attenuation during NAC (P=0.002) were independently associated with partial/complete pathologic response. An NLR score=pre-chemotherapy NLR+ΔNLR correlated with DFS (P=0.006) and OS (P=0.002). Upon preclinical modeling, combining NLR-attenuating anti-Ly6G treatment with gemcitabine/paclitaxel—compared with gemcitabine/paclitaxel or anti-Ly6G alone—not only significantly reduced tumor burden and metastatic outgrowth, but also augmented tumor-infiltrating CD107a+-degranulating CD8+ T-cells (P&amp;lt;0.01) while dampening inflammatory cancer-associated fibroblast (CAF) polarization (P=0.006) and chemoresistant IL-6/STAT-3 signaling in vivo. Neutrophil-derived IL-1β emerged as a novel mediator of stromal inflammation, inducing inflammatory CAF polarization and CAF-tumor cell IL-6/STAT-3 signaling in ex vivo co-cultures. Conclusions: Therapeutic strategies to mitigate neutrophil-CAF-tumor cell IL-1β/IL-6/STAT-3 signaling during NAC may improve pathologic responses and/or survival in PDAC. Citation Format: Iago De Castro Silva, Anna Bianchi, Nilesh Deshpande, Prateek Sharma, Siddharth Mehra, Peter Hosein, Deukwoo Kwon, Nipun Merchant, Jashodeep Datta. Neutrophil-mediated stromal-tumor IL-6/STAT-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C020.

Quantile regression for competing risks data from stratified case-cohort studies: an induced-smoothing approach

ABSTRACT A case-cohort design offers an economical way of investigating an association between exposure variables and risks of disease outcomes compared to a large-scale full cohort study. A stratified sampling in such designs based on the information available for the entire cohort is often considered for improving efficiencies of estimators. In this paper, we consider fitting censored quantile regression models for competing risks data arising from stratified case-cohort designs. We model quantiles for cumulative incidence functions that provide desirable interpretation for competing risks data and flexible ways of assessing covariates effects. For estimation of regression parameters, we consider weighted estimating equations with two-types of weights: the inverses of censoring probabilities and sampling probabilities to account for censoring in competing risks data and biased features in stratified case-cohort samplings, respectively. An induced smoothing approach is applied to obtain computationally more reliable estimates. The resulting estimating functions are smooth in regression parameters, so standard numerical algorithms for point estimation can be readily applied and variances can be estimated via a closed-form expression or computationally efficient resampling method. An iterative algorithm is proposed to simultaneously estimate regression parameters and their variances. Asymptotic properties of the proposed estimators are established. The finite sample properties of the proposed estimators are investigated through extensive simulation studies. They perform reasonably well under practical settings considered. The proposed methods are illustrated with Hodgkin's disease data.

Generalized accelerated failure time model with censored data from case-cohort studies

The case-cohort design is a cost-effective approach commonly used in large cohort studies. Under this design, covariates are collected only for the cases and a small subcohort randomly selected from the entire cohort. In this paper, we consider a flexible generalized accelerated failure time model for fitting case-cohort data. A weighted estimating procedure is proposed and the corresponding asymptotic properties of the resulting estimator are established. Two efficient resampling-based inference procedures which do not involve nonparametric density estimation or numerical derivatives are suggested. The finite sample performance of the proposed estimators is evaluated by simulation studies. Also, a real example is used to demonstrate the application of the proposed methods.

Incidence of new onset glomerulonephritis after SARS-CoV-2 mRNA vaccination is not increased

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95%-credible interval 0.73 –1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95%-confidence interval 0.66–1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental.

Association of the inflammation-related proteome with dementia development at older age: results from a large, prospective, population-based cohort study

BackgroundChronic inflammation is a central feature of several forms of dementia. However, few details on the associations of blood-based inflammation-related proteins with dementia incidence have been explored yet.MethodsThe Olink Target 96 Inflammation panel was measured in baseline serum samples (collected 07/2000–06/2002) of 1782 older adults from a German, population-based cohort study in a case-cohort design. Logistic regression models were used to assess the associations of biomarkers with all-cause dementia, Alzheimer’s disease, and vascular dementia incidence.ResultsDuring 17 years of follow-up, 504 participants were diagnosed with dementia, including 163 Alzheimer’s disease and 195 vascular dementia cases. After correction for multiple testing, 58 out of 72 tested (80.6%) biomarkers were statistically significantly associated with all-cause dementia, 22 with Alzheimer’s disease, and 33 with vascular dementia incidence. We identified four biomarker clusters, among which the strongest representatives, CX3CL1, EN-RAGE, LAP TGF-beta-1, and VEGF-A, were significantly associated with dementia endpoints independently from other inflammation-related proteins. CX3CL1 (odds ratio [95% confidence interval] per 1 standard deviation increase: 1.41 [1.24–1.60]) and EN-RAGE (1.41 [1.25–1.60]) were associated with all-cause dementia incidence, EN-RAGE (1.51 [1.25–1.83]) and LAP TGF-beta-1 (1.46 [1.21–1.76]) with Alzheimer’s disease incidence, and VEGF-A (1.43 [1.20–1.70]) with vascular dementia incidence. All named associations were stronger among APOE ε4-negative subjects.ConclusionWith this large, population-based cohort study, we show for the first time that the majority of inflammation-related proteins measured in blood samples are associated with total dementia incidence. Future studies should concentrate not only on single biomarkers but also on the complex relationships in biomarker clusters.

Cell Cycle Progression Score, but Not Phosphatase and Tensin Homolog Loss, Is an Independent Prognostic Factor for Metastasis in Intermediate- and High-risk Prostate Cancer in Men Treated With and Without Salvage Radiotherapy

The prognostic value for metastasis of the cell-cycle progression score and phosphatase and tensin homolog haven't been evaluated jointly in contemporary men with exclusively intermediate- or high-risk prostate cancer. We evaluated associations of cell-cycle progression and phosphatase and tensin homolog with metastasis-free survival in contemporary intermediate/high-risk prostate cancer patients overall, and intermediate/high-risk men receiving salvage radiotherapy. In a case-cohort of 209 prostatectomy patients with intermediate/high-risk prostate cancer, and a cohort of 172 such men who received salvage radiotherapy, cell-cycle progression score was calculated from RNA expression, and phosphatase and tensin homolog was analyzed by immunohistochemistry. Proportional hazards regression, weighted for case-cohort design or unweighted for the salvage radiotherapy cohort, was used to evaluate associations of cell-cycle progression, phosphatase and tensin homolog with metastasis-free survival. Improvement in model discrimination was evaluated with the concordance index. In the case-cohort 41 men had metastasis, and 17 developed metastasis in the salvage radiotherapy cohort, at median follow-up of 3 and 4 years, respectively. For both case-cohort and salvage radiotherapy cohort, cell-cycle progression was independently associated with metastasis-free survival after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical: hazard ratio (95% confidence interval) = 3.11 (1.70-5.69) and 1.85 (1.19-2.85), respectively. Adding cell-cycle progression to Cancer of the Prostate Risk Assessment Post-Surgical increased the concordance index from 0.861 to 0.899 (case-cohort), and 0.745 to 0.819 (salvage radiotherapy cohort). Although statistically significant in univariate analyses, phosphatase and tensin homolog was no longer significant after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical. Analysis of interaction with National Comprehensive Cancer Network risk group showed that cell-cycle progression had the strongest effect among unfavorable intermediate-risk men. In the first study to evaluate metastasis risk associated with cell-cycle progression and phosphatase and tensin homolog in exclusively intermediate/high-risk prostate cancer, and in such men with salvage radiotherapy, cell-cycle progression but not phosphatase and tensin homolog was associated with significantly increased 2- to 3-fold risk of metastasis after Cancer of the Prostate Risk Assessment Post-Surgical adjustment.

The Oral Microbiome and Lung Cancer Risk: An Analysis of 3 Prospective Cohort Studies.

Previous studies suggested associations between the oral microbiome and lung cancer, but studies were predominantly cross-sectional and underpowered. Using a case-cohort design, 1306 incident lung cancer cases were identified in the Agricultural Health Study; National Institutes of Health-AARP Diet and Health Study; and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Referent subcohorts were randomly selected by strata of age, sex, and smoking history. DNA was extracted from oral wash specimens using the DSP DNA Virus Pathogen kit, the 16S rRNA gene V4 region was amplified and sequenced, and bioinformatics were conducted using QIIME 2. Hazard ratios and 95% confidence intervals were calculated using weighted Cox proportional hazards models. Higher alpha diversity was associated with lower lung cancer risk (Shannon index hazard ratio = 0.90, 95% confidence interval = 0.84 to 0.96). Specific principal component vectors of the microbial communities were also statistically significantly associated with lung cancer risk. After multiple testing adjustment, greater relative abundance of 3 genera and presence of 1 genus were associated with greater lung cancer risk, whereas presence of 3 genera were associated with lower risk. For example, every SD increase in Streptococcus abundance was associated with 1.14 times the risk of lung cancer (95% confidence interval = 1.06 to 1.22). Associations were strongest among squamous cell carcinoma cases and former smokers. Multiple oral microbial measures were prospectively associated with lung cancer risk in 3 US cohort studies, with associations varying by smoking history and histologic subtype. The oral microbiome may offer new opportunities for lung cancer prevention.

Joint semiparametric models for case-cohort designs.

Two-phase studies such as case-cohort and nested case-control studies are widely used cost-effective sampling strategies. In the first phase, the observed failure/censoring time and inexpensive exposures are collected. In the second phase, a subgroup of subjects is selected for measurements of expensive exposures based on the information from the first phase. One challenging issue is how to utilize all the available information to conduct efficient regression analyses of the two-phase study data. This paper proposes a joint semiparametric modeling of the survival outcome and the expensive exposures. Specifically, we assume a class of semiparametric transformation models and a semiparametric density ratio model for the survival outcome and the expensive exposures, respectively. The class of semiparametric transformation models includes the proportional hazards model and the proportional odds model as special cases. The density ratio model is flexible in modeling multivariate mixed-type data. We develop efficient likelihood-based estimation and inference procedures and establish the large sample properties of the nonparametric maximum likelihood estimators. Extensive numerical studies reveal that the proposed methods perform well under practical settings. The proposed methods also appear to be reasonably robust under various model mis-specifications. An application to the National Wilms Tumor Study isprovided.

The impact of metabolic supply lines - and the patterns between them - on the development of distant metastases in 64 women with breast cancer.

Cancer cells upregulate their metabolism to underlie the increased malignant activity. This requires an increased amount of ‘metabolic building materials’, for example glucose, amino acids etc., which have the blood circulation as their principal supply lines. Targeting these metabolic supply lines, and thus the availability of metabolic building materials in the blood, therefore carries treatment potential. A central observation is that the malignant alterations comprise great complexity and that compensatory mechanisms exist. Therefore, targeted supply lines should presumably constitute specific patterns to achieve therapeutic effect. The aim of the present study was to investigate if such patterns could be seen to correlate with the development of distant metastases. The study was conducted using a case-cohort design. In total, 64 women diagnosed with breast cancer between January 2011 and December 2015 were included. Among these, 32 had developed distant metastases and 32 had not. From a blood sample drawn at the time of diagnosis, the levels of glucose (HbA1c), glutamine, arginine and cystathionine were measured. Cox regression was applied to investigate the impact of the supply lines of these ‘building materials’ and specifically the patterns between them on the development of distant metastases. The results demonstrate a significant impact of the investigated metabolic supply lines, centrally in relation to interaction between them and in relation to the impact of the increased cumulated utilization of multiple supply lines simultaneously. In conclusion, the results indicated that the metabolic supply lines may impact clinical outcome, and, in this regard, the results placed a substantial emphasis on the effect of the patterns between these supply lines.