Cancers with epidemiologic signatures of viral oncogenicity among immunocompromised populations in the United States.

BACKGROUND: Immunosuppressed individuals have elevated risk of virus-related cancers. Identifying cancers with elevated risk in people with HIV (PWH) and solid organ transplant recipients (SOTRs), two immunosuppressed populations, may help identify novel etiologic relationships with infectious agents. METHODS: We utilized two linkages of population-based cancer registries with HIV and transplant registries in the United States. Cancer entities were systematically classified based on site and histology codes. Standardized incidence ratios (SIRs) were used to compare risk in PWH and SOTRs with the general population. For selected cancer entities, incidence rate ratios (IRRs) were calculated for indicators of immunosuppression within each population. FINDINGS: We identified 38,047 cancer cases in SOTRs and 53,592 in PWH, yielding overall SIRs of 1.66 (95%CI = 1.65-1.68) and 1.49 (95%CI = 1.47-1.50), respectively. Forty-three cancer entities met selection criteria, including conjunctival squamous cell carcinoma (SCC) (PWH SIR = 7.1, 95%CI = 5.5-9.2; SOTRs SIR = 9.4; 95%CI = 6.8-12.6). Sebaceous adenocarcinoma was elevated in SOTRs (SIR = 16.2; 95%CI = 14.0-18.6) and, among SOTRs, associated with greater risk in lung/heart transplant recipients compared to recipients of other organs (IRR = 2.3; 95%CI = 1.7-3.2). Salivary gland tumors, malignant fibrous histiocytoma (MFH), and intrahepatic cholangiocarcinoma showed elevated risk in SOTRs (SIR = 3.9; SIR = 4.7; and SIR = 3.2, respectively) but not in PWH. However, risks for these cancers were elevated following an AIDS diagnosis among PWH (IRR = 2.4; IRR = 4.3; and IRR = 2.0, respectively). INTERPRETATION: Elevated SIRs among SOTRs and PWH, and associations with immunosuppression within these populations, suggest novel infectious causes for several cancers including conjunctival SCC, sebaceous adenocarcinoma, salivary gland tumors, MFH, and intrahepatic cholangiocarcinoma.

A proteome-wide analysis unveils a core Epstein-Barr virus antibody signature of classic Hodgkin lymphoma across ethnically diverse populations.

Epstein-Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East-Asian hospital-based case-control study. We identified 16 IgG antibodies significantly elevated in EBV-positive cHL compared with controls, defining an "East-Asian antibody signature of EBV-positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case-control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East-Asian antibody signature of EBV-positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV-positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East-Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East-Asian population. This cross-comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti-EBV IgG antibodies (LMP-1, TK, BALF2, BDLF3, and BBLF1), found in both population-specific antibody signatures, represent a "core signature of EBV-positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV-positive cHL independent of population-specific factors.

COVID-19 and long-term impact on symptoms and Health-Related Quality of Life in Costa Rica: the RESPIRA cohort study.

BACKGROUND: Evidence continues to accumulate regarding the potential long-term health consequences of COVID-19 in the population. To distinguish between COVID-19-related symptoms and health limitations from those caused by other conditions, it is essential to compare cases with community controls using prospective data ensuring case-control status. The RESPIRA study addresses this need by investigating the lasting impact of COVID-19 on Health-related Quality of Life (HRQoL) and symptomatology in a population-based cohort in Costa Rica, thereby providing a robust framework for controlling HRQoL and symptoms. METHODS: The study comprised 641 PCR-confirmed, unvaccinated cases of COVID-19 and 947 matched population-based controls. Infection was confirmed using antibody tests on enrollment serum samples and symptoms were monitored monthly for 6 months post-enrolment. Administered at the 6-month visit (occurring between 6- and 2-months post-diagnosis for cases and 6 months after enrollment for controls), HRQoL and Self-Perceived Health Change were assessed using the SF-36, while brain fog, using three items from the Mental Health Inventory (MHI). Regression models were utilized to analyze SF-36, MHI scores, and Self-Perceived Health Change, adjusted for case/control status, severity (mild case, moderate case, hospitalized) and additional independent variables. Sensitivity analyses confirmed the robustness of the findings. RESULTS: Cases showed significantly higher prevalences of joint pain, chest tightness, and skin manifestations, that stabilized at higher frequencies from the fourth month post-diagnosis onwards (2.0%, 1.2%, and 0.8% respectively) compared to controls (0.9%, 0.4%, 0.2% respectively). Cases also exhibited significantly lower HRQoL than controls across all dimensions in the fully adjusted model, with a 12.4 percentage-point difference [95%CI: 9.4-14.6], in self-reported health compared to one year prior. Cases reported 8.0% [95%CI: 4.2, 11.5] more physical limitations, 7.3% [95%CI: 3.5, 10.5] increased lack of vitality, and 6.0% [95%CI: 2.4, 9.0] more brain fog compared to controls with similar characteristics. Undiagnosed cases detected with antibody tests among controls had HRQoL comparable to antibody negative controls. Differences were more pronounced in individuals with moderate or severe disease and among women. CONCLUSIONS: PCR-confirmed unvaccinated cases experienced prolonged HRQoL reductions 6 months to 2 years after diagnosis, this was particularly the case in severe cases and among women. Mildly symptomatic cases showed no significant long-term sequelae.

Early-pregnancy sex steroid and thyroid function hormones, thyroid autoimmunity, and maternal papillary thyroid cancer incidence in the Finnish Maternity Cohort.

Thyroid cancer more commonly affects women than men and is the third most frequently diagnosed cancer among women of reproductive age. We conducted a nested case-control study within the Finnish Maternity Cohort to evaluate pre-diagnostic sex steroid and thyroid function markers in relation to subsequent maternal papillary thyroid cancer. Cases (n = 605) were women ages 18-44 years, who provided an early-pregnancy (<20 weeks gestation) blood sample and were diagnosed with papillary thyroid cancer up to 11 years afterward. Controls (n = 1185) were matched to cases 2:1 by gestational age, mother's age, and date at blood draw. Odds ratios (ORs) for the associations of serum thyroid peroxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), progesterone, and estradiol with papillary thyroid cancer were estimated using conditional logistic regression. TPO-Ab and Tg-Ab positivity (>95th percentile among controls) were associated with more than 3-fold (OR = 3.32, 95% confidence interval [CI] 2.33-4.72) and 2-fold (OR = 2.03, 95% CI 1.41-2.93) increased odds of papillary thyroid cancer, respectively. These associations were similar by time since blood draw, parity, gestational age, smoking status, and age and stage at diagnosis. In models excluding TPO-Ab or Tg-Ab positivity, TPO-Ab (quartile 4 vs. 1: OR = 1.66, 95% CI 1.17-2.37, p-trend = .002) and Tg-Ab (quartile 4 vs. 1: OR = 1.74, 95% CI 1.22-2.49, p-trend = .01) levels were positively associated with papillary thyroid cancer. No associations were observed for estradiol, progesterone, TSH, fT3, or fT4 overall. Our results suggest that thyroid autoimmunity in early pregnancy may increase the risk of maternal papillary thyroid cancer.

Associations of tubal ligation and hysterectomy with serum androgen and estrogen metabolites among postmenopausal women in the Women's Health Initiative Observational Study.

PURPOSE: Hysterectomy is associated with subsequent changes in circulating hormone levels, but the evidence of an association for tubal ligation is unclear. We evaluated whether circulating concentrations of androgens and estrogens differ by tubal ligation or hysterectomy status in postmenopausal women from the Women's Health Initiative (WHI)-Observational Study (OS). METHODS: Serum androgens and estrogens were measured in 920 postmenopausal women who did not use menopausal hormone therapy at the time of blood draw, of whom 139 self-reported a history of tubal ligation and 102 reported hysterectomy (with intact ovaries). Geometric mean hormone concentrations (GMs) and 95% confidence intervals (CIs) associated with a history of tubal ligation or hysterectomy (ever/never), as well as time since procedures, were estimated using adjusted linear regression with inverse probability of sampling weights to account for selection. RESULTS: Circulating levels of 12 androgen/androgen metabolites and 20 estrogen/estrogen metabolites did not differ by tubal ligation status. Among women reporting prior hysterectomy compared to women without hysterectomy, we observed lower levels of several androgens (e.g., testosterone (nmol/L): GMyes 0.46 [95% CI:0.37-0.57] vs. GMno 0.62 [95% CI:0.53-0.72]) and higher levels of estrogen metabolites, for example, 2-hydroxyestrone-3-methyl ether (GMyes 11.1 [95% CI:8.95-13.9] pmol/L vs. GMno 8.70 [95% CI:7.38-10.3]) and 4-methoxyestrone (GMyes 6.50 [95% CI:5.05-8.37] vs. GMno 4.92 [95% CI:4.00-6.05]). CONCLUSION: While we did not observe associations between prior tubal ligation and postmenopausal circulating hormone levels, our findings support that prior hysterectomy was associated with lower circulating testosterone levels and higher levels of some estrogen metabolites, which may have implications for future hormone-related disease risks.

Statin use is not associated with inflammation among Chilean women of Mapuche and non-Mapuche ancestry with gallstones.

Aim: Statins are associated with lower risk of gallstones due to anti-inflammatory effects. We assessed whether statins impact circulating inflammation among Chilean women with gallstones. Materials & methods: 200 Mapuche women were matched on statin use and age to 200 non-Mapuche women in the Chile Biliary Longitudinal Study. We analyzed 92 inflammatory biomarkers using multivariable-adjusted regression models, random forests and pathway analyses. Results: Statins were not significantly associated with any inflammation marker when women were analyzed jointly or stratified by ancestry. No significant associations were found through random forest methods and pathway analyses. Discussion: We did not find significant associations between statin use and inflammation markers in women with gallstones, suggesting that statins do not reduce inflammation once gallstones have formed.

Statins are prescribed to lower cholesterol and can also decrease the risk of gallstone formation by reducing inflammation. We assessed whether statin use reduces inflammation among women who have already developed gallstones. We analyzed 92 inflammation markers among 400 women in Chile, including 200 women with Mapuche Amerindian ancestry and 200 women of Latina/European ancestry. We found that statin use was not correlated with inflammation in this group of women overall nor by ancestry. This may mean that statin use does not reduce inflammation in women who already were diagnosed with gallstones.

Mediation analysis using incomplete information from publicly available data sources.

Our work was motivated by the question whether, and to what extent, well-established risk factors mediate the racial disparity observed for colorectal cancer (CRC) incidence in the United States. Mediation analysis examines the relationships between an exposure, a mediator and an outcome. All available methods require access to a single complete data set with these three variables. However, because population-based studies usually include few non-White participants, these approaches have limited utility in answering our motivating question. Recently, we developed novel methods to integrate several data sets with incomplete information for mediation analysis. These methods have two limitations: (i) they only consider a single mediator and (ii) they require a data set containing individual-level data on the mediator and exposure (and possibly confounders) obtained by independent and identically distributed sampling from the target population. Here, we propose a new method for mediation analysis with several different data sets that accommodates complex survey and registry data, and allows for multiple mediators. The proposed approach yields unbiased causal effects estimates and confidence intervals with nominal coverage in simulations. We apply our method to data from U.S. cancer registries, a U.S.-population-representative survey and summary level odds-ratio estimates, to rigorously evaluate what proportion of the difference in CRC risk between non-Hispanic Whites and Blacks is mediated by three potentially modifiable risk factors (CRC screening history, body mass index, and regular aspirin use).

Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease.

INTRODUCTION: Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD. METHODS: We undertook a nested case-control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970-2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression. RESULTS: Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ - 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99). DISCUSSION: Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk.

Opioid use in cancer patients compared with noncancer pain patients in a veteran population.

BACKGROUND: Opioid safety initiatives may secondarily impact opioid prescribing and pain outcomes for cancer care. METHODS: We reviewed electronic health record data at a tertiary Veterans Affairs system (VA Palo Alto) for all patients from 2015 to 2021. We collected outpatient Schedule II opioid prescriptions data and calculated morphine milligram equivalents (MMEs) using Centers for Disease Control and Prevention conversion formulas. To determine the clinical impact of changes in opioid prescription, we used the highest level of pain reported by each patient on the 0-to-10 Numeric Rating Scale in each year, categorized into mild (0-3), moderate (4-6), and severe (7 and above). RESULTS: Among 89 569 patients, 9073 had a cancer diagnosis. Cancer patients were almost twice as likely to have an opioid prescription compared with noncancer patients (69.0% vs 36.7%, respectively). The proportion of patients who received an opioid prescription decreased from 27.1% to 18.1% (trend P < .01) in cancer patients and from 17.0% to 10.2% in noncancer patients (trend P < .01). Cancer and noncancer patients had similar declines of MMEs per year between 2015 and 2019, but the decline was more rapid for cancer patients (1462.5 to 946.4, 35.3%) compared with noncancer patients (1315.6 to 927.7, 29.5%) from 2019 to 2021. During the study period, the proportion of noncancer patients who experienced severe pain was almost unchanged, whereas it increased among cancer patients, reaching a significantly higher rate than among noncancer patients in 2021 (31.9% vs 27.4%, P < .01). CONCLUSIONS: Our findings suggest potential unintended consequences for cancer care because of efforts to manage opioid-related risks.

Predicting absolute risk for a person with missing risk factors.

We compared methods to project absolute risk, the probability of experiencing the outcome of interest in a given projection interval accommodating competing risks, for a person from the target population with missing predictors. Without missing data, a perfectly calibrated model gives unbiased absolute risk estimates in a new target population, even if the predictor distribution differs from the training data. However, if predictors are missing in target population members, a reference dataset with complete data is needed to impute them and to estimate absolute risk, conditional only on the observed predictors. If the predictor distributions of the reference data and the target population differ, this approach yields biased estimates. We compared the bias and mean squared error of absolute risk predictions for seven methods that assume predictors are missing at random (MAR). Some methods imputed individual missing predictors, others imputed linear predictor combinations (risk scores). Simulations were based on real breast cancer predictor distributions and outcome data. We also analyzed a real breast cancer dataset. The largest bias for all methods resulted from different predictor distributions of the reference and target populations. No method was unbiased in this situation. Surprisingly, violating the MAR assumption did not induce severe biases. Most multiple imputation methods performed similarly and were less biased (but more variable) than a method that used a single expected risk score. Our work shows the importance of selecting predictor reference datasets similar to the target population to reduce bias of absolute risk predictions with missing risk factors.

Addition of polygenic risk score to a risk calculator for prediction of breast cancer in US Black women.

BACKGROUND: Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC (area under the curve). Following publication of the first PRS to perform well in women of African ancestry (AA-PRS), we conducted an external validation of the AA-PRS and then evaluated the addition of the AA-PRS to a risk calculator for incident breast cancer in Black women based on epidemiologic factors (BWHS model). METHODS: Data from the Black Women's Health Study, an ongoing prospective cohort study of 59,000 US Black women followed by biennial questionnaire since 1995, were used to calculate AUCs and 95% confidence intervals (CIs) for discriminatory accuracy of the BWHS model, the AA-PRS alone, and a new model that combined them. Analyses were based on data from 922 women with invasive breast cancer and 1844 age-matched controls. RESULTS: AUCs were 0.577 (95% CI 0.556-0.598) for the BWHS model and 0.584 (95% CI 0.563-0.605) for the AA-PRS. For a model that combined estimates from the questionnaire-based BWHS model with the PRS, the AUC increased to 0.623 (95% CI 0.603-0.644). CONCLUSIONS: This combined model represents a step forward for personalized breast cancer preventive care for US Black women, as its performance metrics are similar to those from models in other populations. Use of this new model may mitigate exacerbation of breast cancer disparities if and when it becomes feasible to include a PRS in routine health care decision-making.

Association of cardiovascular disease management drugs with Lewy body dementia: a case-control study.

Lewy body dementia is the second most common neurodegenerative dementia after Alzheimer's disease. Disease-modifying therapies for this disabling neuropsychiatric condition are critically needed. To identify drugs associated with the risk of developing Lewy body dementia, we performed a population-based case-control study of 148 170 US Medicare participants diagnosed with Lewy body dementia between 1 January 2008 and 31 December 2014 and of 1 253 043 frequency-matched controls. We estimated odds ratios and 95% confidence intervals for the association of Lewy body dementia risk with 1017 prescription drugs overall and separately for the three major racial groups (Black, Hispanic and White Americans). We identified significantly reduced Lewy body dementia risk associated with drugs used to treat cardiovascular diseases (anti-hypertensives: odds ratio = 0.72, 95% confidence interval = 0.70-0.74, P-value = 0; cholesterol-lowering agents: odds ratio = 0.85, 95% confidence interval = 0.83-0.87, P-value = 0; anti-diabetics: odds ratio = 0.83, 95% confidence interval = 0.62-0.72, P-value = 0). Notably, anti-diabetic medications were associated with a larger risk reduction among Black Lewy body dementia patients compared with other racial groups (Black: odds ratio = 0.67, 95% confidence interval = 0.62-0.72, P-value = 0; Hispanic: odds ratio = 0.86, 95% = 0.80-0.92, P-value = 5.16 × 10-5; White: odds ratio = 0.85, 95% confidence interval = 0.82-0.88, P-value = 0). To independently confirm the epidemiological findings, we looked for evidence of genetic overlap between Lewy body dementia and cardiovascular traits using whole-genome sequence data generated for 2591 Lewy body dementia patients and 4027 controls. Bivariate mixed modelling identified shared genetic risk between Lewy body dementia and low-density lipoprotein cholesterol levels, Type 2 diabetes and hypertension. By combining epidemiological and genomic data, we demonstrated that drugs treating cardiovascular diseases are associated with reduced Lewy body dementia risk, and these associations varied across racial groups. Future randomized clinical trials need to confirm our findings, but our data suggest that assiduous management of cardiovascular diseases may be beneficial in this understudied form of dementia.

Severe anal intraepithelial neoplasia trends and subsequent invasive anal cancer in the United States.

BACKGROUND: Anal intraepithelial neoplasia grade III is a precursor to squamous cell carcinoma of the anus for which rates are nearly 20-fold higher in people with HIV than in the general population in the United States. We describe trends in anal intraepithelial neoplasia grade III diagnosis and risk of squamous cell carcinoma of the anus following anal intraepithelial neoplasia grade III by HIV status and sex. METHODS: We used data from a population-based linkage between cancer and HIV registries in 11 US states; Puerto Rico; and Washington, DC, during 1996-2019. We identified all individuals with a diagnosis of anal intraepithelial neoplasia grade III and determined their HIV status. We estimated the average annual percentage change of anal intraepithelial neoplasia grade III using Poisson regression stratified by HIV status and sex. We estimated the 5-year cumulative incidence of squamous cell carcinoma of the anus following an anal intraepithelial neoplasia grade III diagnosis stratified by sex, HIV status, and prior AIDS diagnosis. RESULTS: Among people with HIV, average annual percentage changes for anal intraepithelial neoplasia grade III were 15% (95% confidence interval [CI] = 12% to 17%) per year among females and 12% (95% CI = 11% to 14%) among males. Average annual percentage changes for those without HIV were 8% (95% CI = 7% to 8%) for females and 8% (95% CI = 6% to 9%) for males. Among people with HIV, a prior AIDS diagnosis was associated with a 2.7-fold (95% CI = 2.23 to 3.40) and 1.9-fold (95% CI = 1.72 to 2.02) increased risk of anal intraepithelial neoplasia grade III diagnosis for females and males, respectively. Five-year cumulative incidence of squamous cell carcinoma of the anus following anal intraepithelial neoplasia grade III for people with HIV with a prior AIDS diagnosis were 3.4% and 3.7% for females and males, respectively. CONCLUSIONS: Rates of anal intraepithelial neoplasia grade III diagnoses have increased since 1996, particularly for people with HIV, likely influenced by increased screening. A prior AIDS diagnosis was strongly associated with risk of anal intraepithelial neoplasia grade III diagnosis.

Survival by sex and HIV status in patients with anal cancer in the USA between 2001 and 2019: a retrospective cohort study.

BACKGROUND: The risk of anal cancer is increased among people with HIV, particularly men who have sex with men. Estimating survival by HIV status and sex and identifying groups at high risk is crucial for documenting prognostic differences between populations. We aimed to compare all-cause and anal cancer-specific survival in patients with anal cancer with and without HIV, stratified by sex, and to identify predictors of survival, stratified by HIV status. METHODS: In this retrospective cohort study, we used data from the HIV/AIDS Cancer Match Study of 13 population-based HIV and cancer registries throughout the USA. We included individuals aged 20-79 years diagnosed with invasive anal cancer between 2001 and 2019. To estimate associations between HIV status and both all-cause and anal cancer-specific mortality overall, we used Cox proportional hazards models, adjusting for year of and age at diagnosis, sex, race and ethnicity, histology, cancer stage, region, and treatment. We also calculated sex-specific adjusted hazard ratios (HRs). By HIV status, we identified characteristics associated with mortality. Models among people with HIV were further adjusted for AIDS status and HIV transmission risk group. FINDINGS: Between Jan 1, 2001, and Dec 31, 2019, 1161 (43·6%) of 2662 patients with anal cancer and HIV and 7722 (35·4%) of 21 824 patients without HIV died. HIV was associated with a 1·35 times (95% CI 1·24-1·47) increase in all-cause mortality among male patients and a 2·47 times (2·10-2·90) increase among female patients. Among patients with HIV, all-cause mortality was increased among non-Hispanic Black individuals (adjusted HR 1·19, 95% CI 1·04-1·38), people with AIDS (1·36, 1·10-1·68), people who inject drugs (PWID; 1·49, 1·17-1·90), patients with adenocarcinoma (2·74, 1·82-4·13), and those with no or unknown surgery treatment (1·34, 1·18-1·53). HIV was associated with anal cancer-specific mortality among female patients only (1·52, 1·18-1·97). Among patients with HIV, anal cancer-specific mortality was increased among patients with adenocarcinoma (3·29, 1·89-5·72), those with no or unknown treatment (1·59, 1·17-2·17), and PWID (1·60, 1·05-2·44). INTERPRETATION: HIV was associated with all-cause mortality among patients with anal cancer, especially women. Anal cancer-specific mortality was elevated among female patients with HIV. As screening for anal cancer becomes more widespread, examining the effects of screening on survival by HIV status and sex is crucial. FUNDING: US National Cancer Institute Intramural Research Program.

Real-world use of antiretroviral therapy and risk of cancer among people with HIV in Texas.

BACKGROUND: Combination antiretroviral therapy (cART) may reduce cancer risk among people with HIV (PWH), but cancer-specific associations are incompletely understood. METHODS: We linked HIV and cancer registries in Texas to a national prescription claims database. cART use was quantified as the proportion of days covered (PDC). Cox proportional hazards models assessed associations of cancer risk with cART usage, adjusting for demographic characteristics, AIDS status, and time since HIV report. RESULTS: We evaluated 63 694 PWH followed for 276 804 person-years. The median cART PDC was 21.4% (interquartile range: 0.0-59.8%). cART use was associated with reduced risk of Kaposi sarcoma [adjusted hazard ratio (aHR) 0.48, 95% confidence interval (CI) 0.34-0.68 relative to unexposed status] and non-Hodgkin lymphoma (aHR 0.41, 95% CI 0.31-0.53), liver cancer (aHR 0.61, 95% CI 0.39-0.96), anal cancer (aHR 0.65, 95% CI 0.46-0.92), and a miscellaneous group of 'other' cancers (aHR 0.80, 95% CI 0.66-0.98). In contrast, cART-exposed status was not associated with risk for cervical, lung, colorectal, prostate or breast cancers. CONCLUSION: In a large HIV cohort incorporating data from prescription claims, cART was associated with greatly reduced risks of Kaposi sarcoma and non-Hodgkin lymphoma, and to a lesser degree, reduced risks of liver and anal cancers. These associations likely reflect the beneficial effects of HIV suppression and improved immune control of oncogenic viruses. Efforts to increase cART use and adherence may further decrease cancer incidence among PWH.

Sex differences in cancer incidence among solid organ transplant recipients.

BACKGROUND: Males have 2-3-fold greater risk of cancer than females at most shared anatomic sites, possibly reflecting enhanced immune surveillance against cancer in females. We examined whether these sex differences remained among immunocompromised adults. METHODS: Using the Transplant Cancer Match (TCM) study, we estimated the male-to-female incidence rate ratio in TCM (M:F IRRTransplant) for 15 cancer sites diagnosed between 1995 and 2017 using Poisson regression. Male to female IRRs in the general population (M:F IRRGP) were calculated using expected cancer counts from the Surveillance, Epidemiology, and End Results Program, standardized to the transplant population on age, race and ethnicity, and diagnosis year. Male to female IRRs were compared using a chi-square test. RESULTS: Among 343 802 solid organ transplants, 211 206 (61.4%) were among men and 132 596 (38.6%) among women. An excess cancer incidence in males was seen in transplant recipients, but the sex difference was attenuated for cancers of the lip (M:F IRRTransplant: 1.81 vs M:F IRRGP: 3.96; P < .0001), stomach (1.51 vs 2.09; P = .002), colorectum (0.98 vs 1.43; P < .0001), liver (2.39 vs 3.44; P = .002), kidney (1.67 vs 2.24; P < .0001), bladder (2.02 vs 4.19; P < .0001), Kaposi sarcoma (1.79 vs 3.26; P = .0009), and non-Hodgkin lymphoma (1.34 vs 1.64; P < .0001). The M:F IRRTransplant was not statistically different from the M:F IRRGP for other cancer sites. CONCLUSIONS: Although male solid organ transplant recipients have higher cancer incidence than female recipients, the attenuation in the male to female ratio for many cancers studied relative to the general population might suggest the importance of immunosurveillance, with some loss of advantage in female recipients due to immunosuppression after transplantation.

Frequentist model averaging for analysis of dose-response in epidemiologic studies with complex exposure uncertainty.

In epidemiologic studies, association estimates of an exposure with disease outcomes are often biased when the uncertainties of exposure are ignored. Consequently, corresponding confidence intervals (CIs) will not have correct coverage. This issue is particularly problematic when exposures must be reconstructed from physical measurements, for example, for environmental or occupational radiation doses that were received by a study population for which radiation doses cannot be measured directly. To incorporate complex uncertainties in reconstructed exposures, the two-dimensional Monte Carlo (2DMC) dose estimation method has been proposed and used in various dose reconstruction efforts. The 2DMC method generates multiple exposure realizations from dosimetry models that incorporate various sources of errors to reflect the uncertainty of the dose distribution as well as the uncertainties in individual doses in the exposed population. Traditional measurement-error model approaches, typically based on using mean doses in the dose-exposure analysis, do not fully account exposure uncertainties. A recently developed statistical approach that overcomes many of these limitations by analyzing multiple exposure realizations in relation to disease risk is Bayesian model averaging (BMA). The analytic advantage of the BMA is its ability to better accommodate complex exposure uncertainty in the risk estimation, but a practical. Drawback is its significant computational complexity. In this present paper, we propose a novel frequentist model averaging (FMA) approach which has all the analytical advantages of the BMA method but is much simpler to implement and computationally faster. We show in simulations that, like BMA, FMA yields 95% confidence intervals for association parameters that close to 95% coverage rate. In simulations, the FMA has shorter length of CIs than those of another frequentist approach, the corrected information matrix (CIM) method. We illustrate the similarities in performance of BMA and FMA from a study of exposures from radioactive fallout in Kazakhstan.

Cohort profile: evaluation of immune response and household transmission of SARS-CoV-2 in Costa Rica: the RESPIRA study.

PURPOSE: The RESPIRA cohort aims to describe the nature, magnitude, time course and efficacy of the immune response to SARS-CoV-2 infection and vaccination, population prevalence, and household transmission of COVID-19. PARTICIPANTS: From November 2020, we selected age-stratified random samples of COVID-19 cases from Costa Rica confirmed by PCR. For each case, two population-based controls, matched on age, sex and census tract were recruited, supplemented with hospitalised cases and household contacts. Participants were interviewed and blood and saliva collected for antibodies and PCR tests. Participants will be followed for 2 years to assess antibody response and infection incidence. FINDINGS TO DATE: Recruitment included 3860 individuals: 1150 COVID-19 cases, 1999 population controls and 719 household contacts from 304 index cases. The age and regional distribution of cases was as planned, including four age strata, 30% rural and 70% urban. The control cohort had similar sex, age and regional distribution as the cases according to the study design. Among the 1999 controls recruited, 6.8% reported at enrolment having had COVID-19 and an additional 12.5% had antibodies against SARS-CoV-2. Compliance with visits and specimens has been close to 70% during the first 18 months of follow-up. During the study, national vaccination was implemented and nearly 90% of our cohort participants were vaccinated during follow-up. FUTURE PLANS: RESPIRA will enable multiple analyses, including population prevalence of infection, clinical, behavioural, immunological and genetic risk factors for SARS-CoV-2 acquisition and severity, and determinants of household transmission. We are conducting retrospective and prospective assessment of antibody levels, their determinants and their protective efficacy after infection and vaccination, the impact of long-COVID and a series of ancillary studies. Follow-up continues with bimonthly saliva collection for PCR testing and biannual blood collection for immune response analyses. Follow-up will be completed in early 2024. TRIAL REGISTRATION NUMBER: NCT04537338.

Estimating the cumulative incidence of SARS-CoV-2 infection in Costa Rica: modelling seroprevalence data in a population-based cohort.

Background: The true incidence of SARS-CoV-2 infection in Costa Rica was likely much higher than officially reported, because infection is often associated with mild symptoms and testing was limited by official guidelines and socio-economic factors. Methods: Using serology to define natural infection, we developed a statistical model to estimate the true cumulative incidence of SARS-CoV-2 in Costa Rica early in the pandemic. We estimated seroprevalence from 2223 blood samples collected from November 2020 to October 2021 from 1976 population-based controls from the RESPIRA study. Samples were tested for antibodies against SARS-CoV-2 nucleocapsid and the receptor-binding-domain of the spike proteins. Using a generalized linear model, we estimated the ratio of true infections to officially reported cases. Applying these ratios to officially reported totals by age, sex, and geographic area, we estimated the true number of infections in the study area, where 70% of Costa Ricans reside. We adjusted the seroprevalence estimates for antibody decay over time, estimated from 1562 blood samples from 996 PCR-confirmed COVID-19 cases. Findings: The estimated total proportion infected (ETPI) was 4.0 times higher than the officially reported total proportion infected (OTPI). By December 16th, 2021, the ETPI was 47% [42-52] while the OTPI was 12%. In children and adolescents, the ETPI was 11.0 times higher than the OTPI. Interpretation: Our findings suggest that nearly half the population had been infected by the end of 2021. By the end of 2022, it is likely that a large majority of the population had been infected. Funding: This work was sponsored and funded by the National Institute of Allergy and Infectious Diseases through the National Cancer Institute, the Science, Innovation, Technology and Telecommunications Ministry of Costa Rica, and Costa Rican Biomedical Research Agency-Fundacion INCIENSA (grant N/A).

The Association of Supplemental Nutrition Assistance Program Participation and Food Insufficiency among Households with Children in the United States during COVID-19.

BACKGROUND: As the expansion of Supplemental Nutrition Assistance Program (SNAP) benefits and pandemic emergency assistance programs ended in late 2021, little is known about subsequent trends in food insufficiency (FI) among households with children. OBJECTIVES: This research examined the association between SNAP participation and FI among households with children in the United States, particularly non-Hispanic Black (Black) and Hispanic households. METHODS: This cross-sectional analysis used Household Pulse Survey data collected from December 2021 to May 2022. Spatial analysis was conducted to visualize FI and SNAP participation rates across 50 states. With state SNAP policy rules as exogenous instruments and sociodemographic factors as control variables, 2-stage probit models were utilized to assess the SNAP and FI association among all (n = 135,074), Black (n = 13,940), and Hispanic households with children (n = 17,869). RESULTS: Approximately 13.9% [95% confidence interval (CI): 13.85%, 13.99%] of households experienced FI, and 20.4% (CI: 20.35%, 20.51%) received SNAP benefits. Among Black and Hispanic households, higher rates were observed, with 23.3% (CI: 23.12%, 23.4%) and 20.8% (CI: 20.61%, 20.95%) experiencing FI and 36.3% (CI: 36.1%, 36.5%) and 26.9% (CI: 26.61%, 27.13%) receiving SNAP benefits. These rates varied across states, ranging from 8% (Utah) to 21.1% (Mississippi) for FI and from 8.8% (Utah) to 32.7% (New Mexico) for SNAP participation. SNAP participants demonstrated a 12% lower likelihood of FI than nonparticipants (CI: -0.18, -0.05, P < 0.001). Among Black households, SNAP participants had a 29% lower likelihood of FI than nonparticipants (CI: -0.54, -0.03, P < 0.001). However, SNAP participation was not significant among Hispanic households (P = 0.99), nor did it narrow the FI gap between Hispanic and non-Hispanic households (P = 0.22). CONCLUSIONS: SNAP participation was associated with lower levels of FI among households with children, particularly for Black households. However, there was no significant association between SNAP participation and FI among Hispanic households with children.