Relative Risk Estimates Research Articles

Evaluation of a mobile application to decrease opioid misuse in patients undergoing cesarean section: a randomized controlled trial

BackgroundOpioid misuse and addiction are at epidemic levels in the United States. Postoperative opioid prescription is inconsistent and often excessive, including for cesarean section patients. Technology, such as mobile applications and clinical decision support tools, can be used to decrease opioid use and misuse among patients, and to determine more appropriate prescribing practices for specific procedures. The objective of this study was to examine the preliminary impact of the Continuing Precision Medicine (CPM) mobile application to reduce the use of opioid pain medication among women who underwent cesarean section. The primary outcome is morphine milligram equivalents (MME), while the secondary outcomes will be delay to dosages, decrease of usage, and pain scores.MethodsPatients undergoing cesarean section were randomized to either a control group or an experimental group, which used the CPMRx mobile app to help manage postoperative pain. Logistic regression analyses were run to predict opioid misuse by group (control [electronic monitoring blister pack only] versus CPMRx [electronic monitoring blister pack plus mobile application]) and odds ratios (ORs) were calculated. Relative risk (RR) was also estimated by log-binomial regression.ResultsIn phase I, 105 patients were assessed for eligibility, however, 66 were excluded (not meeting criteria or declined to participate). In phase 2, 98 patients were assessed for eligibility, however, 48 were excluded for the aforementioned. Results of the logistic regression showed that opioid misuse differed significantly by group (χ2 = 7.27, p = 0.007) with participants in the CPMRx group experiencing a 92% reduction in odds of opioid misuse compared to blister packs only (OR = 0.08, p = 0.03). Relative risk estimation by log-binomial regression also revealed that patients in the control group were at 7 times higher risk of opioid misuse than those using the CPMRx app (Wald χ2 = 3.82, RR = 7.00, p = 0.05). Among the 21 participants in Phase I who did not misuse their prescription opioids, the average number of pills used was 2.7 (SD = 3.5); 95% of patients used 8 or fewer pills, 90% used 6 or fewer, 75% used 4 or fewer, and half of participants used 1 or fewer opioids.ConclusionsWomen using the CPMRx mobile application were less likely to misuse their prescription opioids during the postoperative period following cesarean section. A prescription of 7 tablets of 5 mg oxycodone may be a more appropriate prescription size among this group. Systematically right-sizing prescriptions, including for subgroups, may decrease both patient- and community-level risk of opioid misuse and reduce public health burden.Trial registrationThe study was registered at ClinicalTrials.gov (NCT05461196, 18/07/2022).

Using Double Negative Controls to Adjust for Healthy User Bias in a Recombinant Zoster Vaccine Safety Study.

Unmeasured confounding is a major concern in many epidemiologic studies that are not randomized. Negative control methods can detect and reduce confounding by leveraging the proxies of the unmeasured confounders, including negative control outcomes (NCO) and exposures (NCE). An NCO is presumably unaffected by the exposure of interest but would be associated with unmeasured confounders; an NCE presumably does not affect the outcome of interest but would be associated with unmeasured confounders. A recently proposed double negative control method leverages both NCO and NCE for unmeasured confounding bias. To demonstrate this relatively new methodology in pharmacoepidemiologic studies, we re-analyzed data from a prior safety study of Recombinant Zoster Vaccine (RZV). The prior study compared risk of safety outcomes of RZV versus unvaccinated comparators, using logistic regression with propensity score adjustment. We identified NCOs and NCEs that could be used to adjust for unmeasured confounding bias that could arise if RZV recipients are incomparable to the comparators due to unmeasured factors. The double negative control analysis yielded relative risk estimates slightly closer to 1.0 than those reported previously, providing additional evidence of RZV safety that is less vulnerable to unmeasured confounding.

Alcoholic beverage consumption and female breast cancer risk:A systematic review and meta-analysis of prospective cohort studies.

Alcohol consumption is an established cause of female breast cancer. This systematic review examines in detail the association between alcohol and female breast cancer overall and among the described subgroups, using all of the evidence to date. A systematic review of PubMed and Embase was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search included articles published up to November 15, 2023. Meta-analyses and regressions were performed for alcohol consumption of less than 1 standard drink (10 g of ethanol) per day and for a range of alcohol consumption categories in relation to breast cancer. Analyses by menopausal status, hormone receptor status, human epidermal growth factor receptor 2 status, and molecular subtype were performed. The search yielded 5645 publications, of which 23 publications of individual and pooled studies examined the association between overall alcohol consumption and breast cancer incidence. The meta-regression showed a positive association; relative risks (RR) of breast cancer were 1.05 (95% CI: 1.04, 1.06), 1.10 (95% CI: 1.08, 1.12), 1.18 (95% CI: 1.15, 1.21), and 1.22 (95% CI: 1.19, 1.25) for 0.5, 1, 2, and 3 standard drinks per day compared with nondrinking, respectively. A meta-analysis of nine studies indicated that for consumption of less than one standard drink per day, the RR estimate of breast cancer was 1.04 (95% CI: 1.01, 1.07) compared with nondrinking. Consumption of an additional 1 standard drink per day was associated with a higher risk of premenopausal (RR: 1.03 (95% CI: 1.01, 1.06)) and postmenopausal (RR: 1.10 (95% CI: 1.08, 1.12)) breast cancer. Alcohol consumption increases female breast cancer risk, even for women who consume one drink per day. Furthermore, alcohol consumption is associated with both pre- and postmenopausal breast cancer risk. These findings support evidence-based cancer prevention guidelines to reduce alcohol-related risks.

Assessing the contribution of smoking to the disease burden in Belgium, 2013-2020

Abstract Tobacco use remains a challenge given its substantial role in contributing to disability and premature death globally. Understanding its impact on population health, as an attributable burden, can help monitor progress on the effectiveness of tobacco policies. In this study, we used the Comparative Risk Assessment (CRA) method to estimate the share of the disease burden due to smoking in Belgium from 2013 to 2020. Population attributable fractions (PAF) were computed for risk-outcome pairs by age, sex, and region in Belgium for 2013-2020. Exposure estimates were extracted from a time series of the Belgian Health Interview Survey. Dose-response curves or relative risk estimates were drawn from the Global Burden of Disease Study 2019. In Belgium, smoking-related deaths decreased from 12,851 deaths (PAF=11%) in 2013 to 9,413 deaths (PAF=7%) in 2020. Deaths among men (2013: PAF=18%, n = 9859; 2020: PAF=11%, n = 7041) were three times higher than among women (2013: PAF=5%, n = 2991; 2020: PAF=3%, n = 2341). Over time, larynx cancer (2013: PAF=72%, n = 185; 2020: PAF=63%, n = 125), trachea, bronchus, and lung cancer (2013: PAF=60%, n = 4,899; 2020: PAF=60%, n = 3,682), other pharyngeal and oropharyngeal cancers (2013: PAF=47%, n = 118; 2020: PAF=40%, n = 100), mouth cancer (2013: PAF=37%, n = 172; 2020: PAF=30%, n = 122), and aortic aneurysm (2013: PAF=40%, n = 268; 2020: PAF=33%, n = 209) emerged as the primary contributors to smoking-related deaths in Belgium. While the ranking of contributing causes stayed mostly consistent in both genders over the years, cervical cancer (2013: PAF=23%, n = 53; 2020: PAF=21%, n = 64) ranked fourth instead of mouth cancer (2013: PAF=22%, n = 28; 2020: PAF=14%, n = 15) among women. Despite decreasing trends over time, smoking remains a significant contributor to cancer deaths in Belgium, particularly among men. Results from this study can help inform the development of strategies for smoking prevention and reinforce the need for continued efforts in prevention initiatives. Key messages • Cancers are the primary cause of smoking-related deaths in Belgium, with a decline in the death toll over time. • Understanding the role of smoking on population health as an attributable burden can improve health monitoring.

Africa Health Research Institute (AHRI) Household Contact study: a study protocol, statistical analysis and modelling plan

Household case-contact studies are an established method to estimate the relative infectiousness of people with pulmonary tuberculosis. Testing of child household contacts with a QuantiFERON TB Gold plus (QFT) assay provides a proxy measure of M. tuberculosis infection in exposed household members. This study aims to generate data about the effect of antiretroviral treatment (ART) and of tuberculosis symptoms on risk of intra-household M. tuberculosis transmission to children and investigate the conditions under which symptom-agnostic screening should be considered, which could provide evidence to support a paradigm shift in tuberculosis screening strategy. Index people diagnosed with bacteriologically-confirmed pulmonary tuberculosis who have been identified by routine health services and starting tuberculosis treatment at one of the 12 health facilities serving the population of the Africa Health Research Institute health and demographic surveillance area will be eligible for recruitment. For each consenting index participant, we will enroll all household members aged 2-14 years who will undergo a symptom screen and provide a blood sample for a QFT and HIV test. We will compare the proportion of child contacts who are QFT-positive in households of (i) index adults who are living with HIV and taking ART vs not taking ART and (ii) index adults engaged in ART care who report no symptoms vs those who report symptoms. We will use a novel mathematical model, incorporating new insights into TB natural history and transmission, to determine the circumstances under which screening for TB, regardless of reported symptoms, would have most impact on tuberculosis incidence and mortality, and explore comparative cost-effectiveness of interventions along the diagnostic pathway at different levels of the health system. Estimates of relative risk of intra-household M. tuberculosis transmission, combined with healthcare utilisation and cost data, will allow us to generate mathematical model estimates of the potential epidemiological impact and relative cost-effectiveness of different approaches to tuberculosis case-finding including symptom-agnostic tuberculosis screening at different levels of the health system.

Paternal metformin use and risk of congenital malformations in offspring in Norway and Taiwan: population based, cross national cohort study

ObjectiveTo evaluate the association between paternal metformin use and risk of congenital malformations in offspring.DesignPopulation based, cross national cohort study.SettingNorway and Taiwan.Participants619 389 offspring with paternal data during the period...

Polymorbidity and Health Outcomes Among Middle-Aged and Older Adults: Evidence from the Longitudinal Ageing Study in India

Polymorbidity is the leading cause of morbidity and mortality, particularly in the aging population. The present study analyses the prevalence and explores the determinants of polymorbidity among middle-aged and older adults. The study utilizes the 2017–2018 Longitudinal Ageing Study in India (LASI 2017–2018), a national representative dataset on health conditions of people aged 45 years and above, to study the relative risk estimates. The analysis uses the multinomial logit model (MNL) with their relative risk ratios (RRR). The findings of RRR suggest that the risk of polymorbidity significantly depends on parents’ medical history, residing in a front-runner state, and consultation at healthcare centers in both middle-aged and older adults. The prevalence of severe polymorbidity is higher among well-educated individuals and rural residents. The richer household carries a lower risk of polymorbidity, and the older adults from the general caste category are at higher risk of severe polymorbidity. The findings aim to redress the problems attached to the old age population in India. The paper recommends promoting preventive and precautionary attitudes over curative attitudes through health policies by introducing a patient-oriented and disease-centered approach to healthcare provision in India.

Assessing subgroup differences and underlying causes of ozone-associated mortality burden in China using multi-source data

Long-term ozone exposure is a significant public health concern. To mitigate its impact, it is crucial to identify diseases, populations, and regions that are particularly sensitive to ozone. In this study, we used high-quality data and updated relative risk estimates to investigate subgroup differences in mortality burden due to ozone exposure in China. In 2020, nationwide ozone-associated deaths totaled 276,800 (95 % CI: 106,700–451,900), representing 3.2 % of all deaths, with respiratory and cardiovascular diseases accounting for 16.8 % and 83.2 %, respectively. The per capita ozone-associated mortality in China was 20 per 100,000 person-years, with a significantly higher rate observed in elderly individuals aged ≥75 years (189 deaths per 100,000) compared to young individuals aged 30–44 years (1 death per 100,000). There were notable spatial patterns of ozone-associated deaths among the regions, indicating a critical response to ozone levels and population density. Interestingly, urban areas exhibited a 22.4 % lower mortality rate related to ozone compared to rural areas. This difference was attributed to the combined influence of ozone exposure (+19.9 %), population size (+17.7 %), age structure (−39.2 %), and baseline mortality (−20.8 %). By emphasizing subgroup differences and driving factors, these findings significantly enhance the understanding of the ozone-associated mortality burden, providing valuable insights for policymakers.

Unbiased temperature-related mortality estimates using weekly and monthly health data: a new method for environmental epidemiology and climate impact studies

Exposure to environmental factors has a high burden on human health, with millions of premature annual deaths associated with the short-term health effects of ambient temperatures and air pollution. However, direct estimations of exposure-related mortality from real data are still not available in most parts of the world, especially in low-resource settings, due to the unavailability of daily health records to calibrate epidemiological models. In this study, we have filled the crucial gap in available direct estimations by developing a method to make valid inference for the relationship between exposure and response data that uses only exposure and temporally aggregated response data. We provided the mathematical derivation of the method, and compared the results by using simulations applied to daily temperature and daily, weekly, and monthly mortality data. The method was then applied to the newly created database of the EARLY-ADAPT project. The daily and weekly models produced similar and unbiased estimates of the temperature-related relative risks and attributable mortality, with only slightly more imprecision in the weekly model. Even the estimates of the monthly model were unbiased when using enough data, although at the expense of a substantial increase in variability. The real data analysis showed that the similarity between the regional values of two aggregation models increased with the number of years and regions of the dataset, and decreased with the difference in their degree of temporal aggregation. Our method opens the door to conducting epidemiological studies in low-resource settings, where access to daily health data is not possible. Moreover, it allows accurate estimation of the short-term health effects of environmental exposures in near-real time, when daily health data are still not available, such as in the estimation of the mortality burden of recent record-breaking heat episodes. Overall, our method represents an important new approach to how the public health community can use data to create new evidence for research, translation and policy making. European Research Council (ERC).

Health care contact days in older adults enrolled in SWOG cancer clinical trials.

64 Background: Health care contact days—days with health care contact outside the home—are a measure of how much of a patient’s life is consumed by health care. This number of contact days are especially relevant for older adults with advanced cancer facing limited survival. One concern is that patients with different sociodemographic and clinical backgrounds may be at particular risk of increased contact days. Thus, there is a critical need to understand factors associated with contact days. Methods: We linked data from 6 SWOG trials in advanced cancer to Medicare claims data. These trials encompassed a variety of primary cancer types [prostate (S9916, S0421), lung (S0003, S0124, S0819), and pancreas (S0205)]. Health care contact days (days with ambulatory, emergency department, inpatient, or facility-based care) in the first 12 months were calculated using Medicare database files. A day with >1 source of contact counted as 1. We examined sociodemographic (age, race, ethnicity, sex, insurance status, rurality, area deprivation index) and clinical (prognostic risk, cancer type, performance status) predictors of contact days, using negative binomial regression, with a log link and clustering by study ID, including an offset variable for duration of observation. We examined predictors in univariate and multivariable analysis. We report relative risk (RRs) estimates and 95% CI. Results: We included 1,429 patients (median age, 71 years, 7.6% Black, 2.7% Hispanic, 21.4% female, and 23.5% rural residence). Of these, 741 (51.9%) patients died in the first year. The median number of contact days was 48, out of a median of 350 days of observation. At a trial level, median percentage of contact days ranged from 14% (prostate) to 27% (lung). The most common sources of contact days were ambulatory clinician visits (median=17), tests (median=12), and treatments (median=11). In multivariable regression, factors associated with increased contact days included increasing age (per year, RR=1.02 [1.01-1.02], p<.001), insurance status (Medicare alone or with Private or Medicaid insurance, vs Military/VA, none, or other insurance, RR=2.47 [2.16-2.83], p<.001), higher prognostic risk score (RR=1.14 [1.04-1.25], p=.004), and type of cancer (pancreas, RR=1.69 [1.51-1.89] and lung, RR=1.69 [1.54-1.85] vs prostate, p<.001 for both). Conclusions: This novel linkage of trial and claims data to evaluate contact days and associated factors found that older trial participants spent up to one in four days with health care contact. Ambulatory appointments were the most common source of contact days. Encouragingly, rural residence and neighborhood deprivation were not associated with contact days, increasing confidence that participants from diverse geographic areas may receive equitable care in trials. These data highlight the frequency of contact days for trial participants, while identifying factors to consider when benchmarking contact days.

Abstract IA004: Risk of therapy-related subsequent cancers in individuals with germline TP53 variants

Abstract Background. Based primarily on in vitro and animal studies, germline TP53 variants are considered to confer sensitivity to ionizing radiation-induced DNA damage, but data in humans are sparse. We sought to quantify risk of developing radiotherapy and chemotherapy-related subsequent neoplasms by pooling individual-level data from nine cohorts of individuals with confirmed pathogenic/likely pathogenic germline TP53 variants. Methods. 891 individuals were followed from six months after first cancer until diagnosis of a subsequent neoplasm, death or date of last follow-up. Radiotherapy and chemotherapy for each cancer were considered as time-dependent covariates in Cox regression models with age as the time-scale, adjusted for sex and occurrence of prior malignant or benign tumors. Subsequent cancers were classified as in- or out-of-field based on the body region of previous cancers. Results. Among 891 individuals, 643 (72.2%) were female and 297 (33.3%) were diagnosed with a first cancer before age 20 years. Breast cancer was the most commonly diagnosed first cancer (N=371), followed by soft tissue sarcoma (N=131) and central nervous system cancers (N=84). First cancer treatment included radiotherapy for 237 (26.6%) and/or chemotherapy for 421 (47.3%) individuals. Analyses are underway to define the characteristics of subsequent neoplasms (including age at diagnosis, latency, and distribution of diagnosis type) and to calculate relative and absolute risk estimates for radiotherapy and chemotherapy overall and by subsequent neoplasm type. Conclusions. This study will quantify the contribution of radiotherapy and chemotherapy to the risk of subsequent cancers among individuals with Li-Fraumeni syndrome. Understanding the magnitude of this risk will support health care providers and patients in making informed decisions about cancer management. Citation Format: Anita Villani, Payal Khincha, Jessica Hatton, Sara Schonfeld, Catherine Goudie, Leatrisse Oba, Kishan Pithadia, Birte Sänger, Christian Kratz, Anh N. Le, Caitlin Orr, Kara N. Maxwell, Anne Naumer, Jennie Vagher, Wendy Kohlmann, Joshua Schiffman, Elizabeth Santana dos Santos, Orli Michaeli, Jacob J. Carson, Derek S. Tsang, Raymond Kim, Jamie L. Maciaszek, Kim E. Nichols, Victoria E. Goodman, Suzanne P. MacFarland, Lara Reichman, Maria Isabel Achatz, Sharon Savage, David Malkin, Lindsay M. Morton. Risk of therapy-related subsequent cancers in individuals with germline TP53 variants [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA004.

Cancer incidence in a cohort of Danish firefighters: An extended long-term follow-up 1968-2021.

To update and extend the examination of cancer incidence in a cohort of Danish firefighters, now adding 7 years of follow-up and 2766 additional firefighters. The primary focus was directed toward cancer sites that recently contributed to the hazard evaluation conducted by the International Agency for Research on Cancer (IARC). The updated cohort consisted of 11,827 male Danish firefighters who were followed up for cancer from 1968 to 2021. Cohort cancer morbidity was compared with a working population reference group, and standardized incidence ratios (SIR) were used for estimation of relative risks, along with 95% confidence intervals (95% CI). Among full-time firefighters, SIR of skin melanoma was 1.30 (95% CI: 1.02-1.66), and SIR = 1.37 (95% CI: 1.02-1.85) for over 5 years of employment. Slightly positive associations were also observed for cancer of the urinary bladder (SIR = 1.16; 95% CI: 0.93-1.45), prostate (SIR = 1.11; 95% CI: 0.97-1.28), and testis (SIR = 1.11; 95% CI: 0.75-1.63). This updated study provides evidence indicating an elevated risk of skin melanoma in firefighters. Consistent with IARC's evaluation, we also identified positive associations for urinary bladder, prostate, and testis cancer. In contrast, our findings did not suggest an increased risk of colon cancer, non-Hodgkin lymphoma, and mesothelioma. The latter may be due to small numbers in our still relatively young cohort. Continuous follow-up for cancer in firefighters is warranted, including assessment of influence from surveillance bias.

Structure Induced by a Multiple Membership Transformation on the Conditional Autoregressive Model

The objective of disease mapping is to model data aggregated at the areal level. In some contexts, however, (e.g. residential histories, general practitioner catchment areas) when data is arising from a variety of sources, not necessarily at the same spatial scale, it is possible to specify spatial random effects, or covariate effects, at the areal level, by using a multiple membership principle (MM) (Petrof et al., 2020; Gramatica et al., 2021). A weighted average of conditional autoregressive (CAR) spatial random effects embeds spatial information for a spatially-misaligned outcome and estimate relative risk for both frameworks (areas and memberships). In this paper we investigate the theoretical underpinnings of these application of the multiple membership principle to the CAR prior, in particular with regard to parameterisation, properness and identifiability. We carry out simulations involving different numbers of memberships as compared to number of areas and assess impact of this on estimating parameters of interest. Both analytical and simulation study results show under which conditions parameters of interest are identifiable, so that we can offer actionable recommendations to researchers. Finally, we present the results of an application of the multiple membership model to diabetes prevalence data in South London, together with strategic implications for public health considerations.

Risk of stroke in male and female patients with atrial fibrillation in a nationwide cohort

Female sex has been suggested as a risk modifier for stroke in patients with atrial fibrillation (AF) with comorbid prevalent stroke risk factors. Management has evolved over time towards a holistic approach that may have diminished any sex difference in AF-related stroke. In a nationwide cohort of AF patients free from oral anticoagulant treatment, we examine the time trends in stroke risk overall and in relation to risk differences between male and female patients. Here we show that among 158,982 patients with AF (median age 78 years (IQR: 71 to 85); 52% female) the 1-year thromboembolic risk was highest between 1997–2000 with a risk of 5.6% and lowest between 2013–2016 with a risk of 3.8%, declining over the last two decades. The excess stroke risk for female vs male patients has also been declining, with risk-score adjusted relative risk estimates suggesting limited sex-difference in recent years.

Early Symptom Patterns by Tumor Laterality, Age at Onset, Stage, and Symptom-to-Treatment Initiation in Patients with Colorectal Cancer.

In Indonesia incidence of colorectal cancer (CRC) remains high. Information about early symptoms that can offer clinicians insights for timely diagnosis, prompt referral and quick treatment decisions is very limited. This study aims to examine the pattern of CRC early symptoms and its association with tumor laterality, age at onset, metastatic status, and symptom-to-treatment initiation (STI) duration and delay. This cross-sectional study recruits 258 patients diagnosed with CRC between November 2022 and October 2023 from two distinct study databases. Patient baseline characteristics were also obtained from medical records and through interviews at baseline. Symptom-to-treatment initiation (STI) duration was defined as the number of days between the date of the symptom's onset and the date of the first treatment's initiation. Relative risk estimation for metastatic disease and the STI delay, based on tumor laterality and the age at onset group, were estimated using a log-binomial regression for each early symptom. Experiencing abdominal mass as an early symptom is significantly associated with metastatic disease, specifically in right-sided CRC cases (relative risk/RR=2.08, 95% confidence interval/CI 1.29-3.37, p=0.003). In all study subjects, the median STI duration was 182 days (2-5,082 days), with more than half of the subjects experiencing an STI delay of >180 days. Experiencing rectal mass as an early symptom is significantly associated with a higher risk of STI delay >180 days in early onset CRC (RR=1.97, 95% CI 1.27-3.06, p=0.003) and left sided-CRC cases (RR=1.54, 95% CI 1.13-2.08, p=0.005). The non-specific early symptom of weight loss is associated with a higher risk of STI delay >180 days in right-sided CRC cases (RR=1.73, 95% CI 1.06-2.84, p=0.029). The findings underlined the importance of maintaining a high clinical suspicion, particularly in patients with rectal masses and unexplained weight loss, as they might experience STI delay.

Biopsy-verified vulvar lichen sclerosus and the risk of non-vulvar cancer: A nationwide cohort study.

Vulvar lichen sclerosus (VLS) is a chronic inflammatory mucocutaneous disease known to be associated with human papillomavirus-independent vulvar squamous cell carcinoma. Evidence on the association with other types of cancer, however, is sparce. We conducted a large nationwide cohort study examining the incidence of non-vulvar cancers among women with biopsy-verified VLS compared with the general female population. By using the nationwide Pathology Registry, we identified all women in Denmark with a biopsy-verified VLS diagnosis during 1978-2019 (n = 16,921). The cohort was followed up in the Danish Cancer Registry until 2022 for a subsequent non-vulvar cancer diagnosis. Standardized incidence ratios (SIRs) were computed with 95% confidence intervals (CIs) as relative risk estimates of all specific non-vulvar cancer sites. Compared with general female population rates, women with biopsy-verified VLS had decreased rates of several non-vulvar cancers, including HPV-related cancers (combined estimate: SIR = 0.5; 95% CI: 0.3-0.7), and lung (SIR = 0.6; 95% CI: 0.5-0.7), liver (SIR = 0.5; 95% CI: 0.2-0.9), and thyroid cancer (SIR = 0.5; 95% CI: 0.3-0.9). The decreased SIRs tended to sustain throughout the follow-up period following the VLS diagnosis. This large nationwide cohort study shows that women with biopsy-verified VLS may have a long-term reduced risk of developing HPV-related (cervical, vaginal, oropharyngeal, and anal) and smoking-associated cancers (lung, liver, and cervical) as well as thyroid cancer. Future studies focusing on the mechanisms behind the decreased cancer risk are needed.

Why Do Only Some Cohort Studies Find Health Benefits From Low-Volume Alcohol Use? A Systematic Review and Meta-Analysis of Study Characteristics That May Bias Mortality Risk Estimates.

Assumptions about alcohol's health benefits profoundly influence global disease burden estimates and drinking guidelines. Using theory and evidence, we identify and test study characteristics that may bias estimates of all-cause mortality risk associated with low-volume drinking. We identified 107 longitudinal studies by systematic review with 724 estimates of the association between alcohol consumption and all-cause mortality for 4,838,825 participants with 425,564 recorded deaths. "Higher-quality" studies had a mean cohort age of 55 years or younger, followed up beyond 55 years, and excluded former and occasional drinkers from abstainer reference groups. "Low-volume" alcohol use was defined as between one drink per week (>1.30 g ethanol/day) and two drinks per day (<25 g ethanol/ day). Mixed linear regression was used to model relative risks (RRs) of mortality for subgroups of higher- versus lower-quality studies. As predicted, studies with younger cohorts and separating former and occasional drinkers from abstainers estimated similar mortality risk for low-volume drinkers (RR = 0.98, 95% CI [0.87, 1.11]) as abstainers. Studies not meeting these quality criteria estimated significantly lower risk for low-volume drinkers (RR = 0.84, [0.79, 0.89]). In exploratory analyses, studies controlling for smoking and/or socioeconomic status had significantly reduced mortality risks for low-volume drinkers. However, mean RR estimates for low-volume drinkers in nonsmoking cohorts were above 1.0 (RR = 1.16, [0.91, 1.41]). Studies with lifetime selection biases may create misleading positive health associations. These biases pervade the field of alcohol epidemiology and can confuse communications about health risks. Future research should investigate whether smoking status mediates, moderates, or confounds alcohol-mortality risk relationships.

Estimating the Effect of Radical Prostatectomy: Combining Data From the SPCG4 and PIVOT Randomized Trials With Contemporary Cohorts.

Two randomized trials (SPCG4 and PIVOT) have compared surgery to conservative management for localized prostate cancer. The applicability of these trials to contemporary practice remains uncertain. We aimed to develop an individualized prediction model for prostate cancer mortality comparing immediate surgery at a high-volume center to active surveillance. We determined whether the relative risk of prostate cancer mortality with surgery vs observation varied by baseline risk. We then used various estimates of relative risk to estimate 15-year mortality with and without surgery using, as a predictor, risk of biochemical recurrence calculated from a model. We saw no evidence that relative risk varied by baseline risk, supporting the use of a constant relative risk. Compared with observation, surgery was associated with negligible benefit for patients with Grade Group (GG) 1 disease (0.2% mortality reduction at 15 years) and small benefit for patients with GG2 with lower PSA and stage (≤5% mortality reduction). Benefit was greater (6%-9%) for patients with GG3 or GG4 though still modest, but effect estimates varied widely depending on choice of hazard ratio for surgery (6%-36% absolute risk reduction). Surgery should be avoided for men with low-risk (GG1) prostate cancer and for many men with GG2 disease. Surgical benefits are greater in men with higher-risk disease. Integration of findings with a life expectancy model will allow patients to make informed treatment decisions given their oncologic risk, risk of death from other causes, and estimated effects of surgery.

Analysis of the direct economic impact of smoking-related hospitalizations in Italy.

Tobacco-related diseases have a substantial economic impact in terms of medical expenses, loss of productivity, and premature death. Tobacco use is estimated to be responsible for more than 90000 deaths each year in Italy. We aimed to evaluate the annual direct economic impact on the National Health System of hospitalizations attributable to tobacco smoking in Italy. We analyzed data from all the hospitalizations of patients aged ≥30 years that occurred in Italy for 12 selected tobacco-related diseases, during 2018. These diseases included oropharyngeal cancer, esophageal cancer, gastric cancer, lung cancer, pancreatic cancer, bladder cancer, laryngeal cancer, ischemic heart disease, stroke, diseases of arteries, arterioles, and capillaries, pneumonia and influenza, and chronic obstructive pulmonary disease. We obtained information on 984322 hospital discharge records, including each hospitalization's direct costs. Using relative risk estimates from the scientific literature, we computed the population attributable fraction for various tobacco-related diseases to estimate the economic impact attributable to tobacco smoking. One-third of all hospitalizations occurred in 2018 in Italy among people aged ≥30 years for 12 tobacco-related diseases were found to be attributable to smoking, accounting for a total cost of €1.64 billion. Among the diseases considered, those with the highest expenditures attributable to tobacco smoking were ischemic heart disease, cerebrovascular disease, and lung cancer, accounting for €556 million, €290 million, and €229 million, respectively. Tobacco has a substantial economic impact in Italy, accounting for around 6% of the total cost of hospitalizations in 2018. This figure is expected to be largely underestimated due to several conservative assumptions adopted in the statistical analyses. It is imperative to prioritize comprehensive tobacco control measures to counteract the huge healthcare costs due to tobacco smoking.

Population attributable fraction of reproductive factors in triple negative breast cancer by race.

10522 Background: Age-adjusted incidence rates of triple negative breast cancer (TNBC) are higher in African American (AA) women than in non-Hispanic White (White) women. The disproportionate incidence of TNBC in AA women partially drives the 40% higher mortality rate from breast cancer in AA women compared to White women. Several studies have identified lack of breastfeeding and younger age at first birth as risk factors for TNBC. There are large differences in breastfeeding uptake and duration in the US: only 44% of AA women breastfeed for 6 months or longer, compared to 60% of White women. To quantify the contribution of differences in breastfeeding patterns and younger age at first birth to disparities in incidence of TNBC, we calculate the population-attributable fraction (PAF), which is the proportion of the incidence of a disease that may be attributable to a particular exposure. Methods: A systematic review was performed to identify relevant case-control studies. Pooled odds ratios (ORs) for breastfeeding for &lt; 6 months and age at first birth &lt; 25 years were calculated from data extracted from studies using a common effect model. PAF was calculated using the Levin formula. Risk factor population prevalences were extracted from national surveys. Pooled ORs were used as estimates of relative risk (RR). A combined PAF was calculated using the polychoric correlation coefficient between breastfeeding duration and age at first birth to account for contributions of multiple risk factors. Results: Using race specific ORs, the PAF of breastfeeding for &lt; 6 months was 12% (95% confidence interval (CI) 5-20%) among White women and 15% (95% CI 3-26%) among AA women. The PAF of having a child before age 25 was not significantly different from zero for White women (2% (CI -6-11%)) but was significantly different from zero for AA women (21% (CI 5-25%)). The combined PAF was 27% for AA women and 17% for all women in the US. Extrapolating to the US population, we estimated that 4,850 annual cases of TNBC (2,421 among White women and 1,533 among AA women) could be attributed to breastfeeding for &lt; 6 months and age at first birth &lt; 25 years. Conclusions: Given the protective role of breastfeeding against TNBC, policy changes aimed at supporting breastfeeding, addressing structural barriers, and promoting a culture shift could reduce racial disparities in TNBC incidence in the US. [Table: see text]