Mediators of Black-White inequities in cardiovascular mortality among survivors of 18 cancers in the USA.

BACKGROUND: This study aims to quantify Black-White inequities in cardiovascular disease (CVD) mortality among US survivors of 18 adult-onset cancers and the extent to which these inequities are explained by differences in socio-economic and clinical factors. METHODS: Survivors of cancers diagnosed at ages 20-64 years during 2007-16 were identified from 17 Surveillance, Epidemiology and End Results registries. Associations between race and CVD mortality were examined using proportional hazards models. Mediation analyses were performed to quantify the contributions of potential mediators, including socio-economic [health insurance, neighbourhood socio-economic status (nSES), rurality] and clinical (stage, surgery, chemotherapy, radiotherapy) factors. RESULTS: Among 904 995 survivors, 10 701 CVD deaths occurred (median follow-up, 43 months). Black survivors were more likely than White survivors to die from CVD for all 18 cancers with hazard ratios ranging from 1.30 (95% CI = 1.15-1.47) for lung cancer to 4.04 for brain cancer (95% CI = 2.79-5.83). The total percentage mediations (indirect effects) ranged from 24.8% for brain (95% CI=-5.2-59.6%) to 99.8% for lung (95% CI = 61.0-167%) cancers. Neighbourhood SES was identified as the strongest mediator for 14 cancers with percentage mediations varying from 25.0% for kidney cancer (95% CI = 14.1-36.3%) to 63.5% for lung cancer (95% CI = 36.5-108.7%). Insurance ranked second for 12 cancers with percentage mediations ranging from 12.3% for leukaemia (95% CI = 0.7-46.7%) to 31.3% for thyroid cancer (95% CI = 10.4-82.7%). CONCLUSIONS: Insurance and nSES explained substantial proportions of the excess CVD mortality among Black survivors. Mitigating the effects of unequal access to care and differing opportunities for healthy living among neighbourhoods could substantially reduce racial inequities in CVD mortality among cancer survivors.

Nurse Care Management for Opioid Use Disorder Treatment: The PROUD Cluster Randomized Clinical Trial.

Importance: Few primary care (PC) practices treat patients with medications for opioid use disorder (OUD) despite availability of effective treatments. Objective: To assess whether implementation of the Massachusetts model of nurse care management for OUD in PC increases OUD treatment with buprenorphine or extended-release injectable naltrexone and secondarily decreases acute care utilization. Design, Setting, and Participants: The Primary Care Opioid Use Disorders Treatment (PROUD) trial was a mixed-methods, implementation-effectiveness cluster randomized clinical trial conducted in 6 diverse health systems across 5 US states (New York, Florida, Michigan, Texas, and Washington). Two PC clinics in each system were randomized to intervention or usual care (UC) stratified by system (5 systems were notified on February 28, 2018, and 1 system with delayed data use agreement on August 31, 2018). Data were obtained from electronic health records and insurance claims. An implementation monitoring team collected qualitative data. Primary care patients were included if they were 16 to 90 years old and visited a participating clinic from up to 3 years before a system's randomization date through 2 years after. Intervention: The PROUD intervention included 3 components: (1) salary for a full-time OUD nurse care manager; (2) training and technical assistance for nurse care managers; and (3) 3 or more PC clinicians agreeing to prescribe buprenorphine. Main Outcomes and Measures: The primary outcome was a clinic-level measure of patient-years of OUD treatment (buprenorphine or extended-release injectable naltrexone) per 10 000 PC patients during the 2 years postrandomization (follow-up). The secondary outcome, among patients with OUD prerandomization, was a patient-level measure of the number of days of acute care utilization during follow-up. Results: During the baseline period, a total of 130 623 patients were seen in intervention clinics (mean [SD] age, 48.6 [17.7] years; 59.7% female), and 159 459 patients were seen in UC clinics (mean [SD] age, 47.2 [17.5] years; 63.0% female). Intervention clinics provided 8.2 (95% CI, 5.4-∞) more patient-years of OUD treatment per 10 000 PC patients compared with UC clinics (P = .002). Most of the benefit accrued in 2 health systems and in patients new to clinics (5.8 [95% CI, 1.3-∞] more patient-years) or newly treated for OUD postrandomization (8.3 [95% CI, 4.3-∞] more patient-years). Qualitative data indicated that keys to successful implementation included broad commitment to treat OUD in PC from system leaders and PC teams, full financial coverage for OUD treatment, and straightforward pathways for patients to access nurse care managers. Acute care utilization did not differ between intervention and UC clinics (relative rate, 1.16; 95% CI, 0.47-2.92; P = .70). Conclusions and Relevance: The PROUD cluster randomized clinical trial intervention meaningfully increased PC OUD treatment, albeit unevenly across health systems; however, it did not decrease acute care utilization among patients with OUD. Trial Registration: ClinicalTrials.gov Identifier: NCT03407638.

Patient and Provider Factors Associated With Successfully Addressing Medical Needs Using Telehealth: A Cross-Sectional Survey.

Few data exist that highlight areas where telemedicine shines or struggles from the patient perspective. We conducted a retrospective analysis of patient experience data from 19,465 visits using a logistic regression to model the odds a virtual visit addressed a patient's medical needs. Patient age (80 years: OR 0.58; 95% CI, 0.50-0.67 vs 40-64 years), race (Black: 0.68; 95% CI, 0.60-0.76 vs White), and connection (telephone conversion: OR 0.59; 95% CI, 0.53-0.66 vs video success) were associated with a lower likelihood of addressing medical needs; results varied modestly across specialties. These data suggest that while telehealth is generally well accepted by patients, differences are seen among patient factors and specialty.

Twenty-first century house calls: a survey of ambulatory care providers to inform organisational telehealth strategy.

OBJECTIVES: While patient interest in telehealth increases, clinicians' perspectives may influence longer-term adoption. We sought to identify facilitators and barriers to continued clinician incorporation of telehealth into practice. METHODS: A cross-sectional 24-item web-based survey was emailed to 491 providers with ≥50 video visits (VVs) within an academic health system between 1 March 2020 and 31 December 2020. We quantitatively summarised the characteristics and perceptions of respondents by using descriptive and test statistics. We used systematic content analysis to qualitatively code open-ended responses, double coding at least 25%. RESULTS: 247 providers (50.3%) responded to the survey. Seventy-nine per cent were confident in their ability to deliver excellent clinical care through VV. In comparison, 48% were confident in their ability to troubleshoot technical issues. Most clinicians (87%) expressed various concerns about VV. Providers across specialties generally agreed that VV reduced infection risk (71%) and transportation barriers (71%). Three overarching themes in the qualitative data included infrastructure and training, usefulness and expectation setting for patients and providers. DISCUSSION: As healthcare systems plan for future delivery directions, they must address the tension between patients' and providers' expectations of care within the digital space. Telehealth creates new friction, one where the healthcare system must fit into the patient's life rather than the usual dynamic of the patient fitting into the healthcare system. CONCLUSION: Telehealth infrastructure and patient and clinician technological acumen continue to evolve. Clinicians in this survey offered valuable insights into the directions healthcare organisations can take to right-size this healthcare delivery modality.

Sex disparities in the incidence of 21 cancer types: Quantification of the contribution of risk factors.

BACKGROUND: Cancer incidence is higher in men than in women at most shared anatomic sites for currently unknown reasons. The authors quantified the extent to which behaviors (smoking and alcohol use), anthropometrics (body mass index and height), lifestyles (physical activity, diet, medications), and medical history collectively explain the male predominance of risk at 21 shared cancer sites. METHODS: Prospective cohort analyses (n = 171,274 male and n = 122,826 female participants; age range, 50-71 years) in the National Institutes of Health-AARP Diet and Health Study (1995-2011). Cancer-specific Cox regression models were used to estimate male-to-female hazard ratios (HRs). The degree to which risk factors explained the observed male-female risk disparity was quantified using the Peters-Belson method. RESULTS: There were 26,693 incident cancers (17,951 in men and 8742 in women). Incidence was significantly lower in men than in women only for thyroid and gallbladder cancers. At most other anatomic sites, the risks were higher in men than in women (adjusted HR range, 1.3-10.8), with the strongest increases for bladder cancer (HR, 3.33; 95% confidence interval [CI], 2.93-3.79), gastric cardia cancer (HR, 3.49; 95% CI, 2.26-5.37), larynx cancer (HR, 3.53; 95% CI, 2.46-5.06), and esophageal adenocarcinoma (HR, 10.80; 95% CI, 7.33-15.90). Risk factors explained a statistically significant (nonzero) proportion of the observed male excess for esophageal adenocarcinoma and cancers of liver, other biliary tract, bladder, skin, colon, rectum, and lung. However, only a modest proportion of the male excess was explained by risk factors (ranging from 50% for lung cancer to 11% for esophageal adenocarcinoma). CONCLUSIONS: Men have a higher risk of cancer than women at most shared anatomic sites. Such male predominance is largely unexplained by risk factors, underscoring a role for sex-related biologic factors.

Subsequent Primary Cancer Risk Among 5-Year Survivors of Adolescent and Young Adult Cancers.

BACKGROUND: A comprehensive examination of the incidence and mortality of subsequent primary cancers (SPCs) among adolescent and young adult (AYA) cancer survivors in the United States is lacking. METHODS: Cancer incidence and mortality among 170 404 cancer survivors of 5 or more years who were aged 15-39 years at first primary cancer diagnosis during 1975-2013 in 9 Surveillance, Epidemiology, and End Results registries were compared with those in the general population using standardized incidence ratio (SIR), absolute excess incidence (AEI), standardized mortality ratio (SMR), and absolute excess mortality (AEM). RESULTS: During a mean follow-up of 14.6 years, 13 420 SPC cases and 5008 SPC deaths occurred among survivors (excluding the same site as index cancer), corresponding to 25% higher incidence (95% confidence interval [CI] = 1.23 to 1.27, AEI = 10.8 per 10 000) and 84% higher mortality (95% CI = 1.79 to 1.89, AEM = 9.2 per 10 000) than that in the general population. Overall, SPC risk was statistically significantly higher for 20 of 29 index cancers for incidence and 26 for mortality, with the highest SIR among female Hodgkin lymphoma survivors (SIR = 3.05, 95% CI = 2.88 to 3.24, AEI = 73.0 per 10 000) and the highest SMR among small intestine cancer survivors (SMR = 6.97, 95% CI = 4.80 to 9.79, AEM = 64.1 per 10 000). Type-specific SPC risks varied substantially by index cancers; however, SPCs of the female breast, lung, and colorectum combined constituted 36% of all SPC cases and 39% of all SPC deaths, with lung cancer alone representing 11% and 24% of all cases and deaths, respectively. CONCLUSION: AYA cancer survivors are almost twice as likely to die from a new primary cancer as the general population, highlighting the need for primary care clinicians to prioritize cancer prevention and targeted surveillance strategies in these individuals.

Contribution of Etiologic Cofactors to CIN3+ Risk Among Women With Human Papillomavirus-Positive Screening Test Results.

OBJECTIVE: The US screening and management guidelines for cervical cancer are based on the absolute risk of precancer estimated from large clinical cohorts and trials. Given the widespread transition toward screening with human papillomavirus (HPV) testing, it is important to assess which additional factors to include in clinical risk assessment to optimize management of HPV-infected women. MATERIALS AND METHODS: We analyzed data from HPV-infected women, ages 30-65 years, in the National Cancer Institute-Kaiser Permanente Northern California Persistence and Progression study. We estimated the influence of HPV risk group, cytology result, and selected cofactors on immediate risk of cervical intraepithelial neoplasia grade 3 or higher (CIN 3+) among 16,094 HPV-positive women. Cofactors considered included, age, race/ethnicity, income, smoking, and hormonal contraceptive use. RESULTS: Human papillomavirus risk group and cytology test result were strongly correlated with CIN 3+ risk. After considering cytology and HPV risk group, other cofactors (age, race/ethnicity, income, smoking, and hormonal contraceptive use) had minimal impact on CIN 3+ risk and did not change recommended management based on accepted risk thresholds. We had insufficient data to assess the impact of long-duration heavy smoking, parity, history of sexually transmitted infection, or immunosuppression. CONCLUSIONS: In our study at the Kaiser Permanente Northern California, the risk of CIN 3+ was determined mainly by HPV risk group and cytology results, with other cofactors having limited impact in adjusted analyses. This supports the use of HPV and cytology results in risk-based management guidelines.

Association of State Medicaid Income Eligibility Limits and Long-Term Survival After Cancer Diagnosis in the United States.

PURPOSE: To examine the association between historic state Medicaid income eligibility limits and long-term survival among patients with cancer. METHODS: 1,449,144 adults age 18-64 years newly diagnosed with 19 common cancers between 2010 and 2013 were identified from the National Cancer Database. States' Medicaid income eligibility limits were categorized as ≤ 50%, 51%-137%, and ≥ 138% of federal poverty level (FPL). Survival time was measured from diagnosis date through December 31, 2017, for up to an 8-year follow-up. Multivariable Cox proportional hazards models with age as time scale were used to assess associations of eligibility limits and stage-specific survival, adjusting for the effects of sex, metropolitan statistical area, comorbidities, year of diagnosis, facility type and volume, and state. RESULTS: Among patients with newly diagnosed cancer age 18-64 years, patients living in states with lower Medicaid income eligibility limits had worse survival for most cancers in both early and late stages, compared with those living in states with Medicaid income eligibility limits ≥ 138% FPL. A dose-response relationship was observed for most cancers with lower income limits associated with worse survival (13 of 17 cancers evaluated for early-stage cancers, and 11 of 17 cancers evaluated for late-stage cancers, and leukemia and brain tumors with P-trend < .05). CONCLUSION: Lower Medicaid income eligibility limits were associated with worse long-term survival within stage; increasing Medicaid income eligibility may improve survival after cancer diagnosis.

Approaches to Assessing and Adjusting for Selective Outcome Reporting in Meta-analysis.

BACKGROUND: Selective or non-reporting of study outcomes results in outcome reporting bias. OBJECTIVE: We sought to develop and assess tools for detecting and adjusting for outcome reporting bias. DESIGN: Using data from a previously published systematic review, we abstracted whether outcomes were reported as collected, whether outcomes were statistically significant, and whether statistically significant outcomes were more likely to be reported. We proposed and tested a model to adjust for unreported outcomes and compared our model to three other methods (Copas, Frosi, trim and fill). Our approach assumes that unreported outcomes had a null intervention effect with variance imputed based on the published outcomes. We further compared our approach to these models using simulation, and by varying levels of missing data and study sizes. RESULTS: There were 286 outcomes reported as collected from 47 included trials: 142 (48%) had the data provided and 144 (52%) did not. Reported outcomes were more likely to be statistically significant than those collected but for which data were unreported and for which non-significance was reported (RR, 2.4; 95% CI, 1.9 to 3.0). Our model and the Copas model provided similar decreases in the pooled effect sizes in both the meta-analytic data and simulation studies. The Frosi and trim and fill methods performed poorly. LIMITATIONS: Single intervention of a single disease with only randomized controlled trials; approach may overestimate outcome reporting bias impact. CONCLUSION: There was evidence of selective outcome reporting. Statistically significant outcomes were more likely to be published than non-significant ones. Our simple approach provided a quick estimate of the impact of unreported outcomes on the estimated effect. This approach could be used as a quick assessment of the potential impact of unreported outcomes.

A semiparametric Gumbel regression model for analyzing longitudinal data with non-normal tails.

Abnormal longitudinal values in biomarkers can be a sign of abnormal status or signal development of a disease. Identifying new biomarkers for early and efficient disease detection is crucial for disease prevention. Compared to the majority of the healthy general population, abnormal values are located within the tails of the biomarker distribution. Thus, parametric regression models that accommodate abnormal values in biomarkers can better detect the association between biomarkers and disease. In this article, we propose semiparametric Gumbel regression models for (1) longitudinal continuous biomarker outcomes, (2) flexibly modeling the time-effect on the outcome, and (3) accounting for the measurement error in biomarker measurements. We adopted the EM algorithm in combination with a two-dimensional grid search to estimate regression parameters and a function of time-effect. We proposed an efficient asymptotic variance estimator for regression parameter estimates. The proposed estimator is asymptotically unbiased in both theory and simulation studies. We applied the proposed model and two other models to investigate associations between fasting blood glucose biomarkers and potential risk factors from a diabetes ancillary study to the Atherosclerosis Risk in Communities (ARIC) study. The real data application was illustrated by fitting the proposed regression model and graphically evaluating the goodness-of-fit value.

Analysis of Clinician and Patient Factors and Completion of Telemedicine Appointments Using Video.

Importance: Telemedicine provides patients access to episodic and longitudinal care. Policy discussions surrounding future support for telemedicine require an understanding of factors associated with successful video visits. Objective: To assess patient and clinician factors associated with successful and with failed video visits. Design, Setting, and Participants: This was a quality improvement study of 137 846 scheduled video visits at a single academic health system in southeastern Wisconsin between March 1 and December 31, 2020, supplemented with patient experience survey data. Patient information was gathered using demographic information abstracted from the electronic health record and linked with block-level socioeconomic data from the US Census Bureau. Data on perceived clinician experience with technology was obtained using the survey. Main Outcomes and Measures: The primary outcome of interest was the successful completion of a scheduled video visit or the conversion of the video visit to a telephone-based service. Visit types and administrative data were used to categorize visits. Mixed-effects modeling with pseudo R2 values was performed to compare the relative associations of patient and clinician factors with video visit failures. Results: In total, 75 947 patients and 1155 clinicians participated in 137 846 scheduled video encounters, 17 190 patients (23%) were 65 years or older, and 61 223 (81%) patients were of White race and ethnicity. Of the scheduled video encounters, 123 473 (90%) were successful, and 14 373 (10%) were converted to telephone services. A total of 16 776 patients (22%) completed a patient experience survey. Lower clinician comfort with technology (odds ratio [OR], 0.15; 95% CI, 0.08-0.28), advanced patient age (66-80 years: OR, 0.28; 95% CI, 0.26-0.30), lower patient socioeconomic status (including low high-speed internet availability) (OR, 0.85; 95% CI, 0.77-0.92), and patient racial and ethnic minority group status (Black or African American: OR, 0.75; 95% CI, 0.69-0.81) were associated with conversion to telephone visits. Patient characteristics accounted for systematic components for success; marginal pseudo R2 values decreased from 23% (95% CI, 21.1%-26.1%) to 7.8% (95% CI, 6.3%-9.4%) with exclusion of patient factors. Conclusions and Relevance: As policy makers consider expanding telehealth coverage and hospital systems focus on investments, consideration of patient support, equity, and friction should guide decisions. In particular, this quality improvement study suggests that underserved patients may become disproportionately vulnerable by cuts in coverage for telephone-based services.

Risks of subsequent primary cancers among breast cancer survivors according to hormone receptor status.

BACKGROUND: This study was aimed at examining the risks of subsequent primary cancers (SPCs) among breast cancer survivors by hormone receptor (HR) status and age at diagnosis. METHODS: Data from 12 Surveillance, Epidemiology, and End Results registries were used to identify 431,222 breast cancer survivors (at least 1 year) diagnosed between the ages of 20 and 84 years from 1992 to 2015. Risks of SPCs were measured as the standardized incidence ratio (SIR) and the excess absolute risk (EAR) per 10,000 person-years. Poisson regression was used to test the difference in SIRs by HR status. RESULTS: In comparison with the general population, the risk of new cancer diagnoses among survivors was 20% higher for those with HR-positive cancers (SIR, 1.20; 95% confidence interval [CI], 1.19-1.21; EAR, 23.3/10,000 person-years) and 44% higher for those with HR-negative cancers (SIR, 1.44; 95% CI, 1.41-1.47; EAR, 45.2/10,000 person-years), with the risk difference between HR statuses statistically significant. The higher risk after HR-negative cancer was driven by acute nonlymphocytic leukemia and breast, ovarian, peritoneal, and lung cancers. By age at diagnosis, the total EAR per 10,000 person-years ranged from 15.8 (95% CI, 14.1-17.5; SIR, 1.11) among late-onset (age, 50-84 years) HR-positive survivors to 69.4 (95% CI, 65.1-73.7; SIR, 2.24) among early-onset (age, 20-49 years) HR-negative survivors, with subsequent breast cancer representing 73% to 80% of the total EAR. After breast cancer, the greatest EARs were for ovarian cancer among early-onset HR-negative survivors, lung cancer among early- and late-onset HR-negative survivors, and uterine corpus cancer among late-onset HR-positive survivors. CONCLUSIONS: Risks of SPCs after breast cancer differ substantially by subtype and age. This suggests that more targeted approaches for cancer prevention and early-detection strategies are needed in survivorship care planning.

Association of First Primary Cancer With Risk of Subsequent Primary Cancer Among Survivors of Adult-Onset Cancers in the United States.

Importance: The number of cancer survivors who develop new cancers is projected to increase, but comprehensive data on the risk of subsequent primary cancers (SPCs) among survivors of adult-onset cancers are limited. Objective: To quantify the overall and cancer type-specific risks of SPCs among adult-onset cancer survivors by first primary cancer (FPC) types and sex. Design, Setting, and Participants: A retrospective cohort study from 12 Surveillance, Epidemiology, and End Results registries in the United States, that included 1 537 101 persons aged 20 to 84 years diagnosed with FPCs from 1992-2011 (followed up until December 31, 2017) and who survived at least 5 years. Exposures: First primary cancer. Main Outcomes and Measures: Incidence and mortality of SPCs per 10 000 person-years; standardized incidence ratio (SIR) and standardized mortality ratio (SMR) compared with those expected in the general population. Results: Among 1 537 101 survivors (mean age, 60.4 years; 48.8% women), 156 442 SPC cases and 88 818 SPC deaths occurred during 11 197 890 person-years of follow-up (mean, 7.3 years). Among men, the overall risk of developing any SPCs was statistically significantly higher for 18 of the 30 FPC types, and risk of dying from any SPCs was statistically significantly higher for 27 of 30 FPC types as compared with risks in the general population. Among women, the overall risk of developing any SPCs was statistically significantly higher for 21 of the 31 FPC types, and risk of dying from any SPCs was statistically significantly higher for 28 of 31 FPC types as compared with risks in the general population. The highest overall SIR and SMR were estimated among survivors of laryngeal cancer (SIR, 1.75 [95% CI, 1.68-1.83]; incidence, 373 per 10 000 person-years) and gallbladder cancer (SMR, 3.82 [95% CI, 3.31-4.39]; mortality, 341 per 10 000 person-years) among men, and among survivors of laryngeal cancer (SIR, 2.48 [95% CI, 2.27-2.72]; incidence, 336 per 10 000 person-years; SMR, 4.56 [95% CI, 4.11-5.06]; mortality, 268 per 10 000 person-years) among women. Substantial variation existed in the associations of specific types of FPCs with specific types of SPC risk; however, only a few smoking- or obesity-associated SPCs, such as lung, urinary bladder, oral cavity/pharynx, colorectal, pancreatic, uterine corpus, and liver cancers constituted considerable proportions of the total incidence and mortality, with lung cancer alone accounting for 31% to 33% of mortality from all SPCs. Conclusions and Relevance: Among survivors of adult-onset cancers in the United States, several types of primary cancer were significantly associated with greater risk of developing and dying from an SPC, compared with the general population. Cancers associated with smoking or obesity comprised substantial proportions of overall SPC incidence and mortality among all survivors and highlight the importance of ongoing surveillance and efforts to prevent new cancers among survivors.

BBB07 contributes to, but is not essential for, Borrelia burgdorferi infection in mice.

Borrelia burgdorferi, a causative agent of Lyme disease, encodes a protein BBB07 on the genomic plasmid cp26. BBB07 was identified as a candidate integrin ligand based on the presence of an RGD tripeptide motif, which is present in a number of mammalian ligands for ß1 and ß3 integrins . Previous work demonstrated that BBB07 in recombinant form binds to ß1 integrins and induces inflammatory responses in synovial cells in culture. Several transposon mutants in bbb07 were attenuated in an in vivo screen of the transposon library in mice. We therefore tested individual transposon mutant clones in single-strain infections in mice and found that they were attenuated in terms of ID50 but did not have significantly reduced tissue burdens in mice. Based on data presented here we conclude that BBB07 is not essential for, but does contribute to, B. burgdorferi infectivity in mice.

A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs.

BACKGROUND: HPV testing is replacing cytology for cervical cancer screening because of greater sensitivity and superior reassurance following negative tests for the dozen HPV genotypes that cause cervical cancer. Management of women testing positive is unresolved. The need for identification of individual HPV genotypes for clinical use is debated. Also, it is unclear how long to observe persistent infections when precancer is not initially found. METHODS: In the longitudinal NCI-Kaiser Permanente Northern California Persistence and Progression (PaP) Study, we observed the clinical outcomes (clearance, progression to CIN3+, or persistence without progression) of 11,573 HPV-positive women aged 30-65 yielding 14,158 type-specific infections. FINDINGS: Risks of CIN3+ progression differed substantially by type, with HPV16 conveying uniquely elevated risk (26% of infections with seven-year CIN3+ risk of 22%). The other carcinogenic HPV types fell into 3 distinct seven-year CIN3+ risk groups: HPV18, 45 (13% of infections, risks >5%, with known elevated cancer risk); HPV31, 33, 35, 52, 58 (39%, risks >5%); and HPV39, 51, 56, 59, 68 (23%, risks <5%). In the absence of progression, HPV clearance rates were similar by type, with 80% of infections no longer detected within three years; persistence to seven years without progression was uncommon. The predictive value of abnormal cytology was most evident for prevalent CIN3+, but less evident in follow-up. A woman's age did not modify risk; rather it was the duration of persistence that was important. INTERPRETATION: HPV type and persistence are the major predictors of progression to CIN3+; at a minimum, distinguishing HPV16 is clinically important. Dividing the other HPV types into three risk-groups is worth considering.

Sample-weighted semiparametric estimation of cause-specific cumulative risk and incidence using left- or interval-censored data from electronic health records.

Electronic health records (EHRs) can be a cost-effective data source for forming cohorts and developing risk models in the context of disease screening. However, important issues need to be handled: competing outcomes, left-censoring of prevalent disease, interval-censoring of incident disease, and uncertainty of prevalent disease when accurate disease ascertainment is not conducted at baseline. Furthermore, novel tests that are costly and limited in availability can be conducted on stored biospecimens selected as samples from EHRs by using different sampling fractions. We extend sample-weighted semiparametric marginal mixture models to estimating competing risks. For flexible modeling of relative risks, a general transformation of the subdistribution hazard function and regression parameters is used. We propose a numerical algorithm for nonparametrically calculating the maximum likelihood estimates for subdistribution hazard functions and regression parameters. Methods for calculating the consistent confidence intervals for relative and absolute risk estimates are presented. The proposed algorithm and methods show reliable finite sample performance through simulation studies. We apply our methods to a cohort assembled from EHRs at a health maintenance organization where we estimate cumulative risk of cervical precancer/cancer and incidence of infection-clearance by HPV genotype among human papillomavirus (HPV) positive women. There is no significant difference in 3-year HPV-clearance rates across different HPV types, but 3-year cumulative risk of progression-to-precancer/cancer from HPV-16 is relatively higher than the other HPV genotypes.

Prioritized concordance index for hierarchical survival outcomes.

We propose an extension of Harrell's concordance (C) index to evaluate the prognostic utility of biomarkers for diseases with multiple measurable outcomes that can be prioritized. Our prioritized concordance index measures the probability that, given a random subject pair, the subject with the worst disease status as of a time τ has the higher predicted risk. Our prioritized concordance index uses the same approach as the win ratio, by basing generalized pairwise comparisons on the most severe or clinically important comparable outcome. We use an inverse probability weighting technique to correct for study-specific censoring. Asymptotic properties are derived using U-statistic properties. We apply the prioritized concordance index to two types of disease processes with a rare primary outcome and a more common secondary outcome. Our simulation studies show that when a predictor is predictive of both outcomes, the new concordance index can gain efficiency and power in identifying true prognostic variables compared to using the primary outcome alone. Using the prioritized concordance index, we examine whether novel clinical measures can be useful in predicting risk of type II diabetes in patients with impaired glucose resistance whose disease status can also regress to normal glucose resistance. We also examine the discrimination ability of four published risk models among ever smokers at risk of lung cancer incidence and subsequent death.

Trends in Major Gastrectomy for Cancer: Frequency and Outcomes.

BACKGROUND: Declining incidence of gastric cancer in the USA has presumably resulted in lower rates of major gastrectomy for cancer. The impact on perioperative outcomes remains undefined. The aims of this study were to characterize national trends in frequency of major gastrectomy for cancer, identify factors associated with in-hospital mortality, and examine outcome disparities by race/ethnicity. METHODS: Nationwide inpatient sample data from 1993 to 2013 were queried for procedural and diagnostic codes (ICD-9) relating to total and partial gastrectomy procedures. Gastric resections for cancer were compared to those for peptic ulcer disease for reference. Patient demographics, comorbidity score, mortality, and hospital characteristics were recorded as covariates. RESULTS: A significant decrease in annual rates of partial and total gastrectomy was observed from 1993 to 2013 (p < 0.0001). The change in absolute number and percent decline was greater for partial gastrectomy (- 39.3%) than total gastrectomy (- 19%). There was a 34.0% decrease in gastrectomy for cancer in Whites and a 61.2% increase among Hispanic patients over two decades. In-hospital mortality also significantly decreased over the study period (7.7% to 2.7%). Factors associated with lower mortality rates included male sex and treatment at urban teaching hospitals. Analysis of trends revealed that gastrectomy for cancer was performed with increasing frequency at urban teaching hospitals. CONCLUSIONS: The frequency of major gastric resections in the USA has declined over two decades. Overall, in-hospital mortality rates also have decreased significantly. Declining in-hospital mortality after gastrectomy for cancer is associated with more frequent treatment at urban teaching hospitals.

Automated Cervical Screening and Triage, Based on HPV Testing and Computer-Interpreted Cytology.

Background: State-of-the-art cervical cancer prevention includes human papillomavirus (HPV) vaccination among adolescents and screening/treatment of cervical precancer (CIN3/AIS and, less strictly, CIN2) among adults. HPV testing provides sensitive detection of precancer but, to reduce overtreatment, secondary "triage" is needed to predict women at highest risk. Those with the highest-risk HPV types or abnormal cytology are commonly referred to colposcopy; however, expert cytology services are critically lacking in many regions. Methods: To permit completely automatable cervical screening/triage, we designed and validated a novel triage method, a cytologic risk score algorithm based on computer-scanned liquid-based slide features (FocalPoint, BD, Burlington, NC). We compared it with abnormal cytology in predicting precancer among 1839 women testing HPV positive (HC2, Qiagen, Germantown, MD) in 2010 at Kaiser Permanente Northern California (KPNC). Precancer outcomes were ascertained by record linkage. As additional validation, we compared the algorithm prospectively with cytology results among 243 807 women screened at KPNC (2016-2017). All statistical tests were two-sided. Results: Among HPV-positive women, the algorithm matched the triage performance of abnormal cytology. Combined with HPV16/18/45 typing (Onclarity, BD, Sparks, MD), the automatable strategy referred 91.7% of HPV-positive CIN3/AIS cases to immediate colposcopy while deferring 38.4% of all HPV-positive women to one-year retesting (compared with 89.1% and 37.4%, respectively, for typing and cytology triage). In the 2016-2017 validation, the predicted risk scores strongly correlated with cytology (P < .001). Conclusions: High-quality cervical screening and triage performance is achievable using this completely automated approach. Automated technology could permit extension of high-quality cervical screening/triage coverage to currently underserved regions.

Validation of a Human Papillomavirus (HPV) DNA Cervical Screening Test That Provides Expanded HPV Typing.

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity (Becton Dickinson Diagnostics, Sparks, MD), a nine-channel HPV test recently approved by the FDA, by assessing (i) the association of Onclarity types/channels with precancer/cancer; (ii) HPV type/channel agreement between the results of Onclarity and cobas (Roche Molecular Systems, Pleasanton, CA), another FDA-approved test; and (iii) Onclarity typing for all types/channels compared to typing results from a research assay (linear array [LA]; Roche). We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample (n = 9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2; Qiagen, Germantown, MD). A subset had already been tested by cobas and LA (n = 1,965). Cervical histopathology was ascertained from electronic health records. Hierarchical Onclarity channels showed a significant linear association with histological severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other 12 types as a pool (sample-weighted kappa value of 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and groups of types identified by LA (kappa values from 0.80 for HPV39/68/35 to 0.97 for HPV16). Onclarity typing results corresponded well to histopathology and to an already validated HPV DNA test and could provide additional clinical typing if such discrimination is determined to be clinically desirable.