Visualizing External Validity: Graphical Displays to Inform the Extension of Treatment Effects from Trials to Clinical Practice.

BACKGROUND: In the presence of effect measure modification, estimates of treatment effects from randomized controlled trials may not be valid in clinical practice settings. The development and application of quantitative approaches for extending treatment effects from trials to clinical practice settings is an active area of research. METHODS: In this article, we provide researchers with a practical roadmap and four visualizations to assist in variable selection for models to extend treatment effects observed in trials to clinical practice settings and to assess model specification and performance. We apply this roadmap and visualizations to an example extending the effects of adjuvant chemotherapy (5-fluorouracil vs. plus oxaliplatin) for colon cancer from a trial population to a population of individuals treated in community oncology practices in the United States. RESULTS: The first visualization screens for potential effect measure modifiers to include in models extending trial treatment effects to clinical practice populations. The second visualization displays a measure of covariate overlap between the clinical practice populations and the trial population. The third and fourth visualizations highlight considerations for model specification and influential observations. The conceptual roadmap describes how the output from the visualizations helps interrogate the assumptions required to extend treatment effects from trials to target populations. CONCLUSIONS: The roadmap and visualizations can inform practical decisions required for quantitatively extending treatment effects from trials to clinical practice settings.

Hypertension and one-year risk of all-cause mortality among women with treated HIV in the United States.

OBJECTIVE: Hypertension is a critical cause of cardiovascular disease, and women with HIV have a higher prevalence of hypertension than women without HIV. The relationship between hypertension and mortality has not been well characterized in women with treated HIV. Here, we estimate the effect of hypertension on 1-year risk of all-cause mortality among women with HIV on antiretroviral therapy (ART) in the United States. DESIGN: An analysis of multicenter, observational cohort data from the Women's Interagency HIV Study (WIHS) collected between 1995 and 2019. METHODS: We included women with HIV who reported ever using ART. We used parametric g-computation to estimate the effect of hypertension (SBP ≥140  mmHg, DBP ≥90 mmHg, or use of hypertensive medication) on all-cause mortality within 1 year of a WIHS visit. RESULTS: Among 2929 unique women, we included 57 034 visits with a median age of 45 (interquartile range: 39, 52) years. Women had hypertension at 34.5% of visits, and 641 deaths occurred within 1 year of a study visit. Comparing women at visits with hypertension to women at visits without hypertension, the standardized 1-year risk ratio for mortality was 1.16 [95% confidence interval (95% CI): 1.01-1.33]. The risk ratios were higher in Hispanic (risk ratio: 1.23, 95% CI: 0.86-1.77) and non-Hispanic black women (risk ratio: 1.19, 95% CI: 1.04-1.37) and lower in non-Hispanic white women (risk ratio: 0.93, 95% CI: 0.58-1.48). CONCLUSION: Among women with treated HIV, those with hypertension, compared with those without, had an increased 1-year risk of all-cause mortality.

Comparing Trial and Real-world Adjuvant Oxaliplatin Delivery in Patients With Stage III Colon Cancer Using a Longitudinal Cumulative Dose.

Importance: Delivery of adjuvant chemotherapy can differ substantially between trial and real-world populations. Adherence metrics like relative dose intensity (RDI) cannot capture the timing of modifications and mask differences in the total amount of chemotherapy received. Objective: To compare oxaliplatin delivery between MOSAIC trial participants and patients treated in the US Oncology Network with stage III colon cancer using a longitudinal cumulative dose (LCD). Design, Setting, and Participants: This cohort study used secondary data from the MOSAIC trial, an international randomized clinical trial (concluded in 2004), and electronic health records from US Oncology (2009-2018), a network of community oncology practices in the US. It included participants in MOSAIC with stage III colon cancer who were randomized to receive treatment with oxaliplatin and fluorouracil/leucovorin (n = 663) and US Oncology patients with stage III colon cancer who were treated with a modified FOLFOX-6 regimen (n = 2523). Exposures: Oxaliplatin and fluorouracil/leucovorin. Outcomes and Measures: We evaluated RDI and LCD over time and at the end of treatment in the MOSAIC and US Oncology populations. We used bootstrapping to estimate 95% confidence bands for LCD differences between the populations. Results: The 663 MOSAIC participants (296 women [44.7%]) and 2523 US Oncology patients (1245 women [49.4%]) were generally similar with respect to demographic characteristics. Median RDI was lower in US Oncology (80% in MOSAIC vs 70% in US Oncology). The LCD also suggested differences in the total amount of oxaliplatin received between populations; the final median LCD in US Oncology was 10.2% lower than in MOSAIC, equivalent to receiving 1.2 fewer treatment cycles less of oxaliplatin. This difference only began 133 days into treatment and persisted after accounting for covariates, likely in terms of more frequent oxaliplatin treatment discontinuation in US Oncology patients than their MOSAIC counterparts. Conclusions and Relevance: The study results suggest that real-world patients in community practice in the US treated with modified FOLFOX 6 received less oxaliplatin than their historical counterparts in the MOSAIC trial, with differences manifesting late in the treatment course. The LCD allowed us to identify the amount and extent of these differences, the timing of which was unclear when using RDI alone. Trial Registration: ClinicalTrials.gov identifier: NCT00275210.

Hepatitis C coinfection and extrahepatic cancer incidence among people living with HIV.

OBJECTIVES: We assessed the incidence of extrahepatic cancer among people with HIV/HCV coinfection and the potential impact of direct-acting antivirals (DAAs) on extrahepatic cancer risk among people with HIV/HCV coinfection. DESIGN: Our study cohort included adults who initiated HIV care at a CNICS site in the US during 1995-2017, excluding those with previous cancer and without HCV testing. METHODS: We used Cox regression to estimate hazard ratios for extrahepatic cancer incidence among patients with HIV/HCV coinfection compared with those with HIV monoinfection. Standardized morbidity ratio (SMR) weights were used to create a 'pseudopopulation' in which all patients were treated with antiretroviral therapy (ART), and to compare extrahepatic cancer incidence among patients with untreated HIV/HCV coinfection with the incidence that would have been observed if they had been successfully treated for HCV. RESULTS: Of 18 422 adults, 1775 (10%) had HCV RNA and 10 899 (59%) were on ART at baseline. Incidence rates of any extrahepatic cancer among patients with HIV/HCV coinfection and HIV monoinfection were 1027 and 771 per 100 000 person-years, respectively. In SMR-weighted analyses, the risk of any extrahepatic cancer among patients with untreated HCV coinfection at baseline was similar to the risk if they had been successfully treated for HCV. Patients with untreated HCV coinfection at baseline had higher incidence of kidney, lung and inflammation-related cancers than if their HCV had been successfully treated, but these associations were not statistically significant. CONCLUSIONS: We did not find evidence that treating HCV coinfection with DAAs would reduce the incidence of extrahepatic cancers among people with HIV receiving ART.

A new smoking cessation 'cascade' among women with or at risk for HIV infection.

OBJECTIVES: The aim of this study was to define a smoking cessation 'cascade' among USA women with and without HIV and examine differences by sociodemographic characteristics. DESIGN: An observational cohort study using data from smokers participating in the Women's Interagency HIV Study between 2014 and 2019. METHODS: We followed 1165 women smokers with and without HIV from their first study visit in 2014 or 2015 until an attempt to quit smoking within approximately 3 years of follow-up, initial cessation (i.e. no restarting smoking within approximately 6 months of a quit attempt), and sustained cessation (i.e. no restarting smoking within approximately 12 months of a quit attempt). Using the Aalen-Johansen estimator, we estimated the cumulative probability of achieving each step, accounting for the competing risk of death. RESULTS: Forty-five percent of smokers attempted to quit, 27% achieved initial cessation, and 14% achieved sustained cessation with no differences by HIV status. Women with some post-high school education were more likely to achieve each step than those with less education. Outcomes did not differ by race. Thirty-six percent [95% confidence interval (95% CI): 31-42] of uninsured women attempted to quit compared with 47% (95% CI: 44-50) with Medicaid and 49% (95% CI: 41-59) with private insurance. CONCLUSION: To decrease smoking among USA women with and without HIV, targeted, multistage interventions, and increased insurance coverage are needed to address shortfalls along this cascade.

Associations between HIV, antiretroviral therapy and preterm birth in the US Women's Interagency HIV Study, 1995-2018: a prospective cohort.

OBJECTIVE: To evaluate the associations of HIV infection with preterm birth (PTB), and of HIV antiretroviral therapy (ART) with PTB. METHODS: We analysed singleton live-born pregnancies among women from 1995 to 2019 in the Women's Interagency HIV Study, a prospective cohort of US women with, or at risk for, HIV. The primary exposures were HIV status and ART use before delivery [none, monotherapy or dual therapy, or highly active antiretroviral therapy (HAART)]. The primary outcome was PTB < 34 weeks, and, secondarily, < 28 and < 37 weeks. We analysed self-reported birth data, and separately modelled the associations between HIV and PTB, and between ART and PTB, among women with HIV. We used modified Poisson regression, and adjusted for age, race, parity, tobacco use and delivery year, and, when modelling the impact of ART, duration from HIV diagnosis to delivery, nadir CD4 count, and pre-pregnancy viral load and CD4 count. RESULTS: We analysed 488 singleton deliveries (56% exposed to HIV) to 383 women. The risk of PTB < 34 weeks was similar among women with and without HIV, but the risk of PTB < 37 weeks was higher [32% vs. 23%; adjusted risk ratio (aRR) = 1.43; 95% confidence interval (CI): 1.07-1.91] among women with HIV. The risk of PTB < 34 weeks was lower among women with HIV receiving HAART than among those receiving no ART (7% vs. 26%; aRR:0.19; 95% CI: 0.08-0.44). The associations between HAART and PTB < 28 and < 37 weeks were similar. CONCLUSIONS: Antiretroviral therapy exposure was associated with a decreased risk of PTB among a US cohort of women with HIV. Given the growing concerns about ART and adverse pregnancy outcomes, this finding that ART may be protective for PTB is reassuring.

Transportability From Randomized Trials to Clinical Care: On Initial HIV Treatment With Efavirenz and Suicidal Thoughts or Behaviors.

In an analysis of randomized trials, use of efavirenz for treatment of human immunodeficiency virus (HIV) infection was associated with increased suicidal thoughts/behaviors. However, analyses of observational data have found no evidence of increased risk. To assess whether population differences might explain this divergence, we transported the effect of efavirenz use from these trials to a specific target population. Using inverse odds weights and multiple imputation, we transported the effect of efavirenz on suicidal thoughts/behaviors in these randomized trials (participants were enrolled in 2001-2007) to a trials-eligible cohort of US adults initiating antiretroviral therapy while receiving HIV clinical care at medical centers between 1999 and 2015. Overall, 8,291 cohort participants and 3,949 trial participants were eligible. Prescription of antidepressants (19% vs. 13%) and injection drug history (16% vs. 10%) were more frequent in the cohort than in the trial participants. Compared with the effect in trials, the estimated hazard ratio for efavirenz on suicidal thoughts/behaviors was attenuated in our target population (trials: hazard ratio (HR) = 2.3 (95% confidence interval (CI): 1.2, 4.4); transported: HR = 1.8 (95% CI: 0.9, 4.4)), whereas the incidence rate difference was similar (trials: HR = 5.1 (95% CI: 1.6, 8.7); transported: HR = 5.4 (95% CI: -0.4, 11.4)). In our target population, there was greater than 20% attenuation of the hazard ratio estimate as compared with the trials-only estimate. Transporting results from trials to a target population is informative for addressing external validity.

Incident obstructive lung disease and mortality among people with HIV and a history of injecting drugs.

OBJECTIVE: People with HIV (PWH) experience increased prevalence of obstructive lung disease (OLD), regardless of greater observed smoking behaviors. We investigated whether the effect of incident OLD on mortality differed by HIV and HIV viral suppression among persons who inject drugs (PWID) and report smoking history. DESIGN: ALIVE is a longitudinal, observational cohort study of HIV-positive and seronegative PWID. This analysis included participants who had at least one spirometry measure to assess OLD between 2007 and 2016, excluding those who never smoked (5%, n = 62) or had baseline OLD (17%, n = 269). METHODS: Incident OLD occurred when the first prebronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) less than 0.70 during follow-up. The effect of incident OLD on all-cause mortality was estimated in PWH and seronegative participants using inverse-probability-of-treatment-weighted marginal structural models controlling for baseline (age, race, sex, calendar year, smoking pack-years) and time-varying (smoking intensity, viral suppression, and calendar time) confounders. RESULTS: Among 1204 participants, 269 (22.3%) and 157 (13.0%) experienced incident OLD and death, respectively, over a median of five person-years of follow-up. There was no effect of OLD on mortality among seronegative participants [hazard ratio = 0.84, 95% confidence interval (CI): 0.47-1.48]; however, PWH diagnosed with OLD experienced an increased mortality risk (hazard ratio = 1.71, 95% CI: 1.04-2.80) during follow-up. HIV viral suppression did not confound or modify the effect of OLD on mortality among PWH. CONCLUSION: There was an apparent effect of OLD on all-cause mortality irrespective of viral suppression among PWH but not among seronegative persons, after accounting for baseline and time-varying confounders. These results highlight the need for enhanced screening and management of OLD among PWH.

Introducing longitudinal cumulative dose to describe chemotherapy patterns over time: Case study of a colon cancer trial.

Adjuvant chemotherapy regimens take months to complete. Despite this, studies evaluate chemotherapy adherence via measures assessed at the end of treatment (eg, number of patients missing any dose, relative dose intensity [RDI]). This approach ignores information like the timing of treatment delays. We propose longitudinal cumulative dose (LCD) to integrate impacts of dose reductions, missed doses and dose delays over time. We obtained data from the 2246 participants in the MOSAIC trial randomized to FOLFOX (all three agents) or 5-FU/LV (only 5-fluorouracil and leucovorin). We evaluated proportions of patients stopping treatment early and reducing, missing or delaying a dose in each arm for each chemotherapy agent at each cycle. We calculated LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each agent and compared it over time and at 24 weeks between treatment arms. Participants randomized to FOLFOX were more likely to stop treatment, reduce doses, miss doses or delay cycles; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. The LCD for 5-fluorouracil differed between arms (FOLFOX arm median: 81%; 5-FU/LV arm median: 96%). Visualizing LCD highlighted the timing of deviations from standard administration in a way RDI could not, with major differences in 5-fluorouracil LCD across treatment arms beginning after the sixth dose. Further evaluation of LCD and its impacts on clinical outcomes may clarify mechanisms for heterogeneous patient outcomes.

Clinical Effectiveness of Integrase Strand Transfer Inhibitor-Based Antiretroviral Regimens Among Adults With Human Immunodeficiency Virus: A Collaboration of Cohort Studies in the United States and Canada.

BACKGROUND: Integrase strand transfer inhibitor (InSTI)-based regimens are now recommended as first-line antiretroviral therapy (ART) for adults with human immunodeficiency virus, but evidence on long-term clinical effectiveness of InSTI-based regimens remains limited. We examined whether InSTI-based regimens improved longer-term clinical outcomes. METHODS: We included participants from clinical cohorts in the North American AIDS Cohort Collaboration on Research and Design who initiated their first ART regimen, containing either InSTI (ie, raltegravir, dolutegravir, and elvitegravir-cobicistat) or efavirenz (EFV) as an active comparator, between 2009 and 2016. We estimated observational analogs of 6-year intention-to-treat and per-protocol risks, risk differences (RDs), and hazard ratios (HRs) for the composite outcome of AIDS, acute myocardial infarction, stroke, end-stage renal disease, end-stage liver disease, or death. RESULTS: Of 15 993 participants, 5824 (36%) initiated an InSTI-based and 10 169 (64%) initiated an EFV-based regimen. During the 6-year follow-up, 440 in the InSTI group and 1097 in the EFV group incurred the composite outcome. The estimated 6-year intention-to-treat risks were 14.6% and 14.3% for the InSTI and EFV groups, respectively, corresponding to a RD of 0.3% (95% confidence interval, -2.7% to 3.3%) and a HR of 1.08 (.97-1.19); the estimated 6-year per-protocol risks were 12.2% for the InSTI group and 11.9% for the EFV group, corresponding to a RD of 0.3% (-3.0% to 3.7%) and a HR of 1.09 (.96-1.25). CONCLUSIONS: InSTI- and EFV-based initial ART regimens had similar 6-year composite clinical outcomes. The risk of adverse clinical outcomes remains substantial even when initiating modern ART.

Modeling Combination Interventions to Prevent Human Immunodeficiency Virus in Adolescent Girls and Young Women in South Africa (HIV Prevention Trials Network 068).

BACKGROUND: Combination interventions may be an effective way to prevent human immunodeficiency virus (HIV) in adolescent girls and young women. However, current studies are not designed to understand which specific interventions and combinations will be most effective. We estimate the possible impacts of interventions on a combination of factors associated with HIV. METHODS: We used the g-formula to model interventions on combinations of HIV risk factors to identify those that would prevent the most incident HIV infections, including low school attendance, intimate partner violence, depression, transactional sex, and age-disparate partnerships. We used data from the HIV Prevention Trials Network (HPTN) 068 study in rural South Africa from 2011 to 2017. We estimated HIV incidence under a potential intervention that reduced each risk factor and compared this to HIV incidence under the current distribution of these risk factors. RESULTS: Although many factors had strong associations with HIV, potential intervention estimates did not always suggest large reductions in HIV incidence because the prevalence of risk factors was low. When modeling combination effects, an intervention to increase schooling, decrease depression, and decease transactional sex showed the largest reduction in incident infection (risk difference, -1.4%; 95% confidence interval [CI], -2.7% to -.2%), but an intervention on only transactional sex and depression still reduced HIV incidence by -1.3% (95% CI, -2.6% to -.2%). CONCLUSIONS: To achieve the largest reductions in HIV, both prevalence of the risk factor and strength of association with HIV must be considered. Additionally, intervening on more risk factors may not necessarily result in larger reductions in HIV incidence.

Use of Intrauterine Devices and Risk of Human Immunodeficiency Virus Acquisition Among Insured Women in the United States.

Concerns have been raised about progestin-containing contraceptives and the risk of human immunodeficiency virus (HIV) acquisition. Based on health insurance data from women in the United States with intrauterine device (IUD) insertions during 2011-2018, there was no increased risk of incident HIV diagnosis for levonorgestrel-releasing IUDs versus copper IUDs.

The Effects of Hepatitis C Treatment Eligibility Criteria on All-cause Mortality Among People With Human Immunodeficiency Virus.

BACKGROUND: The cost of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) prompted many payers to restrict treatment to patients who met non-evidence-based criteria. These restrictions have implications for survival of people with HCV, especially for people with human immunodeficiency virus (HIV)/HCV coinfection who are at high risk for liver disease progression. The goal of this work was to estimate the effects of DAA access policies on 10-year all-cause mortality among people with HIV. METHODS: The study population included 3056 adults with HIV in the Women's Interagency HIV Study and Multicenter AIDS Cohort Study from 1 October 1994 through 30 September 2015. We used the parametric g-formula to estimate 10-year all-cause mortality under DAA access policies that included treating (i) all people with HCV; (ii) only people with suppressed HIV; (iii) only people with severe fibrosis; and (iv) only people with HIV suppression and severe fibrosis. RESULTS: The 10-year risk difference of treating all coinfected persons with DAAs compared with no treatment was -3.7% (95% confidence interval [CI], -9.1% to .6%). Treating only those with suppressed HIV and severe fibrosis yielded a risk difference of -1.1% (95% CI, -2.8% to .6%), with 51% (95% CI, 38%-59%) of coinfected persons receiving DAAs. Treating a random selection of 51% of coinfected persons at baseline decreased the risk by 1.9% (95% CI, -4.7% to .3%). CONCLUSIONS: Restrictive DAA access policies may decrease survival compared to treating similar proportions of people with HIV/HCV coinfection with DAAs at random. These findings suggest that lives could be saved by thoughtfully revising access policies.

Body mass index, calcium supplementation and risk of colorectal adenomas.

Calcium supplementation (1,200 mg/day) did not significantly reduce colorectal adenomas in our recent randomized, controlled trial (Vitamin D/Calcium Polyp Prevention Study, VCPPS, 2004-2013) in contrast to our previous trial (Calcium Polyp Prevention Study, CPPS, 1988-1996). To reconcile these findings, we identified participant characteristics that differed between the study populations and modified the effect of calcium supplementation on adenomas or high-risk findings (advanced or multiple adenomas). Compared to the CPPS, more participants in the VCPPS were obese (body mass index (BMI) ≥30 kg/m2 ; 37.5% vs. 24.4%) and fewer had normal BMI (BMI <25 kg/m2 ; 18.5% vs. 31%). BMI appeared to modify the effect of calcium supplementation on adenomas and especially on high risk-findings: in the VCPPS, there was a 44% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.56, 95% CI = 0.26-1.23), but not among overweight (RR = 1.09, 95% CI = 0.62-1.91) or obese (RR = 1.54, 95% CI = 0.92-2.57) individuals (pinteraction = 0.03). Similarly, in the CPPS, there was a 56% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.44, 95% CI = 0.26-0.74), but not among overweight (RR = 0.87, 95% CI = 0.55-1.39) or obese (RR = 1.02, 95% CI = 0.57-1.82) individuals (pinteraction = 0.02). Standardization of each trial's findings to the BMI distribution in the other attenuated calcium's protective effect on adenomas in the CPPS but enhanced it in the VCPPS. In conclusion, 1,200 mg/day calcium supplementation may reduce risk of colorectal adenomas among those with normal BMI but not in overweight or obese individuals; and differences in BMI distribution partially account for the apparent difference in calcium efficacy between the two trials.

Past-month cannabis use among U.S. individuals from 2002-2015: An age-period-cohort analysis.

BACKGROUND: Cannabis is the most commonly used illicit drug among U.S. adolescents and adults, but little is known about factors that drive trends in cannabis use prevalence. To better understand drivers of these trends, we aimed to estimate age, period, and cohort effects on past-month cannabis use among U.S. individuals age 12 and older from 2002 to 2015. METHODS: We conducted an age-period-cohort analysis on past-month cannabis use among participants ages 12 and older using the National Survey on Drug Use and Health (NSDUH), an annual cross-sectional nationally-representative survey of drug use. Additionally, we examined how age, period, and cohort effects differed across gender. Participants (n = 779,799) self-reported cannabis patterns using a computer-assisted telephone interview (CATI). RESULTS: Past-month cannabis use in this population increased from 6.0% in 2002 to 8.1% in 2015. Distinct age, period, and cohort effects were observed. Compared to participants ages 12-13, participants ages 18-21 (PR: 16.8, 95% CI: 15.6, 18.1) and 22-25 (PR: 13.2, 95% CI: 12.2, 14.4) had dramatically higher prevalence of past-month cannabis use. Compared to participants in 2002, participants in 2014 (PR: 1.2, 95% CI: 1.1, 1.4) and 2014 (PR: 1.2, 95% CI: 1.1, 1.4) had slightly higher prevalence of past-month cannabis use. Compared to the 1940s birth cohort, the 1950s birth cohort (PR: 1.8, 95% CI: 1.5, 2.2) had a higher prevalence of past-month cannabis use. CONCLUSIONS: Past-month cannabis use is prevalent and increasing among U.S. adults. Distinct age, period, and cohort effects are at play, though age effects are strongest.

Estimating the Impact of Changes to Occupational Standards for Silica Exposure on Lung Cancer Mortality.

BACKGROUND: Respiratory exposure to silica is associated with the risk of death owing to malignant and nonmalignant disease. 2.3 million US workers are exposed to silica. Occupational exposure limits for silica are derived from a number of lines of evidence, including observational studies. Observational studies may be subject to healthy worker survivor bias, which could result in underestimates of silica's impact on worker mortality and, in turn, bias risk estimates for occupational exposure limits. METHODS: Using data on 65,999 workers pooled across multiple industries, we estimate the impacts of several hypothetical occupational exposure limits on silica exposure on lung cancer and all-cause mortality. We use the parametric g-formula, which can account for healthy worker survivor bias. RESULTS: Assuming we could eliminate occupational exposure, we estimate that there would be 20.7 fewer deaths per 1,000 workers in our pooled study by age 80 (95% confidence interval = 14.5, 26.8), including 3.91 fewer deaths owing to lung cancer (95% CI = 1.53, 6.30). Less restrictive interventions demonstrated smaller but still substantial risk reductions. CONCLUSIONS: Our results suggest that occupational exposure limits for silica can be further strengthened to reduce silica-associated mortality and illustrate how current risk analysis for occupational limits can be improved.

Optimizing research in symptomatic uterine fibroids with development of a computable phenotype for use with electronic health records.

BACKGROUND: Women with symptomatic uterine fibroids can report a myriad of symptoms, including pain, bleeding, infertility, and psychosocial sequelae. Optimizing fibroid research requires the ability to enroll populations of women with image-confirmed symptomatic uterine fibroids. OBJECTIVE: Our objective was to develop an electronic health record-based algorithm to identify women with symptomatic uterine fibroids for a comparative effectiveness study of medical or surgical treatments on quality-of-life measures. Using an iterative process and text-mining techniques, an effective computable phenotype algorithm, composed of demographics, and clinical and laboratory characteristics, was developed with reasonable performance. Such algorithms provide a feasible, efficient way to identify populations of women with symptomatic uterine fibroids for the conduct of large traditional or pragmatic trials and observational comparative effectiveness studies. Symptomatic uterine fibroids, due to menorrhagia, pelvic pain, bulk symptoms, or infertility, are a source of substantial morbidity for reproductive-age women. Comparing Treatment Options for Uterine Fibroids is a multisite registry study to compare the effectiveness of hormonal or surgical fibroid treatments on women's perceptions of their quality of life. Electronic health record-based algorithms are able to identify large numbers of women with fibroids, but additional work is needed to develop electronic health record algorithms that can identify women with symptomatic fibroids to optimize fibroid research. We sought to develop an efficient electronic health record-based algorithm that can identify women with symptomatic uterine fibroids in a large health care system for recruitment into large-scale observational and interventional research in fibroid management. STUDY DESIGN: We developed and assessed the accuracy of 3 algorithms to identify patients with symptomatic fibroids using an iterative approach. The data source was the Carolina Data Warehouse for Health, a repository for the health system's electronic health record data. In addition to International Classification of Diseases, Ninth Revision diagnosis and procedure codes and clinical characteristics, text data-mining software was used to derive information from imaging reports to confirm the presence of uterine fibroids. Results of each algorithm were compared with expert manual review to calculate the positive predictive values for each algorithm. RESULTS: Algorithm 1 was composed of the following criteria: (1) age 18-54 years; (2) either ≥1 International Classification of Diseases, Ninth Revision diagnosis codes for uterine fibroids or mention of fibroids using text-mined key words in imaging records or documents; and (3) no International Classification of Diseases, Ninth Revision or Current Procedural Terminology codes for hysterectomy and no reported history of hysterectomy. The positive predictive value was 47% (95% confidence interval 39-56%). Algorithm 2 required ≥2 International Classification of Diseases, Ninth Revision diagnosis codes for fibroids and positive text-mined key words and had a positive predictive value of 65% (95% confidence interval 50-79%). In algorithm 3, further refinements included ≥2 International Classification of Diseases, Ninth Revision diagnosis codes for fibroids on separate outpatient visit dates, the exclusion of women who had a positive pregnancy test within 3 months of their fibroid-related visit, and exclusion of incidentally detected fibroids during prenatal or emergency department visits. Algorithm 3 achieved a positive predictive value of 76% (95% confidence interval 71-81%). CONCLUSION: An electronic health record-based algorithm is capable of identifying cases of symptomatic uterine fibroids with moderate positive predictive value and may be an efficient approach for large-scale study recruitment.

Chronic hepatitis C virus infection and subsequent HIV viral load among women with HIV initiating antiretroviral therapy.

OBJECTIVES: One in four persons living with HIV is coinfected with hepatitis C virus (HCV). Biological and behavioral mechanisms may increase HIV viral load among coinfected persons. Therefore, we estimated the longitudinal effect of chronic HCV on HIV suppression after ART initiation among women with HIV (WWH). DESIGN: HIV RNA was measured every 6 months among 441 WWH in the Women's Interagency HIV Study who initiated ART from 2000 to 2015. METHODS: Log-binomial regression models were used to compare the proportion of study visits with detectable HIV RNA between women with and without chronic HCV. Robust sandwich variance estimators accounted for within-person correlation induced by repeated HIV RNA measurements during follow-up. We controlled for confounding and selection bias (because of loss to follow-up and death) using inverse probability-of-exposure-and-censoring weights. RESULTS: One hundred and fourteen women (25%) had chronic HCV before ART initiation. Overall, the proportion of visits with detectable HIV RNA was similar among women with and without chronic HCV [relative risk (RR) 1.19 (95% CI 0.72, 1.95)]. Six months after ART initiation, the proportion of visits with detectable HIV RNA among women with chronic HCV was 1.88 (95% CI 1.41-2.51) times that among women without HCV, at 2 years, the ratio was 1.60 (95% CI 1.17-2.19), and by 6 years there was no difference (1.03; 95% CI 0.60-1.79). CONCLUSION: Chronic HCV may negatively impact early HIV viral response to ART. These findings reaffirm the need to test persons with HIV for HCV infection, and increase engagement in HIV care and access to HCV treatment among persons with HIV/HCV coinfection.

Smoking, HIV, and risk of pregnancy loss.

OBJECTIVE: Cigarette smoking during pregnancy increases risks of poor pregnancy outcomes including miscarriage and stillbirth (pregnancy loss), but the effect of smoking on pregnancy loss among HIV-infected women has not been explored. Here, investigated the impact of smoking on risk of pregnancy loss among HIV-positive and HIV-negative women, and estimated the potential impact of realistic smoking cessation interventions on risk of pregnancy loss among HIV-positive women. DESIGN: We analyzed pregnancy outcomes in HIV-positive and HIV-negative participants in the Women's Interagency HIV Study between 1994 and 2014. METHODS: We estimated effects of current smoking at or immediately before pregnancy on pregnancy loss; we controlled for confounding using regression approaches, and estimated potential impact of realistic smoking cessation interventions using a semiparametric g-formula approach. RESULTS: Analysis examined 1033 pregnancies among 659 women. The effect of smoking on pregnancy loss differed dramatically by HIV status: adjusted for confounding, the risk difference comparing current smokers to current nonsmokers was 19.2% (95% confidence limit 10.9-27.5%) in HIV-positive women and 9.7% (95% confidence limit 0.0-19.4%) in HIV-negative women. These results were robust to sensitivity analyses. We estimated that we would need to offer a realistic smoking cessation intervention to 36 women to prevent one pregnancy loss. CONCLUSION: Smoking is a highly prevalent exposure with important consequences for pregnancy in HIV-positive pregnant women in the United States, even in the presence of potent highly active antiretroviral therapy. This evidence supports greater efforts to promote smoking cessation interventions among HIV-positive women, especially those who desire to become pregnant.