Staging and clean room: Constructs designed to facilitate transparency and reduce bias in comparative analyses of real-world data.

PURPOSE: We describe constructs designed to protect the integrity of the results from comparative analyses using real-world data (RWD): staging and clean room. METHODS: Staging involves performing sequential preliminary analyses and evaluating the population size available and potential bias before conducting comparative analyses. A clean room involves restricted access to data and preliminary results, policies governing exploratory analyses and protocol deviations, and audit trail. These constructs are intended to allow decisions about protocol deviations, such as changes to design or model specification, to be made without knowledge of how they might affect subsequent analyses. We describe an example for implementing staging with a clean room. RESULTS: Stage 1 may involve selecting a data source, developing and registering a protocol, establishing a clean room, and applying inclusion/exclusion criteria. Stage 2 may involve attempting to achieve covariate balance, often through propensity score models. Stage 3 may involve evaluating the presence of residual confounding using negative control outcomes. After each stage, check points may be implemented when a team of statisticians, epidemiologists and clinicians masked to how their decisions may affect study outcomes, reviews the results. This review team may be tasked with making recommendations for protocol deviations to address study precision or bias. They may recommend proceeding to the next stage, conducting additional analyses to address bias, or terminating the study. Stage 4 may involve conducting the comparative analyses. CONCLUSIONS: The staging and clean room constructs are intended to protect the integrity and enhance confidence in the results of analyses of RWD.

Cost and Utilization Impacts of a Medicaid Managed Care Organization's Behavioral Health Wraparound Program.

Wraparound programs that provide comprehensive evidence-based outpatient treatment, transportation, social services, and housing supports have shown promise for improving clinical behavioral health-related outcomes to reduce the need for institutionalized care; however, the majority of evidence is based on wraparound programs for children. This study examined the impact of a wraparound program for adult Medicaid managed care organization members with serious mental health or substance use disorders on health care costs and utilization. This retrospective observational study used 2013-2018 claims data collected from a large Medicaid managed care organization operating in multiple states. We used an intention-to-treat difference-in-difference study design to examine the association of the wraparound with costs and utilization. Adult Medicaid members with an emergency department (ED) or inpatient visit for a behavioral health condition (index visit) were eligible for the study. Outcomes included all-cause and behavioral health-related costs and utilization during follow-up after the index visit's admission date. Outcomes were calculated overall, as well as separately by inpatient, ED, and outpatient/wraparound settings. We found that during the first post-admission month, the wraparound program was associated with 27.6 percentage points (PP) and 27.2 PP reductions in the number of behavioral health-related inpatient nights and costs, respectively. However, during subsequent months (median follow-up ranging from 7 to 10 months) there were no associations with per-member-per-month total all-cause or behavioral health-related costs. Nonetheless, the wraparound program was associated with 12.3 PP reduction in all-cause cost during the entire study period among a subset of members who were high cost at the baseline. Reduced hospital utilization and costs during the first month of wraparound services were fully counteracted by outpatient, housing, and other wraparound services costs during the following months. This indicates the importance of proper payment arrangements with value-based contracting or performance targets with wraparound services providers to align the objective of reducing inpatient use. Future wraparound programs may consider a more focused recruitment from high-cost members with complex care needs. However, our estimates were conservative given that it's from a single Medicaid managed care organization's perspective and some benefit from investing in addressing social needs may be realized in longer term (beyond our study period). States' Medicaid programs may consider the longer-term cost and broader, societal benefit of wraparound investment.

Healthcare resource use and costs associated with chronic kidney disease in US private insurance patients with multiple myeloma.

OBJECTIVES: Within a median 1.2 years after patients have an initial diagnosis with multiple myeloma, up to 61% were diagnosed with renal impairment and 50% were diagnosed with chronic kidney disease. This study estimated economic burden associated with chronic kidney disease in multiple myeloma patients in the US. METHODS: In this retrospective cohort study, patients ≥18 years old with ≥1 inpatient or ≥ 2 outpatient multiple myeloma diagnoses between 1 January 2008 and 31 March 2015 were identified from MarketScan® Commercial and Medicare Supplemental Databases. Chronic kidney disease patients had ≥1 diagnosis of chronic kidney disease Stages 1-5 (first chronic kidney disease diagnosis date = index date) on or after the first multiple myeloma diagnosis, and were propensity score matched 1:1 to multiple myeloma patients without chronic kidney disease, end-stage renal disease, dialysis, or other type of chronically impaired renal function. All patients had ≥six-month continuous enrollment prior to index date and were followed for ≥one month from index date until the earliest of inpatient death, end of continuous enrollment, or end of the study period (30 September 2015). The per-patient per-year healthcare resource utilization and costs were measured during follow-up. Costs were total reimbursed amount in 2016 US dollars. RESULTS: A total of 2541 multiple myeloma patients with chronic kidney disease stages 1-5 and 2541 matched controls met the study criteria and were respectively 69.3 and 69.6 years, 54.5% and 55.3% men, and had 572.2 and 533.4 mean days of follow up. Compared to controls, chronic kidney disease patients had significantly (all P < 0.001) higher proportions (57.1% vs. 32.1%) and frequency (1.2 vs. 0.5) of inpatient admissions, frequency of emergency room visits (5.1 vs. 3.3), and total costs ($106,634 vs. $71,880). Sensitivity analyses found that patients with chronic kidney disease, end-stage renal disease, or dialysis had $78,455 ( P < 0.001) higher costs (per-patient per-year) than matched controls. CONCLUSIONS: The economic burden associated with chronic kidney disease in patients with multiple myeloma was estimated to be between $34,754 and $78,455 per-patient per-year. Given its substantial clinical and economic impact, preservation of renal function is important in multiple myeloma patient care.

Association of Serum Lipids and Coronary Heart Disease in Contemporary Observational Studies.

BACKGROUND: The use of statins increased among US adults with high coronary heart disease (CHD) risk after publication of the 2001 cholesterol treatment guidelines. METHODS AND RESULTS: We analyzed the association between lipids and CHD among 9578 REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants and 346,595 Kaiser Permanente Southern California (KPSC) members with baseline lipid measurements in 2003 to 2007. We performed the same analyses among 14,590 Atherosclerosis Risk In Communities (ARIC) study participants with lipid measurements in 1987 to 1989. Analyses were restricted to blacks and whites 45 to 64 years of age without CHD who were not taking statins at baseline. Total cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured at baseline. Low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and ratios of total to high-density lipoprotein cholesterol and triglycerides to high-density lipoprotein cholesterol were calculated. The prevalence of diabetes mellitus, history of stroke, and antihypertensive medication use increased at higher low-density lipoprotein cholesterol in ARIC but not in REGARDS or KPSC. Over 8.9 years of follow-up, 225 CHD events occurred in REGARDS, 6547 events in KPSC, and 583 events in ARIC. After multivariable adjustment, less favorable lipid levels were associated with higher hazard ratios for CHD in ARIC. These associations were attenuated in REGARDS and KPSC. For example, the hazard ratio associated with the highest versus lowest quartile of low-density lipoprotein cholesterol (≥ 146 versus ≤ 102 mg/dL) was 1.89 (95% confidence interval, 1.42-2.51) in ARIC, 1.25 (95% confidence interval, 0.81-1.92) in REGARDS, and 1.49 (95% confidence interval, 1.38-1.61) in KPSC. CONCLUSION: The association between lipids and CHD in contemporary studies may be attenuated by the preferential use of statins by high-risk individuals.

Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis.

OBJECTIVES: To compare the coronary heart disease risk among patients with rheumatoid arthritis (RA) initiating common biologic disease-modifying antirheumatic drugs of different mechanisms. METHODS: We conducted a retrospective cohort study of patients with RA enrolled in Medicare, a public health plan covering >90% of US residents 65 years or older, from 2006 to 2012 who (1) initiated a biologic, (2) had complete medical and pharmacy coverage for at least 12 months before biologic initiation and (3) were free of coronary heart disease at the time of initiation. We compared the incidence rates (IRs) of (1) acute myocardial infarction (AMI) and (2) a composite outcome of AMI or coronary revascularisation and used multivariable adjusted Cox regression models to examine the associations between the type of biologic and the two outcomes. RESULTS: We identified 47 193 eligible patients with RA with mean age 64 (SD 13) years; 85% were women. Crude IRs for AMI ranged from 5.7 to 8.8 cases per 1000 person-years (PYs). AMI risk was significantly elevated among antitumour necrosis factor (anti-TNF) initiators overall (adjusted HR (aHR) 1.3; 95% CI 1.0 to 1.6) and individually among etanercept (aHR 1.3; 95% CI 1.0 to 1.8) and infliximab (aHR 1.3; 95% CI 1.0 to 1.6) compared with abatacept initiators. Crude IRs for the composite outcome ranged from 7.6 to 14.5 per 1000 PYs. Tocilizumab initiators were at reduced risk of the composite outcome compared with abatacept initiators (aHR 0.64, 95% CI 0.41 to 0.99). DISCUSSION: Findings from this observational study of patients with RA suggested that anti-TNF biologics may be associated with higher AMI risk compared with abatacept.

Algorithms to Identify Statin Intolerance in Medicare Administrative Claim Data.

PURPOSE: To compare characteristics of patients with possible statin intolerance identified using different claims-based algorithms versus patients with high adherence to statins. METHODS: We analyzed 134,863 Medicare beneficiaries initiating statins between 2007 and 2011. Statin intolerance and discontinuation, and high adherence to statins, defined by proportion of days covered ≥80 %, were assessed during the 365 days following statin initiation. Definition 1 of statin intolerance included statin down-titration or discontinuation with ezetimibe initiation, having a claim for a rhabdomyolysis or antihyperlipidemic event followed by statin down-titration or discontinuation, or switching between ≥3 types of statins. Definition 2 included beneficiaries who met Definition 1 and those who down-titrated statin intensity. We also analyzed beneficiaries who met Definition 2 of statin intolerance or discontinued statins. RESULTS: The prevalence of statin intolerance was 1.0 % (n = 1320) and 5.2 % (n = 6985) using Definitions 1 and 2, respectively. Overall, 45,266 (33.6 %) beneficiaries had statin intolerance by Definition 2 or discontinued statins and 55,990 (41.5 %) beneficiaries had high adherence to statins. Compared with beneficiaries with high adherence to statins, those with statin intolerance and who had statin intolerance or discontinued statins were more likely to be female versus male, and black, Hispanic or Asian versus white. The multivariable adjusted odds ratio for statin intolerance by Definitions 1 and 2 comparing patients initiating high versus low/moderate intensity statins were 2.82 (95%CI: 2.42-3.29), and 8.58 (8.07-9.12), respectively, and for statin intolerance or statin discontinuation was 2.35 (2.25-2.45). CONCLUSIONS: Definitions of statin intolerance presented herein can be applied to analyses using administrative claims data.

Agreement between Medicare pharmacy claims, self-report, and medication inventory for assessing lipid-lowering medication use.

BACKGROUND: Medicare claims have been used to study lipid-lowering medication (LLM) use among US adults. METHODS: We analyzed the agreement between Medicare claims for LLM and LLM use indicated by self-report during a telephone interview and, separately, by a medication inventory performed during an in-home study visit upon enrollment into the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. We included REGARDS participants ≥65 years enrolled in 2006-2007 with Medicare pharmacy benefits (Part D) from 120 days before their telephone interview through their medication inventory (n = 899). RESULTS: Overall, 39.2% and 39.5% of participants had a Medicare claim for an LLM within 120 days prior to their interview and medication inventory, respectively. Also, 42.7% of participants self-reported using LLMs, and 41.8% had an LLM in their medication inventory. The Kappa statistic (95% confidence interval [CI]) for agreement of Medicare claims with self-report and medication inventory was 0.68 (0.63-0.73) and 0.72 (0.68-0.77), respectively. No Medicare claims for LLMs were present for 22.1% (95%CI: 18.1-26.6%) of participants who self-reported taking LLMs and 18.9% (15.1-23.3%) with LLMs in their medication inventory. Agreement between Medicare claims and self-report was lower among Black male individuals (Kappa = 0.34 [95%CI: 0.14-0.54]) compared with Black female individuals (0.70 [0.61-0.79]), White male individuals (0.65 [0.56-0.75]), and White female individuals (0.79 [0.72-0.86]). Agreement between Medicare claims and the medication inventory was also low among Black male individuals (Kappa = 0.48 [95%CI: 0.29-0.66]). CONCLUSIONS: Although substantial agreement exists, many Medicare beneficiaries who self-report LLM use or have LLMs in a medication inventory have no claims for these medications. Copyright © 2016 John Wiley & Sons, Ltd.

Optimal use of available claims to identify a Medicare population free of coronary heart disease.

We examined claims-based approaches for identifying a study population free of coronary heart disease (CHD) using data from 8,937 US blacks and whites enrolled during 2003-2007 in a prospective cohort study linked to Medicare claims. Our goal was to minimize the percentage of persons at study entry with self-reported CHD (previous myocardial infarction or coronary revascularization). We assembled 6 cohorts without CHD claims by requiring 6 months, 1 year, or 2 years of continuous Medicare fee-for-service insurance coverage prior to study entry and using either a fixed-window or all-available look-back period. We examined adding CHD-related claims to our "base algorithm," which included claims for myocardial infarction and coronary revascularization. Using a 6-month fixed-window look-back period, 17.8% of participants without claims in the base algorithm reported having CHD. This was reduced to 3.6% using an all-available look-back period and adding other CHD claims to the base algorithm. Among cohorts using all-available look-back periods, increasing the length of continuous coverage from 6 months to 1 or 2 years reduced the sample size available without lowering the percentage of persons with self-reported CHD. This analysis demonstrates approaches for developing a CHD-free cohort using Medicare claims.

Mechanisms Influencing Circadian Blood Pressure Patterns Among Individuals with HIV.

HIV+ individuals have an increased risk for cardiovascular disease (CVD), but the mechanisms behind this association are poorly understood. While hypertension is a well-established CVD risk factor, clinic-based blood pressure (BP) assessment by itself cannot identify several important BP patterns, including white coat hypertension, masked hypertension, nighttime hypertension, and nighttime BP dipping. These BP patterns can be identified over a 24-h period by ambulatory BP monitoring (ABPM). In this review, we provide an overview of the potential value of conducting ABPM in HIV+ individuals. ABPM phenotypes associated with increased CVD risk include masked hypertension (i.e., elevated out-of-clinic BP despite non-elevated clinic BP), nighttime hypertension, and a non-dipping BP pattern (i.e., a drop in BP of <10 % from daytime to nighttime). These adverse ABPM phenotypes may be highly relevant in the setting of HIV infection, given that increased levels of inflammatory biomarkers, high psychosocial burden, high prevalence of sleep disturbance, and autonomic dysfunction have been commonly reported in HIV+ persons. Additionally, although antiretroviral therapy (ART) is associated with lower AIDS-related morbidity and CVD risk, the mitochondrial toxicity, oxidative stress, lipodystrophy, and insulin resistance associated with long-term ART use potentially lead to adverse ABPM phenotypes. Existing data on ABPM phenotypes in the setting of HIV are limited, but suggest an increased prevalence of a non-dipping BP pattern. In conclusion, identifying ABPM phenotypes may provide crucial information regarding the mechanisms underlying the excess CVD risk in HIV+ individuals.

Measuring personal heat exposure in an urban and rural environment.

Previous studies have linked heat waves to adverse health outcomes using ambient temperature as a proxy for estimating exposure. The goal of the present study was to test a method for determining personal heat exposure. An occupationally exposed group (urban groundskeepers in Birmingham, AL, USA N=21), as well as urban and rural community members from Birmingham, AL (N=30) or west central AL (N=30) wore data logging temperature and light monitors clipped to the shoe for 7 days during the summer of 2012. We found that a temperature monitor clipped to the shoe provided a comfortable and feasible method for recording personal heat exposure. Ambient temperature (°C) recorded at the nearest weather station was significantly associated with personal heat exposure [ß 0.37, 95%CI (0.35, 0.39)], particularly in groundskeepers who spent more of their total time outdoors [ß 0.42, 95%CI (0.39, 0.46)]. Factors significantly associated with lower personal heat exposure include reported time indoors [ß -2.02, 95%CI (-2.15, -1.89)], reported income>20K [ß -1.05, 95%CI (-1.79, -0.30)], and measured % body fat [ß -0.07, 95%CI (-0.12, -0.02)]. There were significant associations between income and % body fat with lower indoor and nighttime exposures, but not with outdoor heat exposure, suggesting modifications of the home thermal environment play an important role in determining overall heat exposure. Further delineation of the effect of personal characteristics on heat exposure may help to develop targeted strategies for preventing heat-related illness.

Short- and long-term sunlight radiation and stroke incidence.

OBJECTIVE: Examine whether long- and short-term sunlight radiation is related to stroke incidence. METHODS: Fifteen-year residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine sunlight radiation (insolation) and temperature exposure for a cohort of 16,606 stroke and coronary artery disease-free black and white participants aged ≥45 years from the 48 contiguous United States. Fifteen-, 10-, 5-, 2-, and 1-year exposures were used to predict stroke incidence during follow-up in Cox proportional hazard models. Potential confounders and mediators were included during model building. RESULTS: Shorter exposure periods exhibited similar, but slightly stronger relationships than longer exposure periods. After adjustment for other covariates, the previous year's monthly average insolation exposure below the median gave a hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.15-2.26), and the previous year's highest compared to the second highest quartile of monthly average maximum temperature exposure gave an HR of 1.92 (95%, 1.27-2.92). INTERPRETATION: These results indicate a relationship between lower levels of sunlight radiation and higher stroke incidence. The biological pathway of this relationship is not clear. Future research will show whether this finding stands, the pathway for this relationship, and whether it is due to short- or long-term exposures.

Sunlight exposure and cardiovascular risk factors in the REGARDS study: a cross-sectional split-sample analysis.

BACKGROUND: Previous research has suggested that vitamin D and sunlight are related to cardiovascular outcomes, but associations between sunlight and risk factors have not been investigated. We examined whether increased sunlight exposure was related to improved cardiovascular risk factor status. METHODS: Residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine previous-year sunlight radiation exposure for 17,773 black and white participants aged 45+ from the US. Exploratory and confirmatory analyses were performed by randomly dividing the sample into halves. Logistic regression models were used to examine relationships with cardiovascular risk factors. RESULTS: The lowest, compared to the highest quartile of insolation exposure was associated with lower high-density lipoprotein levels in adjusted exploratory (-2.7 mg/dL [95% confidence interval: -4.2, -1.2]) and confirmatory (-1.5 mg/dL [95% confidence interval: -3.0, -0.1]) models. The lowest, compared to the highest quartile of insolation exposure was associated with higher systolic blood pressure levels in unadjusted exploratory and confirmatory, as well as the adjusted exploratory model (2.3 mmHg [95% confidence interval: 0.8, 3.8]), but not the adjusted confirmatory model (1.6 mg/dL [95% confidence interval: -0.5, 3.7]). CONCLUSIONS: The results of this study suggest that lower long-term sunlight exposure has an association with lower high-density lipoprotein levels. However, all associations were weak, thus it is not known if insolation may affect cardiovascular outcomes through these risk factors.

Spatiotemporal association between birth outcomes and coke production and steel making facilities in Alabama, USA: a cross-sectional study.

BACKGROUND: Previous research has shown exposure to air pollution increases the risk of adverse birth outcomes, although the effects of residential proximity to significant industrial point sources are less defined. The objective of the current study was to determine whether yearly reported releases from major industrial point sources are associated with adverse birth outcomes. METHODS: Maternal residence from geocoded Alabama birth records between 1991 and 2010 were used to calculate distances from coke and steel production industries reporting emissions to the U.S. Environmental Protection Agency. Logistic regression models were built to determine associations between distance or yearly fugitive emissions (volatile organic compounds, polycyclic aromatic compounds, and metals) from reporting facilities and preterm birth or low birth weight, adjusting for covariates including maternal age, race, payment method, education level, year and parity. RESULTS: A small but significant association between preterm birth and residential proximity (≤5.0 km) to coke and steel production facilities remained after adjustment for covariates (OR 1.05 95% CI: 1.01,1.09). Above average emissions from these facilities of volatile organic compounds during the year of birth were associated with low birth weight (OR 1.17 95% CI: 1.06, 1.29), whereas metals emissions were associated with preterm birth (OR 1.07 95% CI: 1.01, 1.14). CONCLUSIONS: The present investigation suggests fugitive emissions from industrial point sources may increase the risk of adverse birth outcomes in surrounding neighborhoods. Further research teasing apart the relationship between exposure to emissions and area-level deprivation in neighborhoods surrounding industrial facilities and their combined effects on birth outcomes is needed.

The relationship between long-term sunlight radiation and cognitive decline in the REGARDS cohort study.

Sunlight may be related to cognitive function through vitamin D metabolism or circadian rhythm regulation. The analysis presented here sought to test whether ground and satellite measures of solar radiation are associated with cognitive decline. The study used a 15-year residential history merged with satellite and ground monitor data to determine sunlight (solar radiation) and air temperature exposure for a cohort of 19,896 cognitively intact black and white participants aged 45+ from the 48 contiguous United States. Exposures of 15, 10, 5, 2, and 1-year were used to predict cognitive status at the most recent assessment in logistic regression models; 1-year insolation and maximum temperatures were chosen as exposure measures. Solar radiation interacted with temperature, age, and gender in its relationships with incident cognitive impairment. After adjustment for covariates, the odds ratio (OR) of cognitive decline for solar radiation exposure below the median vs above the median in the 3rd tertile of maximum temperatures was 1.88 (95 % CI: 1.24, 2.85), that in the 2nd tertile was 1.33 (95 % CI: 1.09, 1.62), and that in the 1st tertile was 1.22 (95 % CI: 0.92, 1.60). We also found that participants under 60 years old had an OR = 1.63 (95 % CI: 1.20, 2.22), those 60-80 years old had an OR = 1.18 (95 % CI: 1.02, 1.36), and those over 80 years old had an OR = 1.05 (0.80, 1.37). Lastly, we found that males had an OR = 1.43 (95 % CI: 1.22, 1.69), and females had an OR = 1.02 (0.87, 1.20). We found that lower levels of solar radiation were associated with increased odds of incident cognitive impairment.

Environmental Public Health Applications Using Remotely Sensed Data.

We describe a remote sensing and GIS-based study that has three objectives: (1) characterize fine particulate matter (PM2.5), insolation and land surface temperature using NASA satellite observations, EPA ground-level monitor data and North American Land Data Assimilation System (NLDAS) data products on a national scale; (2) link these data with public health data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) national cohort study to determine whether these environmental risk factors are related to cognitive decline, stroke and other health outcomes; and (3) disseminate the environmental datasets and public health linkage analyses to end users for decision-making through the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) system. This study directly addresses a public health focus of the NASA Applied Sciences Program, utilization of Earth Sciences products, by addressing issues of environmental health to enhance public health decision-making.

Real-world comparative effectiveness of sotorasib versus docetaxel in second line and beyond among patients with advanced non-small cell lung cancer (NSCLC).

OBJECTIVES: To evaluate the comparative effectiveness of sotorasib monotherapy versus docetaxel as monotherapy or combination therapy in patients with pretreated KRAS G12C-mutated advanced NSCLC in the real-world. METHODS: A US-based electronic health record-derived de-identified database was used in this study. Patients with pretreated KRAS G12C-mutated advanced NSCLC who initiated sotorasib between May 28, 2021, and September 30, 2022, and docetaxel between January 1, 2019, and September 30, 2022 (to enhance sample size), were included, with a minimum of 12-month opportunity for follow-up. Treatment groups were balanced via overlap weighting propensity score methods. Median OS in the 2L and 2L+ settings were calculated using Kaplan-Meier estimates. Hazard ratios (HRs) were estimated via Cox proportional hazard models. RESULTS: Overall, the clinical characteristics in sotorasib and docetaxel cohorts were balanced after propensity score weighting. At baseline, most patients were > 65 years of age, had ECOG performance status of 0-1, were from the community practice setting, had advanced stage at initial diagnosis, and had prior anti-PD-(L)1 treatment and/or platinum-based chemotherapy. In the 2L setting, the median OS (95 % CI) for sotorasib (N=102) and docetaxel (N=58) patients was 10.2 (7.6-16.3) and 6.0 (4.2-11.0) months, respectively, with a corresponding mortality HR (95 % CI) of 0.62 (0.41-0.93). In the 2L+ setting, the median OS (95 % CI) for sotorasib (N=164) and docetaxel (N=116) was 10.2 (8.0-14.6) and 7.2 (5.1-10.6) months, respectively, with a corresponding mortality HR (95 % CI) of 0.65 (0.49-0.87). In patients with prior anti-PD-(L)1 treatment, the mortality HR (95 % CI) in the sotorasib group versus docetaxel was 0.61 (0.39-0.94) and 0.65 (0.48-0.89) in the 2L and 2L+ settings, respectively. Findings from other subgroups were consistent with the primary analyses. CONCLUSION: In this real-world comparative analysis of patients with pretreated KRAS G12C-mutated advanced NSCLC, sotorasib monotherapy demonstrated a longer median OS compared to docetaxel monotherapy or combination therapy.

Lipoprotein(a) and Major Adverse Cardiovascular Events in Patients With or Without Baseline Atherosclerotic Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) [Lp(a)] is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). However, whether the optimal Lp(a) threshold for risk assessment should differ based on baseline ASCVD status is unknown. OBJECTIVES: The purpose of this study was to assess the association between Lp(a) and major adverse cardiovascular events (MACE) among patients with and without baseline ASCVD. METHODS: We studied a retrospective cohort of patients with Lp(a) measured at 2 medical centers in Boston, Massachusetts, from 2000 to 2019. To assess the association of Lp(a) with incident MACE (nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or cardiovascular mortality), Lp(a) percentile groups were generated with the reference group set at the first to 50th Lp(a) percentiles. Cox proportional hazards modeling was used to assess the association of Lp(a) percentile group with MACE. RESULTS: Overall, 16,419 individuals were analyzed with a median follow-up of 11.9 years. Among the 10,181 (62%) patients with baseline ASCVD, individuals in the 71st to 90th percentile group had a 21% increased hazard of MACE (adjusted HR: 1.21; P < 0.001), which was similar to that of individuals in the 91st to 100th group (adjusted HR: 1.26; P < 0.001). Among the 6,238 individuals without established ASCVD, there was a continuously higher hazard of MACE with increasing Lp(a), and individuals in the 91st to 100th Lp(a) percentile group had the highest relative risk with an adjusted HR of 1.93 (P < 0.001). CONCLUSIONS: In a large, contemporary U.S. cohort, elevated Lp(a) is independently associated with long-term MACE among individuals with and without baseline ASCVD. Our results suggest that the threshold for risk assessment may be different in primary vs secondary prevention cohorts.

Area-level risk factors for adverse birth outcomes: trends in urban and rural settings.

BACKGROUND: Significant and persistent racial and income disparities in birth outcomes exist in the US. The analyses in this manuscript examine whether adverse birth outcome time trends and associations between area-level variables and adverse birth outcomes differ by urban-rural status. METHODS: Alabama births records were merged with ZIP code-level census measures of race, poverty, and rurality. B-splines were used to determine long-term preterm birth (PTB) and low birth weight (LBW) trends by rurality. Logistic regression models were used to examine differences in the relationships between ZIP code-level percent poverty or percent African-American with either PTB or LBW. Interactions with rurality were examined. RESULTS: Population dense areas had higher adverse birth outcome rates compared to other regions. For LBW, the disparity between population dense and other regions increased during the 1991-2005 time period, and the magnitude of the disparity was maintained through 2010. Overall PTB and LBW rates have decreased since 2006, except within isolated rural regions. The addition of individual-level socioeconomic or race risk factors greatly attenuated these geographical disparities, but isolated rural regions maintained increased odds of adverse birth outcomes. ZIP code-level percent poverty and percent African American both had significant relationships with adverse birth outcomes. Poverty associations remained significant in the most population-dense regions when models were adjusted for individual-level risk factors. CONCLUSIONS: Population dense urban areas have heightened rates of adverse birth outcomes. High-poverty African American areas have higher odds of adverse birth outcomes in urban versus rural regions. These results suggest there are urban-specific social or environmental factors increasing risk for adverse birth outcomes in underserved communities. On the other hand, trends in PTBs and LBWs suggest interventions that have decreased adverse birth outcomes elsewhere may not be reaching isolated rural areas.

Incident CHD and ischemic stroke associated with lipoprotein(a) by levels of Factor VIII and inflammation.

BACKGROUND: Inflammation and coagulation may contribute to the increased risk for atherosclerotic cardiovascular disease (ASCVD) associated with high lipoprotein(a). The association of lipoprotein(a) with ASCVD is stronger in individuals with high versus low high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation. OBJECTIVES: Determine the association of lipoprotein(a) with incident ASCVD by levels of coagulation Factor VIII controlling for hs-CRP. METHODS: We analyzed data from 6,495 men and women 45 to 84 years of age in the Multi-Ethnic Study of Atherosclerosis (MESA) without prevalent ASCVD at baseline (2000-2002). Lipoprotein(a) mass concentration, Factor VIII coagulant activity, and hs-CRP were measured at baseline and categorized as high or low (≥75th or <75th percentile of the distribution). Participants were followed for incident coronary heart disease (CHD) and ischemic stroke through 2015. RESULTS: Over a median follow-up of 13.9 years, there were 390 CHD and 247 ischemic stroke events. The hazard ratio (95%CI) for CHD associated with high lipoprotein(a) (≥40.1 versus <40.1 mg/dL) including adjustment for hs-CRP among participants with low and high Factor VIII was 1.07 (0.80-1.44) and 2.00 (1.33-3.01), respectively (p-value for interaction 0.016). The hazard ratio (95%CI) for CHD associated with high lipoprotein(a) including adjustment for Factor VIII was 1.16 (0.87-1.54) and 2.00 (1.29-3.09) among participants with low and high hs-CRP, respectively (p-value for interaction 0.042). Lp(a) was not associated with ischemic stroke regardless of Factor VIII or hs-CRP levels. CONCLUSION: High lipoprotein(a) is a risk factor for CHD in adults with high levels of hemostatic or inflammatory markers.

Lipoprotein(a) and the Risk for Recurrent Atherosclerotic Cardiovascular Events Among Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: Many adults with chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (ASCVD) have high lipoprotein(a) levels. It is unclear whether high lipoprotein(a) levels confer an increased risk for recurrent ASCVD events in this population. We estimated the risk for recurrent ASCVD events associated with lipoprotein(a) in adults with CKD and prevalent ASCVD. Study Design: Observational cohort study. Setting & Participants: We included 1,439 adults with CKD and prevalent ASCVD not on dialysis enrolled in the Chronic Renal Insufficiency Cohort study between 2003 and 2008. Exposure: Baseline lipoprotein(a) mass concentration, measured using a latex-enhanced immunoturbidimetric assay. Outcomes: Recurrent ASCVD events (primary outcome), kidney failure, and death (exploratory outcomes) through 2019. Analytical Approach: We used Cox proportional-hazards regression models to estimate adjusted HR (aHRs) and 95% CIs. Results: Among participants included in the current analysis (mean age 61.6 years, median lipoprotein(a) 29.4 mg/dL [25th-75th percentiles 9.9-70.9 mg/dL]), 641 had a recurrent ASCVD event, 510 developed kidney failure, and 845 died over a median follow-up of 6.6 years. The aHR for ASCVD events associated with 1 standard deviation (SD) higher log-transformed lipoprotein(a) was 1.04 (95% CI, 0.95-1.15). In subgroup analyses, 1 SD higher log-lipoprotein(a) was associated with an increased risk for ASCVD events in participants without diabetes (aHR, 1.23; 95% CI, 1.02-1.48), but there was no evidence of an association among those with diabetes (aHR, 0.99; 95% CI, 0.88-1.10, P comparing aHRs = 0.031). The aHR associated with 1 SD higher log-lipoprotein(a) in the overall study population was 1.16 (95% CI, 1.04-1.28) for kidney failure and 1.02 (95% CI, 0.94-1.11) for death. Limitations: Lipoprotein(a) was not available in molar concentration. Conclusions: Lipoprotein(a) was not associated with the risk for recurrent ASCVD events in adults with CKD, although it was associated with a risk for kidney failure.