Journal articles: 'Marginal Structural Cox models'

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Ali, R. Ayesha, M. Adnan Ali, and Zhe Wei. "On computing standard errors for marginal structural Cox models." Lifetime Data Analysis 20, no. 1 (April 18, 2013): 106–31. http://dx.doi.org/10.1007/s10985-013-9255-7.

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Enders, Dirk, Susanne Engel, Roland Linder, and Iris Pigeot. "Robust versus consistent variance estimators in marginal structural Cox models." Statistics in Medicine 37, no. 24 (June 11, 2018): 3455–70. http://dx.doi.org/10.1002/sim.7823.

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Xiao, Yongling, Erica E. M. Moodie, and Michal Abrahamowicz. "Comparison of Approaches to Weight Truncation for Marginal Structural Cox Models." Epidemiologic Methods 2, no. 1 (January 8, 2013): 1–20. http://dx.doi.org/10.1515/em-2012-0006.

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Westreich, D., S. R. Cole, P. C. Tien, J. S. Chmiel, L. Kingsley, M. J. Funk, K. Anastos, and L. P. Jacobson. "Time Scale and Adjusted Survival Curves for Marginal Structural Cox Models." American Journal of Epidemiology 171, no. 6 (February 5, 2010): 691–700. http://dx.doi.org/10.1093/aje/kwp418.

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Karim, Mohammad Ehsanul, John Petkau, Paul Gustafson, Robert W. Platt, and Helen Tremlett. "Comparison of statistical approaches dealing with time-dependent confounding in drug effectiveness studies." Statistical Methods in Medical Research 27, no. 6 (September 21, 2016): 1709–22. http://dx.doi.org/10.1177/0962280216668554.

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In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models are frequently used to deal with such confounding. To avoid some of the problems of fitting marginal structural Cox model, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding. We carry out simulation studies to assess the suitability of the sequential Cox approach for analyzing time-to-event data in the presence of a time-dependent covariate that may or may not be a time-dependent confounder. Results from these simulations revealed that the sequential Cox approach is not as effective as marginal structural Cox model in addressing the time-dependent confounding. The sequential Cox approach was also found to be inadequate in the presence of a time-dependent covariate. We propose a modified version of the sequential Cox approach that correctly estimates the treatment effect in both of the above scenarios. All approaches are applied to investigate the impact of beta-interferon treatment in delaying disability progression in the British Columbia Multiple Sclerosis cohort (1995–2008).

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Westreich, Daniel, Stephen R. Cole, Enrique F. Schisterman, and Robert W. Platt. "A simulation study of finite-sample properties of marginal structural Cox proportional hazards models." Statistics in Medicine 31, no. 19 (April 11, 2012): 2098–109. http://dx.doi.org/10.1002/sim.5317.

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Burne, Rebecca M., and Michal Abrahamowicz. "Adjustment for time-dependent unmeasured confounders in marginal structural Cox models using validation sample data." Statistical Methods in Medical Research 28, no. 2 (August 24, 2017): 357–71. http://dx.doi.org/10.1177/0962280217726800.

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Large databases used in observational studies of drug safety often lack information on important confounders. The resulting unmeasured confounding bias may be avoided by using additional confounder information, frequently available in smaller clinical “validation samples”. Yet, no existing method that uses such validation samples is able to deal with unmeasured time-varying variables acting as both confounders and possible mediators of the treatment effect. We propose and compare alternative methods which control for confounders measured only in a validation sample within marginal structural Cox models. Each method corrects the time-varying inverse probability of treatment weights for all subject-by-time observations using either regression calibration of the propensity score, or multiple imputation of unmeasured confounders. Two proposed methods rely on martingale residuals from a Cox model that includes only confounders fully measured in the large database, to correct inverse probability of treatment weight for imputed values of unmeasured confounders. Simulation demonstrates that martingale residual-based methods systematically reduce confounding bias over naïve methods, with multiple imputation including the martingale residual yielding, on average, the best overall accuracy. We apply martingale residual-based imputation to re-assess the potential risk of drug-induced hypoglycemia in diabetic patients, where an important laboratory test is repeatedly measured only in a small sub-cohort.

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Bruneau, Pierre, Fahim Ashkar, and Bernard Bobée. "SMPLNORM : Un modèle simple pour obtenir les probabilités conjointes de deux débits et le niveau qui en dépend." Canadian Journal of Civil Engineering 21, no. 5 (October 1, 1994): 883–95. http://dx.doi.org/10.1139/l94-094.

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Most bivariate models assume the same type of marginal distribution, with two parameters, for two variables (gamma, type I extreme values, and so forth). The disadvantage of these models is that it is often difficult to make adjustments for observed flows. This study shows the application flexibility of a program that calculates the joint probability of two variables, Q1, and Q2, with marginal distributions that have three parameters. The program can also provide the probability of nonexceedence of a third variable, H, mathematically related to the first two variables. Two applications are discussed, in which Q1 and Q2 are the flows of two rivers controlling the variable H, which is a level in both cases. Theoretically, this model could also be applied to other types of variables. The proposed model is based on the hypothesis that a Box–Cox type of power transformation could reduce the marginal distributions of Q1 and Q2 to a normal distribution. One of the main conclusions of the study addresses the importance of taking into account the correlation between Q1 and Q2 to obtain a valid estimate of H. Key words: hydrology, statistics, bivariate models, Box–Cox, flow, water level. [Traduit par la rédaction]

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Santacatterina, Michele, Celia García‐Pareja, Rino Bellocco, Anders Sönnerborg, Anna Mia Ekström, and Matteo Bottai. "Optimal probability weights for estimating causal effects of time‐varying treatments with marginal structural Cox models." Statistics in Medicine 38, no. 10 (December 27, 2018): 1891–902. http://dx.doi.org/10.1002/sim.8080.

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Madden, Jamie M., Finbarr P. Leacy, Lina Zgaga, and Kathleen Bennett. "Fitting Marginal Structural and G-Estimation Models Under Complex Treatment Patterns: Investigating the Association Between De Novo Vitamin D Supplement Use After Breast Cancer Diagnosis and All-Cause Mortality Using Linked Pharmacy Claim and Registry Data." American Journal of Epidemiology 189, no. 3 (November 1, 2019): 224–34. http://dx.doi.org/10.1093/aje/kwz243.

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Abstract Studies have shown that accounting for time-varying confounding through time-dependent Cox proportional hazards models may provide biased estimates of the causal effect of treatment when the confounder is also a mediator. We explore 2 alternative approaches to addressing this problem while examining the association between vitamin D supplementation initiated after breast cancer diagnosis and all-cause mortality. Women aged 50–80 years were identified in the National Cancer Registry Ireland (n = 5,417) between 2001 and 2011. Vitamin D use was identified from linked prescription data (n = 2,570). We sought to account for the time-varying nature of vitamin D use and time-varying confounding by bisphosphonate use using 1) marginal structural models (MSMs) and 2) G-estimation of structural nested accelerated failure-time models (SNAFTMs). Using standard adjusted Cox proportional hazards models, we found a reduction in all-cause mortality in de novo vitamin D users compared with nonusers (hazard ratio (HR) = 0.84, 95% confidence interval (CI): 0.73, 0.99). Additional adjustment for vitamin D and bisphosphonate use in the previous month reduced the hazard ratio (HR = 0.45, 95% CI: 0.33, 0.63). Results derived from MSMs (HR = 0.44, 95% CI: 0.32, 0.61) and SNAFTMs (HR = 0.45, 95% CI: 0.34, 0.52) were similar. Utilizing MSMs and SNAFTMs to account for time-varying bisphosphonate use did not alter conclusions in this example.

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Karim, Mohammad Ehsanul, Paul Gustafson, John Petkau, Yinshan Zhao, Afsaneh Shirani, Elaine Kingwell, Charity Evans, Mia van der Kop, Joel Oger, and Helen Tremlett. "Marginal Structural Cox Models for Estimating the Association Between β-Interferon Exposure and Disease Progression in a Multiple Sclerosis Cohort." American Journal of Epidemiology 180, no. 2 (June 17, 2014): 160–71. http://dx.doi.org/10.1093/aje/kwu125.

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Karim, Mohammad Ehsanul, John Petkau, Paul Gustafson, Helen Tremlett, and The Beams Study Group. "On the application of statistical learning approaches to construct inverse probability weights in marginal structural Cox models: Hedging against weight-model misspecification." Communications in Statistics - Simulation and Computation 46, no. 10 (May 11, 2017): 7668–97. http://dx.doi.org/10.1080/03610918.2016.1248574.

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Terrier, Benjamin, Evguenia Krastinova, Isabelle Marie, David Launay, Adeline Lacraz, Pauline Belenotti, Luc de Saint-Martin, et al. "Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey." Blood 119, no. 25 (June 21, 2012): 5996–6004. http://dx.doi.org/10.1182/blood-2011-12-396028.

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Abstract Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.

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Onozawa, Satoshi, Tomomi Kimura, Yuichiro Ito, and Tadao Akizawa. "Estimating the causal effect of transient anemia status on renal and cardiovascular outcomes in community-dwelling patients in Japan at the beginning of impaired renal function using marginal structural modeling." Clinical and Experimental Nephrology 26, no. 2 (October 1, 2021): 178–89. http://dx.doi.org/10.1007/s10157-021-02137-1.

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Abstract Background Anemia status may be transient. Causal associations between changes in anemia status over time and adverse outcome development are not well characterized in community-dwelling subjects at the beginning of impaired kidney function. Methods This retrospective cohort study used annual health checkup and medical and pharmacy claims data from the JMDC between January 2005 and June 2019. Community-dwelling subjects in Japan with a pre-index estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 followed by a subsequent eGFR < 60 mL/min/1.73 m2 (index) were included. The composite renal outcome was ≥ 30% eGFR reduction over 3 years from baseline, serum creatinine doubling, progression to chronic dialysis, kidney transplantation, or eGFR < 15 mL/min/1.73 m2. The composite cardiovascular outcome was fatal and non-fatal unstable angina, myocardial infarction, heart failure, or cerebrovascular event. Time-dependent anemia risk was evaluated using Breslow’s estimator and marginal structural Cox models (MSM). Results In 32,870 included subjects, 1,396 had anemia at baseline. Adverse outcome incidence was higher in the baseline anemic group, but absolute differences in renal and cardiovascular outcomes between groups were diminished after adjusting for baseline characteristics. In MSM, time-dependent anemia status was associated with higher risk of renal (hazard ratio [95% confidence interval]; 2.6 [1.7–3.8]) and cardiovascular (1.6 [1.2–2.2]) outcomes and mortality (2.8 [1.8–4.3]). Absolute differences in survival probabilities were retained over time but were clinically marginal (1.1–2.7% over 6 years). Conclusions Even in subjects at the very early stage of impaired kidney function, early detection and treatment of anemia may help reduce the development of negative sequelae.

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Pons, Marion, Sylvie Chevret, Karine Briot, Maria-Antonietta d’Agostino, Christian Roux, Maxime Dougados, and Anna Molto. "Evaluation of long-term TNFi effectiveness after a first switch in early axial spondyloarthritis considering time-varying prescription bias: an inverse-probability weighting analysis of the DESIR cohort." RMD Open 8, no. 1 (January 2022): e001846. http://dx.doi.org/10.1136/rmdopen-2021-001846.

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ObjectiveTo evaluate long-term effectiveness of tumour necrosis factor inhibitor (TNFi) after a first switch, and their associated factors in an early axial spondyloarthritis (axSpA) population, considering time-varying prescription bias.MethodsObservational prospective cohort (DEvenir des Spondylarthropathies Indifférenciées Récentes) with 5 years of follow-up, including 708 TNFi-naïve patients with early axSpA. Long-term effectiveness of TNFi after a first switch (ASAS40 response after at least 2 visits under treatment) were estimated using marginal structural models (implementing inverse-probability weighting and iterative propensity scores). Factors associated with the outcome were explored by multivariate Cox regression models.ResultsThe hazard to present an ASAS40 response after a first TNFi switch was increased (HR=2.4 (95% CI 1.9 to 3.0)); this response ratio was slightly lower compared with the response in TNFi naïve patients after a first TNFi (HR=3.3 (95% CI 2.9 to 3.8)). HLA-B27 positive was the only factor independently associated with ASAS40 response after a first TNFi switch.ConclusionAfter application of innovative methods to overcome time-varying prescription bias, the magnitude of the TNFi response after a first switch was found to be numerically lower but clinically relevant from the response in TNFi-naïve patients.

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Severus, W. E., I. A. Lipkovich, R. W. Licht, A. H. Young, W. Greil, T. Ketter, W. Deberdt, and M. Tohen. "In search of optimal lithium levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005." European Psychiatry 25, no. 8 (December 2010): 443–49. http://dx.doi.org/10.1016/j.eurpsy.2009.10.009.

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AbstractPurposeThe aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder.MethodsA post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment.ResultsThe LoLi group (< 0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR] = 1.96, p = 0.042), but not depressive (HR = 2.11, p = 0.272) episodes, compared to the combined medium (0.6–0.79 mmol/L) and high lithium level (≥ 0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥ 0.8 mmol/L) for new manic/mixed (HR = 0.96, p = 0.893) or depressive (HR = 0.95, p = 0.922) episodes. The LoOL group (< 10 mg/day) showed a significantly increased risk of depressive (HR = 2.24, p = 0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10–20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR = 0.94, p = 0.895).ConclusionLithium levels ≥ 0.6 mmol/L and olanzapine doses ≥ 10 mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.

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Yuan, Shiqi, Chong Chen, Fengshuo Xu, Didi Han, Rui Yang, Shuai Zheng, Mengmeng Qiao, Xiaxuan Huang, and Jun Lyu. "Antithrombotic Therapy Improves ICU Mortality of Septic Patients with Peripheral Vascular Disease." International Journal of Clinical Practice 2022 (March 16, 2022): 1–6. http://dx.doi.org/10.1155/2022/1288535.

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Objective. The effectiveness of antithrombotic drugs for treating sepsis is controversial. Here, we explore the association between antithrombotic therapy and intensive care unit (ICU) mortality for septic patients with peripheral vascular disease. Methods. This retrospective cohort study uses data from the Medical Information Mart for Intensive Care (MIMIC)-III database. Kaplan–Meier survival analyses were used to examine mortality among different groups. Cox regression and marginal structural Cox models (MSCMs) were used to adjust for confounding factors. Main Results. The final cohort from the MIMIC-III database included 776 patients, of which 701 survived and 75 perished. The anticoagulant (AC) group and the antiplatelet-anticoagulation (AC-AP) group survived better than the group without antithrombotic treatment (non-AT). The AC and AC-AP groups showed a 0.363-fold and 0.373-fold risk of ICU mortality, respectively, compared with the non-AT group when controlling for age, gender, CRRT, alcohol, heart failure, hypertension, diabetes, obesity, renal failure, liver disease, INR, PT, PPT, and SpO2. Antiplatelet therapy did not reduce ICU mortality. The same trends were apparent from the MSCM. In addition, the AC-AP group exhibited a lower risk of bleeding complications. Conclusion. Although the antithrombotic group (AC and AC-AP groups) demonstrated a higher sequential organ failure assessment (SOFA) score than the group without antithrombotic treatment (non-AT group), the risk of ICU mortality was lower without increasing the risk of bleeding complications. Our study further suggested that anticoagulation therapy may benefit the prognosis of septic patients with peripheral vascular disease.

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Singh, N., A. Peterson, A. Baraff, P. Bhatti, A. Gopal, N. Smith, J. Barton, J. Curtis, C. LI, and N. Weiss. "POS1434 USE OF BIOLOGIC OR TARGETED SYNTHETIC DISEASE MODIFYING ANTI-RHEUMATIC DRUGS AND THE RISK OF LYMPHOMA IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1060.2–1061. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3408.

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BackgroundEpidemiologic studies suggest that disease duration and degree of inflammatory activity of rheumatoid arthritis (RA) contribute to lymphoma development (1). Whether the decrease in inflammatory burden seen with use of biologic or targeted synthetic disease modifying anti-rheumatic drugs (bDMARDs or tsDMARDs) translates into a lower risk of lymphoma in RA needs to be studied.ObjectivesThe objective of our study was to examine the effect of administration of b/tsDMARDS on the incidence of lymphoma relative to conventional synthetic DMARDs (csDMARDs) in an inception cohort of Veterans with RA.MethodsWe identified patients >18 years of age diagnosed with RA in any US Veterans Affairs (VA) facility from 1/1/2002 and 12/31/2018 using the VA Corporate Data Warehouse (CDW). To be included, each patient was required to meet the following criteria: 2+ RA diagnostic codes at least 7 days apart but no more than 365 days apart; 2) a prescription for a csDMARD within 90 days of the first RA diagnosis; and 3) an inpatient or outpatient visit 30 days to 2 years preceding first RA diagnosis (indicating they are a regular user of the VA). The csDMARDs included in these analyses were: methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. The bDMARDs included were tumor necrosis factor inhibitors (TNFi) and non-TNFi biologics such as tocilizumab, rituximab, abatacept, and biosimilars; tsDMARD was tofacitinib. Patients with prevalent lymphoma were excluded. Lymphoma diagnoses were identified using International Classification of Diseases Version 9, 10 and Oncology (ICD9, ICD10, ICDO) codes.We used marginal structural models as described by Hernan et al (2) and time-varying Cox models to control for confounding by indication while evaluating this association. We adjusted for baseline demographics (age, sex, race, ethnicity, year of cohort entry, rheumatology visits), and time-varying CRP and time-varying Rheumatoid Disease Comorbidity Index (RDCI) (3) to control for confounding.Results27,421 Veterans with RA met our eligibility criteria. Most of the Veterans (56%) were in the age range 61-80 years old; 89% male, 76% White, 14% African American. 8,225 (30%) patients were treated with a b-/tsDMARD. The crude incidence rates were 1.71 (95% CI 1.5-1.94) per 1000 person-years for those only on csDMARDs and 1.78 (95% CI 1.44-2.18) for patients during or following use of a b/tsDMARDs. After adjustment with both time-fixed and time-varying covariates using marginal structural models, the incidence of lymphoma was not different between patients who did and did not use a b/tsDMARD (hazard ratio=1.06, 95% CI= 0.82-1.37) (Table 1).Table 1.Estimates of Effect of bDMARD or tsDMARD use on Lymphoma relative to use of csDMARDsMarginal Structural Models; adjusted for:@Demographics1.04(0.80, 1.34)#Demographics + CRP1.06(0.82, 1.37)* per 1000 person-years@Demographics = age, gender, race, ethnicity, rheumatology visits, and year of cohort entry#Adjusts for CRP, baseline rheumatology visits (yes/no) and RDCI.CRP = C-Reactive Protein, RDCI = Rhematic Disease Comorbidity Index, CI = Confidence Interval, b/tsDMARD = biologic or targeted synthetic DMARD, csDMARD = conventional synthetic DMARDConclusionIn this large study using the nationwide VA data, we did not observe an association between the use of b/ts DMARDs and an increased risk of lymphoma.References[1]Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006;54(3):692-701.[2]Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11(5):550-60.[3]England BR, Sayles H, Mikuls TR, Johnson DS, Michaud K. Validation of the rheumatic disease comorbidity index. Arthritis care & research. 2015;67(6):865-72.Disclosure of InterestsNone declared

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Szabo, Shelagh M., Katherine Gooch, Carol Schermer, David Walker, G. Lozano-Ortega, Basia Rogula, Alison Deighton, Edward Vonesh, and Noll Campbell. "Association between cumulative anticholinergic burden and falls and fractures in patients with overactive bladder: US-based retrospective cohort study." BMJ Open 9, no. 5 (May 2019): e026391. http://dx.doi.org/10.1136/bmjopen-2018-026391.

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ObjectiveTo estimate the association between cumulative anticholinergic burden and falls and fractures in patients with overactive bladder (OAB).DesignA retrospective claims-based study (2007–2015) of patients with OAB; outcomes from a subset were contrasted to a non-OAB comparison.SettingUnited States, commercially and Medicare-insured population.Participants154 432 adults with OAB and 86 966 adults without OAB, mean age of 56 years, and 67.9% women.Main outcome measuresCumulative anticholinergic burden, a unitless value representing exposure over time, was estimated over the 12 months pre-index (‘at baseline’) and every 6 months post index. Burden was categorised as no burden (0), low burden (1–89), medium burden (90–499) or high burden (500+). Unadjusted rates of falls or fractures were estimated, and the increased risk associated with anticholinergic burden (measured at the closest 6-month interval prior to a fall or fracture) was assessed using a Cox proportional hazards model and a marginal structural model.ResultsMedian (IQR) baseline anticholinergic burden was 30 (0.0–314.0) and higher among older (≥65 years, 183 [3.0–713.0]) versus younger (<65 years, 13 [0.0–200.0]) adults. The unadjusted rate of falls or fractures over the period was 5.0 per 100 patient-years, ranging from 3.1 (95% CI 3.0–3.2) for those with no burden, to 7.4 (95% CI 7.1–7.6) for those with high burden at baseline. The adjusted risk of falls and fractures was greater with higher anticholinergic burden in the previous 6 months, with an HR of 1.2 (95% CI 1.2 to 1.3) for low burden versus no burden, to 1.4 (95% CI 1.3 to 1.4) for high versus no burden. Estimates from marginal structural models adjusting for time-varying covariates were lower but remained significantly higher with a higher anticholinergic burden. Rates of falls and fractures were approximately 40% higher among those with OAB (vs those without).ConclusionHigher levels of anticholinergic burden are associated with higher rates of falls and fractures, highlighting the importance of considering anticholinergic burden when treating patients with OAB.

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Neugebauer, Romain, Malini Chandra, Antonio Paredes, David J. Graham, Carolyn McCloskey, and Alan S. Go. "A Marginal Structural Modeling Approach with Super Learning for a Study on Oral Bisphosphonate Therapy and Atrial Fibrillation." Journal of Causal Inference 1, no. 1 (May 29, 2013): 21–50. http://dx.doi.org/10.1515/jci-2012-0003.

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AbstractPurpose: Observational studies designed to investigate the safety of a drug in a postmarketing setting typically aim to examine rare and non-acute adverse effects in a population that is not restricted to particular patient subgroups for which the therapy, typically a drug, was originally approved. Large healthcare databases and, in particular, rich electronic medical record (EMR) databases, are well suited for the conduct of these safety studies since they can provide detailed longitudinal information on drug exposure, confounders, and outcomes for large and representative samples of patients that are considered for treatment in clinical settings. Analytic efforts for drawing valid causal inferences in such studies are faced with three challenges: (1) the formal definition of relevant effect measures addressing the safety question of interest; (2) the development of analytic protocols to estimate such effects based on causal methodologies that can properly address the problems of time-dependent confounding and selection bias due to informative censoring, and (3) the practical implementation of such protocols in a large clinical/medical database setting. In this article, we describe an effort to specifically address these challenges with marginal structural modeling based on inverse probability weighting with data reduction and super learning.Methods: We describe the principles of, motivation for, and implementation of an analytical protocol applied in a safety study investigating possible effects of exposure to oral bisphosphonate therapy on the risk of non-elective hospitalization for atrial fibrillation or atrial flutter among older women based on EMR data from the Kaiser Permanente Northern California integrated health care delivery system. Adhering to guidelines brought forward by Hernan (Epidemiology 2011;22:290-1), we start by framing the safety research question as one that could be directly addressed by a sequence of ideal randomized experiments before describing the estimation approach that we implemented to emulate inference from such trials using observational data.Results: This report underlines the important computation burden involved in the application of the current R implementation of super learning with large data sets. While computing time and memory requirements did not permit aggressive estimator selection with super learning, this analysis demonstrates the applicability of simplified versions of super learning based on select sets of candidate learners to avoid complete reliance on arbitrary selection of parametric models for confounding and selection bias adjustment. Results do not raise concern over the safety of one-year exposure to BP but may suggest residual bias possibly due to unmeasured confounders or insufficient parametric adjustment for observed confounders with the candidate learners selected.Conclusions: Adjustment for time-dependent confounding and selection bias based on the ad hoc inverse probability weighting approach described in this report may provide a feasible alternative to extended Cox modeling or the point treatment analytic approaches (e.g. based on propensity score matching) that are often adopted in safety research with large data sets. Alternate algorithms are needed to permit the routine and more aggressive application of super learning with large data sets.

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THAMER, MAE, MIGUEL A. HERNÁN, YI ZHANG, DENNIS COTTER, and MICHELLE PETRI. "Prednisone, Lupus Activity, and Permanent Organ Damage." Journal of Rheumatology 36, no. 3 (February 4, 2009): 560–64. http://dx.doi.org/10.3899/jrheum.080828.

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Objective.To estimate the effect of corticosteroids (prednisone dose) on permanent organ damage among persons with systemic lupus erythematosus (SLE).Methods.We identified 525 patients with incident SLE in the Hopkins Lupus Cohort. At each visit, clinical activity indices, laboratory data, and treatment were recorded. The study population was followed from the month after the first visit until June 29, 2006, or attainment of irreversible organ damage, death, loss to follow-up, or receipt of pulse methylprednisolone therapy. We estimated the effect of cumulative average dose of prednisone on organ damage using a marginal structural model to adjust for time-dependent confounding by indication due to SLE disease activity.Results.Compared with non-prednisone use, the hazard ratio of organ damage for prednisone was 1.16 (95% CI 0.54, 2.50) for cumulative average doses > 0–180 mg/month, 1.50 (95% CI 0.58, 3.88) for > 180–360 mg/month, 1.64 (95% CI 0.58, 4.69) for > 360–540 mg/month, and 2.51 (95% CI 0.87, 7.27) for > 540 mg/month. In contrast, standard Cox regression models estimated higher hazard ratios at all dose levels.Conclusion.Our results suggest that low doses of prednisone do not result in a substantially increased risk of irreversible organ damage.

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Bansal, Nisha, Dawei Xie, Daohang Sha, Lawrence J. Appel, Rajat Deo, Harold I. Feldman, Jiang He, et al. "Cardiovascular Events after New-Onset Atrial Fibrillation in Adults with CKD: Results from the Chronic Renal Insufficiency Cohort (CRIC) Study." Journal of the American Society of Nephrology 29, no. 12 (October 30, 2018): 2859–69. http://dx.doi.org/10.1681/asn.2018050514.

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BackgroundAtrial fibrillation (AF), the most common sustained arrhythmia in CKD, is associated with poor clinical outcomes in both patients without CKD and patients with dialysis-treated ESRD. However, less is known about AF-associated outcomes in patients with CKD who do not require dialysis.MethodsTo prospectively examine the association of new-onset AF with subsequent risks of cardiovascular disease events and death among adults with CKD, we studied participants enrolled in the Chronic Renal Insufficiency Cohort Study who did not have AF at baseline. Outcomes included heart failure, myocardial infarction, stroke, and death occurring after diagnosis of AF. We used Cox regression models and marginal structural models to examine the association of incident AF with subsequent risk of cardiovascular disease events and death, adjusting for patient characteristics, laboratory values, and medication use.ResultsAmong 3080 participants, 323 (10.5%) developed incident AF during a mean 6.1 years of follow-up. Compared with participants who did not develop AF, those who did had higher adjusted rates of heart failure (hazard ratio [HR], 5.17; 95% confidence interval [95% CI], 3.89 to 6.87), myocardial infarction (HR, 3.64; 95% CI, 2.50 to 5.31), stroke (HR, 2.66; 95% CI, 1.50 to 4.74), and death (HR, 3.30; 95% CI, 2.65 to 4.12). These associations remained robust with additional adjustment for biomarkers of inflammation, cardiac stress, and mineral metabolism; left ventricular mass; ejection fraction; and left atrial diameter.ConclusionsIncident AF is independently associated with two- to five-fold increased rates of developing subsequent heart failure, myocardial infarction, stroke, or death in adults with CKD. These findings have important implications for cardiovascular risk reduction.

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Regal, Ronald R., and Ernest B. Hook. "Marginal versus conditional versus ‘structural source’ models: a rationale for an alternative to log-linear methods for capture-recapture estimates." Statistics in Medicine 17, no. 1 (January 15, 1998): 69–74. http://dx.doi.org/10.1002/(sici)1097-0258(19980115)17:1<69::aid-sim729>3.0.co;2-q.

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Resche-Rigon, Matthieu, Marie Robin, Regis Peffault de Latour, Sylvie Chevret, and Gerard P. Socie. "Estimating the Causal Effect of Some Exposure From Nonrandomized Studies: The Example of Reduced Intensity Conditioning (RIC) in Hematological Diseases." Blood 114, no. 22 (November 20, 2009): 3365. http://dx.doi.org/10.1182/blood.v114.22.3365.3365.

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Abstract Abstract 3365 Poster Board III-253 Introduction: Although allogeneic SCT with RIC has now gained wide acceptance, its eventual benefit again non-transplant approach is largely unknown (outside the setting of large randomized trials). When evaluating the impact on survival of reduced intensity conditioning in malignant hematological diseases, standard estimations based on Cox regression from observational databases could be biased because they ignore covariates that confound treatment decision. In this setting, we applied and compared two different statistical methods that were developed to control for confounding in estimating exposure (or treatment) effect from epidemiological studies. Patients and Methods: The statistical challenge was that allograft tended to be given when a patient was in advanced phase of his/her hematological malignancy, so that treatment was confounded by performance indicators, which in turn lie on the causal pathway between treatment and outcome. Thus, comparison of outcome first used propensity score (PS) analyses that attempt to create a comparison group of non-treated patients that closely resembles the group of treated patients by matching for the likelihood that a given patient has received the treatment. Then, we used marginal structural models (MSMs) that consist in creating, by using inverse probability of treatment weights, a pseudo-population in which the probability of treatment does no longer depend on covariates, and the effect of treatment on outcome is the same as in the original population. Result: Reduced intensity conditioning allograft was performed in 82 patients with chemotherapy-sensitive patients relapsing after autologous transplantation. Patients with myeloma (MM, 23 pts), follicular lymphoma (FL, 28 pts) or Hodgkin disease (HD, 31 pts), were compared to 276 patients who relapsed after autologous transplantation but did not underwent allogeneic stem cell transplantation (142 MM, 115 FL and 19 HD). From original datasets, 21 (91%) matched pairs could be constituted from MM patients, as compared to 19 (68%) of the FL patients, down to 15 (48%) of the HD patients. Based on these PS-matched samples, a significant benefit of reduced intensity conditioning as compared with non allografted patients was observed in MM, with estimated hazard ratio (HR) of death at 0.34 (95% confidence interval, CI: 0.14-0.88), as well as in FL (HR= 0.78, 95%CI: 0.27;2.30) and in HD (HR= 0.24; 95%CI: 0.09-0.62). MSM-based analyses that applied to the reweighted populations confirmed these trends towards survival benefits in FL, though partially erased in MM and HD. Conclusions: We reported the application of marginal structural models, a new class of causal models to estimate the effect of nonrandomized treatments as an alternative to PS based approaches in small samples. We expect that an increasing number of physicians involved in clinical cohorts become familiar with these novel and appealing quantitative methods when assessing innovative treatment effects. Disclosures: No relevant conflicts of interest to declare.

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Thomas, Emma G., Matthew J. Spittal, Faye S. Taxman, Cheneal Puljević, Edward B. Heffernan, and Stuart A. Kinner. "Association between contact with mental health and substance use services and reincarceration after release from prison." PLOS ONE 17, no. 9 (September 7, 2022): e0272870. http://dx.doi.org/10.1371/journal.pone.0272870.

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Objective People released from prison who experience mental health and substance use problems are at high risk of reincarceration. This study aimed to examine the association between contact with mental health and substance use treatment services, and reincarceration, among adults released from prison. Methods Pre-release survey data from 1,115 adults released from prisons in Queensland, Australia were linked with administrative health and correctional records covering a median of 787 days post-release. We constructed marginal structural Cox proportional hazards models, adjusting for pre-release variables and time-varying indicators of emergent mental health and substance use problems, to examine the association between contact with mental health and substance use treatment services, and reincarceration. Results The adjusted hazard ratio (AHR) for reincarceration associated with mental health service contact was 1.76 (95%CI 1.23,2.51). Among those not on parole following release, the AHR for reincarceration associated with substance use treatment service contact was 3.16 (95%CI 2.09,4.77); we found no evidence for an association among those who were released on parole (AHR = 1.07; 95%CI 0.80,1.43). Conclusions Although we cannot eliminate the possibility of residual confounding, our findings suggest that infrequent or unsustained contact with community-based mental health and substance use treatment services is not protective against reincarceration, and may even be iatrogenic. Increased investment in high-quality and timely behavioural health services for people released from prison may simultaneously improve health outcomes, and reduce reincarceration.

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Munir, Muhammad Bilal, Patrick Hlavacek, Allison Keshishian, Jennifer D. Guo, Rajesh Mallampati, Mauricio Ferri, Cristina Russ, et al. "Contemporary clinical and economic outcomes among oral anticoagulant treated and untreated elderly patients with atrial fibrillation: Insights from the United States Medicare database." PLOS ONE 17, no. 2 (February 17, 2022): e0263903. http://dx.doi.org/10.1371/journal.pone.0263903.

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Background Oral anticoagulants (OACs) mitigate the risk of stroke in atrial fibrillation (AF) patients. Objective Elderly AF patients who were treated with OACs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin) were compared against AF patients who were not treated with OACs with respect to their clinical and economic outcomes. Methods Newly diagnosed AF patients were identified between January 2013 and December 2017 in the Medicare database. Evidence of an OAC treatment claim on or after the first AF diagnosis was used to classify patients into treatment-defined cohorts, and these cohorts were further stratified based on the initial OAC prescribed. The risks of stroke/systemic embolism (SE), major bleeding (MB), and death were analyzed using inverse probability treatment weighted time-dependent Cox regression models, and costs were compared with marginal structural models. Results The two treatment groups were composed of 1,421,187 AF patients: OAC treated (N = 583,350, 41.0% [36.4% apixaban, 4.9% dabigatran, 0.1% edoxaban, 26.7% rivaroxaban, and 31.9% warfarin patients]) and untreated (N = 837,837, 59.0%). OAC-treated patients had a lower adjusted risk of stroke/SE compared to untreated patients (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.68–0.72). Additionally patients receiving OACs had a lower adjusted risk of death (HR: 0.56; 95% CI: 0.55–0.56) and a higher risk of MB (HR: 1.57; 95% CI: 1.54–1.59) and this trend was consistent across each OAC sub-group. The OAC-treated cohort had lower adjusted total healthcare costs per patient per month ($4,381 vs $7,172; p < .0001). Conclusion For the OAC-treated cohort in this elderly US population, stroke/SE and all-cause death were lower, while risk of MB was higher. Among OAC treated patients, total healthcare costs were lower than those of the untreated cohort.

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Jansz, Thijs T., Marlies Noordzij, Anneke Kramer, Eric Laruelle, Cécile Couchoud, Frederic Collart, Aleix Cases, et al. "Survival of patients treated with extended-hours haemodialysis in Europe: an analysis of the ERA-EDTA Registry." Nephrology Dialysis Transplantation 35, no. 3 (November 18, 2019): 488–95. http://dx.doi.org/10.1093/ndt/gfz208.

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Abstract Background Previous US studies have indicated that haemodialysis with ≥6-h sessions [extended-hours haemodialysis (EHD)] may improve patient survival. However, patient characteristics and treatment practices vary between the USA and Europe. We therefore investigated the effect of EHD three times weekly on survival compared with conventional haemodialysis (CHD) among European patients. Methods We included patients who were treated with haemodialysis between 2010 and 2017 from eight countries providing data to the European Renal Association–European Dialysis and Transplant Association Registry. Haemodialysis session duration and frequency were recorded once every year or at every change of haemodialysis prescription and were categorized into three groups: CHD (three times weekly, 3.5–4 h/treatment), EHD (three times weekly, ≥6 h/treatment) or other. In the primary analyses we attributed death to the treatment at the time of death and in secondary analyses to EHD if ever initiated. We compared mortality risk for EHD to CHD with causal inference from marginal structural models, using Cox proportional hazards models weighted for the inverse probability of treatment and censoring and adjusted for potential confounders. Results From a total of 142 460 patients, 1338 patients were ever treated with EHD (three times, 7.1 ± 0.8 h/week) and 89 819 patients were treated exclusively with CHD (three times, 3.9 ± 0.2 h/week). Crude mortality rates were 6.0 and 13.5/100 person-years. In the primary analyses, patients treated with EHD had an adjusted hazard ratio (HR) of 0.73 [95% confidence interval (CI) 0.62–0.85] compared with patients treated with CHD. When we attributed all deaths to EHD after initiation, the HR for EHD was comparable to the primary analyses [HR 0.80 (95% CI 0.71–0.90)]. Conclusions EHD is associated with better survival in European patients treated with haemodialysis three times weekly.

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Memel, Zoe N., Jenny J. Lee, Andrea S. Foulkes, Raymond T. Chung, Tanayott Thaweethai, and Patricia P. Bloom. "Association of Statins and 28-Day Mortality Rates in Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 Infection." Journal of Infectious Diseases 225, no. 1 (October 19, 2021): 19–29. http://dx.doi.org/10.1093/infdis/jiab539.

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Abstract Background Statins may be protective in severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection. The aim of the current study was to evaluate the effect of in-hospital statin use on 28-day mortality rates and intensive care unit (ICU) admission among patients with SARS-CoV-2, stratified into 4 groups: those who used statins before hospitalization (treatment continued or discontinued in the hospital) and those who did not (treatment newly initiated in the hospital or never initiated). Methods In a cohort study of 1179 patients with SARS-CoV-2, record review was used to assess demographics, laboratory measurements, comorbid conditions, and time from admission to death, ICU admission, or discharge. Using marginal structural Cox models, we estimated hazard ratios (HRs) for death and ICU admission. Results Among 1179 patients, 676 (57%) were male, 443 (37%) were >65 years old, and 493 (46%) had a body mass index ≥30 (calculated as weight in kilograms divided by height in meters squared). Inpatient statin use reduced the hazard of death (HR, 0.566; P=.008). This association held among patients who did and those who did not use statins before hospitalization (HR, 0.270 [P=.003] and 0.493 [P=.04], respectively). Statin use was associated with improved time to death for patients aged >65 years but not for those ≤65 years old. Conclusion Statin use during hospitalization for SARS-CoV-2 infection was associated with reduced 28-day mortality rates. Well-designed randomized control trials are needed to better define this relationship.

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Kirchgesner, Julien, Nynne Nyboe Andersen, Fabrice Carrat, Tine Jess, and Laurent Beaugerie. "Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study." Gut 69, no. 5 (August 24, 2019): 852–58. http://dx.doi.org/10.1136/gutjnl-2019-318932.

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ObjectivePatients with IBD are at increased risk of acute arterial events. Antitumour necrosis factor (TNF) agents and thiopurines may, via their anti-inflammatory properties, lower the risk of acute arterial events. The aim of this study was to assess the impact of thiopurines and anti-TNFs on the risk of acute arterial events in patients with IBD.DesignPatients aged 18 years or older and affiliated to the French national health insurance with a diagnosis of IBD were followed up from 1 April 2010 until 31 December 2014. The risks of acute arterial events (including ischaemic heart disease, cerebrovascular disease and peripheral artery disease) were compared between thiopurines and anti-TNFs exposed and unexposed patients with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, traditional cardiovascular risk factors, comorbidities and IBD disease activity.ResultsAmong 177 827 patients with IBD (96 111 (54%) women, mean age at cohort entry 46.2 years (SD 16.3), 90 205 (50.7%) with Crohn’s disease (CD)), 4145 incident acute arterial events occurred (incidence rates: 5.4 per 1000 person-years). Compared with unexposed patients, exposure to anti-TNFs (HR 0.79, 95% CI 0.66 to 0.95), but not to thiopurines (HR 0.93, 95% CI 0.82 to 1.05), was associated with a decreased risk of acute arterial events. The magnitude in risk reduction was highest in men with CD exposed to anti-TNFs (HR 0.54, 95% CI 0.40 to 0.72).ConclusionExposure to anti-TNFs is associated with a decreased risk of acute arterial events in patients with IBD, particularly in men with CD.

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Chirgwin, Jacquie H., Anita Giobbie-Hurder, Alan S. Coates, Karen N. Price, Bent Ejlertsen, Marc Debled, Richard D. Gelber, et al. "Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence." Journal of Clinical Oncology 34, no. 21 (July 20, 2016): 2452–59. http://dx.doi.org/10.1200/jco.2015.63.8619.

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Purpose To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial. Methods The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor–positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards models were used to evaluate the relationship between DFS and treatment adherence (persistence [duration] and compliance with dosage). Competing risks regression was used to assess demographic, disease, and treatment characteristics of the women who stopped treatment early because of adverse events. Results Both aspects of low adherence (early cessation of letrozole and a compliance score of < 90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event. Conclusion Both persistence and compliance are associated with DFS. Toxicity management and, for sequential treatments, patient and physician awareness, may improve adherence.

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Hoque, M. R., A. Aviña, M. De Vera, Y. Qian, J. Esdaile, and H. Xie. "SAT0175 IMPACT OF ANTIMALARIAL ADHERENCE ON MORTALITY AMONG PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: A POPULATION-BASED COHORT STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1029.1–1029. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3340.

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Background:Evidence has consistently shown that adherence to AM is poor in systemic lupus erythematosus (SLE) patients. However, data on the impact of adherence to AM on mortality is scarce.Objectives:To assess the effect of AM adherence on all-cause mortality in SLE patients from the general population.Methods:This study used administrative databases from British Columbia, Canada. We created an incident SLE cohort between January 01, 1997, and March 31, 2015, using the physician billing data and a 7-year washout period. The inclusion criteria were at least two physician visits, at least two months apart, within two years, with an ICD-9 code (710.0) or ICD-10 code (M32.1, M32.8, M32.9) for SLE. Follow-up started at the first day of having both SLE and AM, i.e., at the SLE index date (second ICD code) for those whose first AM use occurred before the SLE index date, or the date of the first AM use if otherwise. Our outcome was all-cause mortality, obtained from the vital statistics registry. In the analysis, the follow-up time was divided into 30-days windows, for a total of 293,190 person-months. For each window, a measure of adherence, the proportion of days covered (PDC), was calculated and categorized as adherent (PDC≥0.90), non-adherent (0<PDC<0.90), and discontinuer (no drug or PDC = 0). We used both Cox’s proportional hazards models and marginal structural models (MSM) to estimate the effect of AM adherence on all-cause mortality. Both analysis controlled for baseline demographics (age, sex, residence, income quintile), as well as the following baseline and time-varying covariates: immunosuppressive and other medications, hospitalizations, impatient, and other visits, and Charlson comorbidity index. To account for the possibility of a few time-varying covariates being mediators in the causal pathway from AM adherence to mortality, which may cause the Cox model to yield biased estimates of the adherence effects, we conducted the MSM analysis that can produce valid estimates as it balances the distributions of time-varying confounders among the three adherence groups via inverse probability weighting.Results:We identified 3,385 individuals with incident SLE (mean age 47.3 years, 89% were women) who had at least one filled AM prescription. Over the mean follow-up of 6.66 years, 288 (8.5%) incident SLE patients died. The incidence rate (IR) of mortality for AM adherent, non-adherent, and discontinuer patients were 4.31, 11.86, and 19.51 per 1000 person-years, respectively. Using the Cox model, the adjusted hazard ratio (HRs) obtained for AM adherent and non-adherent SLE patients were 0.20 and 0.66, respectively, compared to discontinuer SLE patients (Table 1). Using MSM, those adjusted HRs were found as 0.18 and 0.64. Also, the adjusted HRs for adherers compared to the non-adherers were 0.30 (Cox) and 0.28 (MSM). A statistically significant linear trend in the HRs of mortality risk over the adherence levels was found (Table 1, Linear Trend).Table 1.Adherence LevelsNo. of DeathsIR Ratios (95%CI)Adjusted Cox HRs (95%CI)Adjusted MSM HRs (95%CI)Discontinuer (Reference)198Non-adherent470.61(0.44-0.84)0.66(0.47-0.93)0.64(0.46-0.89)Adherent430.22(0.16-0.31)0.20(0.14-0.28)0.18(0.12-0.25)Contrast: Partial vs. Full0.36(0.24-0.55)0.30(0.19-0.46)0.28(0.18-0.42)Linear Trend0.32(0.25-0.41)0.29(0.23-0.37)Conclusion:SLE patients that adhere to AM therapy have a lower risk of death than patients who do not adhere or who discontinue AM (5 and 3 times, respectively) in both the MSM and Cox analysis. Our findings support the importance of AM adherence to prevent premature deaths in SLE patients.Disclosure of Interests:None declared

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Marathe, Gayatri, Erica E. M. Moodie, Marie-Josée Brouillette, Joseph Cox, Charlotte Lanièce Delaunay, Curtis Cooper, Mark Hull, et al. "Depressive symptoms are no longer a barrier to HCV treatment initiation in the HIV–HCV co-infected population in Canada." Antiviral Therapy 27, no. 1 (February 2022): 135965352110676. http://dx.doi.org/10.1177/13596535211067610.

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Background Psychiatric illness was a major barrier for HCV treatment during the Interferon (IFN) treatment era due to neuropsychiatric side effects. While direct acting antivirals (DAA) are better tolerated, patient-level barriers persist. We aimed to assess the effect of depressive symptoms on time to HCV treatment initiation among HIV–HCV co-infected persons during the IFN (2003–2011) and second-generation DAA (2013–2020) eras. Methods We used data from the Canadian Co-infection Cohort, a multicentre prospective cohort, and its associated sub-study on Food Security (FS). We predicted Center for Epidemiologic Studies Depression Scale-10 (CES-D-10) classes for depressive symptoms indicative of a depression risk using a random forest classifier and corrected for misclassification using predictive value-based record-level correction. We used marginal structural Cox proportional hazards models with inverse weighting for competing risks (death) to assess the effect of depressive symptoms on treatment initiation among HCV RNA-positive participants. Results We included 590 and 1127 participants in the IFN and DAA eras. The treatment initiation rate increased from 9 (95% confidence interval (CI): 7–10) to 21 (95% CI: 19–22) per 100 person-years from the IFN to DAA era. Treatment initiation was lower among those with depressive symptoms compared to those without in the IFN era (hazard ratio: 0.81 (95% CI: 0.69–0.95)) and was higher in the DAA era (1.19 (95% CI: 1.10–1.27)). Conclusion Depressive symptoms no longer appear to be a barrier to HCV treatment initiation in the co-infected population in the DAA era. The higher rate of treatment initiation in individuals with depressive symptoms suggests those previously unable to tolerate IFN are now accessing treatment.

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Cohen, Seth M., Hui-Jie Lee, David A. Leiman, Nelson Roy, and Stephanie Misono. "Associations between Community-Acquired Pneumonia and Proton Pump Inhibitors in the Laryngeal/Voice-Disordered Population." Otolaryngology–Head and Neck Surgery 160, no. 3 (November 13, 2018): 519–25. http://dx.doi.org/10.1177/0194599818811292.

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Objectives To examine the relationship between community-acquired pneumonia (CAP) and proton pump inhibitor (PPI) treatment among patients with laryngeal/voice disorders. Study Design Retrospective cohort analysis. Setting Large national administrative US claims database. Subjects and Methods Patients were included if they were ≥18 years old; had outpatient treatment for a laryngeal/voice disorder from January 1, 2010, to December 31, 2014 (per International Classification of Diseases, Ninth Revision, Clinical Modification codes); had 12 months of continuous enrollment prior to the index date (ie, first diagnosis of laryngeal/voice disorder); had no preindex diagnosis of CAP; and had prescription claims captured from 1 year preindex to end of follow-up. Patient demographics, comorbid conditions, index laryngeal diagnosis, number of unique preindex patient encounters, and CAP diagnoses during the postindex 3 years were collected. Two models—a time-dependent Cox regression model and a propensity score–based approach with a marginal structural model—were separately performed for patients with and without pre–index date PPI prescriptions. Results A total of 392,355 unique patients met inclusion criteria; 188,128 (47.9%) had a PPI prescription. The 3-year absolute risk for CAP was 4.0% and 5.3% among patients without and with preindex PPI use, respectively. For patients without and with pre–index date PPI use, the CAP occurrence for a person who had already received a PPI is 30% to 50% higher, respectively, than for a person who had not yet had a PPI but may receive one later. Conclusions Patients without and with pre–index date PPI use experienced a roughly 30% to 50% increased likelihood of CAP, respectively, as compared with patients who had not had PPI prescriptions.

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Veluswamy, Rajwanth, Jiayi Ji, Liangyuan Hu, Xiaoliang Wang, Cardinale B. Smith, and Minal Kale. "Effect of first-line pembrolizumab treatment in individuals with advanced non-small cell lung cancer and poor performance status." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e18796-e18796. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e18796.

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e18796 Background: There is limited evidence supporting the optimal use of immune checkpoint inhibitors (ICIs) in NSCLC patients with poor performance status (PS), as clinical trials exclude these patients. In this study, we use real-world oncology data to determine the impact of first line pembrolizumab vs. no treatment in high PD(L)-1 expressing cancers in individuals with advanced NSCLC and ECOG PS ≥2. Methods: We performed a retrospective cohort study of patients with advanced NSCLC with ECOG PS ≥2 between 09/01/2014 and 02/18/2020, using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Patients were included if they were PD(L)-1 high (≥50%) and had clinical and treatment information recorded within 90 days of diagnosis. Real-world overall survival (rwOS) was defined as time from diagnosis to death (censored at last EHR activity). Median rwOS was estimated using weighted Kaplan-Meier methods. A marginal Cox structural model with inverse probability of treatment weighting was used to adjust for selection bias and estimate the effectiveness of pembrolizumab. The inverse probability weights were estimated using an ensemble machine learning technique, Super Learner, based on age, gender, race, practice type and smoking history. Adjusted hazard ratios (aHR) were estimated using weighted Cox proportional hazards models. Stratified analysis was conducted by ECOG PS (2 vs >2). Results: 217 (16%) individuals with advanced NSCLC and high PD(L)-1 expression received no treatment, compared to 546 (39%) individuals who received 1L pembrolizumab. The no-treatment group had a lower proportion of ECOG 2 compared to the pembrolizumab group (Table). Median rwOS in the no-treatment group was 2.4 months, compared to 7.1 months in the pembrolizumab group (p<0.001). In unadjusted survival analyses in the entire cohort and in cohorts stratified by ECOG status, treatment with pembrolizumab was associated with a significantly lower risk of death (hazard ratio [HR]: 0.38, 95% Confidence Interval [CI]: 0.31-0.45). In adjusted analyses, individuals treated with pembrolizumab had improved survival (HR: 0.40, 95% CI: 0.35-0.45). Conclusions: Our analysis of real-world clinical oncology data demonstrated that 1L treatment with pembrolizumab was associated with significantly improved rwOS among individuals with ECOG ≥ 2. [Table: see text]

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De Stavola, Bianca L., and Rhian M. Daniel. "Marginal Structural Models." Epidemiology 23, no. 2 (March 2012): 233–37. http://dx.doi.org/10.1097/ede.0b013e318245847e.

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Kennedy, Mary Clare, Alexis Crabtree, Seonaid Nolan, Wing Yin Mok, Zishan Cui, Mei Chong, Amanda Slaunwhite, and Lianping Ti. "Discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain with and without opioid use disorder in British Columbia, Canada: A retrospective cohort study." PLOS Medicine 19, no. 12 (December 1, 2022): e1004123. http://dx.doi.org/10.1371/journal.pmed.1004123.

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Background The overdose crisis in North America has prompted system-level efforts to restrict opioid prescribing for chronic pain. However, little is known about how discontinuing or tapering prescribed opioids for chronic pain shapes overdose risk, including possible differential effects among people with and without concurrent opioid use disorder (OUD). We examined associations between discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain, stratified by diagnosed OUD and prescribed opioid agonist therapy (OAT) status. Methods and findings For this retrospective cohort study, we used a 20% random sample of residents in the provincial health insurance client roster in British Columbia (BC), Canada, contained in the BC Provincial Overdose Cohort. The study sample included persons aged 14 to 74 years on long-term opioid therapy for pain (≥90 days with ≥90% of days on therapy) between October 2014 and June 2018 (n = 14,037). At baseline, 7,256 (51.7%) persons were female, the median age was 55 years (quartile 1–3: 47–63), 227 (1.6%) persons had been diagnosed with OUD (in the past 3 years) and recently (i.e., in the past 90 days) been prescribed OAT, and 483 (3.4%) had been diagnosed with OUD but not recently prescribed OAT. The median follow-up duration per person was 3.7 years (quartile 1–3: 2.6–4.0). Marginal structural Cox regression with inverse probability of treatment weighting (IPTW) was used to estimate the effect of prescribed opioid treatment for pain status (discontinuation versus tapered therapy versus continued therapy [reference]) on risk of overdose (fatal or nonfatal), stratified by the following groups: people without diagnosed OUD, people with diagnosed OUD receiving OAT, and people with diagnosed OUD not receiving OAT. In marginal structural models with IPTW adjusted for a range of demographic, prescription, comorbidity, and social-structural exposures, discontinuing opioids (i.e., ≥7-day gap[s] in therapy) was associated with increased overdose risk among people without OUD (adjusted hazard ratio [AHR] = 1.44; 95% confidence interval [CI] 1.12, 1.83; p = 0.004), people with OUD not receiving OAT (AHR = 3.18; 95% CI 1.87, 5.40; p < 0.001), and people with OUD receiving OAT (AHR = 2.52; 95% CI 1.68, 3.78; p < 0.001). Opioid tapering (i.e., ≥2 sequential decreases of ≥5% in average daily morphine milligram equivalents) was associated with decreased overdose risk among people with OUD not receiving OAT (AHR = 0.31; 95% CI 0.14, 0.67; p = 0.003). The main study limitations are that the outcome measure did not capture overdose events that did not result in a healthcare encounter or death, medication dispensation may not reflect medication adherence, residual confounding may have influenced findings, and findings may not be generalizable to persons on opioid therapy in other settings. Conclusions Discontinuing prescribed opioids was associated with increased overdose risk, particularly among people with OUD. Prescribed opioid tapering was associated with reduced overdose risk among people with OUD not receiving OAT. These findings highlight the need to avoid abrupt discontinuation of opioids for pain. Enhanced guidance is needed to support prescribers in implementing opioid therapy tapering strategies with consideration of OUD and OAT status.

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Xing, Yihan, Tan Aditya Dwi Santoso, and Yucong Ma. "Technical–Economic Feasibility Analysis of Subsea Shuttle Tanker." Journal of Marine Science and Engineering 10, no. 1 (December 26, 2021): 20. http://dx.doi.org/10.3390/jmse10010020.

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This paper presents the technical and economic feasibility analysis of the subsea shuttle tanker (SST). The SST is proposed as an alternative to subsea pipelines and surface tankers with the primary purpose of transporting CO2 autonomously underwater from onshore facilities to subsea wells for direct injection at marginal subsea fields. In contrast to highly weather-dependent surface tanker operations, the SST can operate in any condition underwater. The technical–economic analysis is performed in two steps. First, the SST’s technical feasibility is evaluated by investigating designs with lower and higher capacities. The purpose is to observe the appearance of technical limits (if present) when the SST is scaled down or up in size. Second, an economic analysis is performed using the well-reviewed cost models from the publicly available Zero Emissions Platform (ZEP) and Maritime Un-manned Navigation through Intelligence in Networks (MUNIN) D9.3 reports. The scenarios considered are CO2 transport volumes of 1 to 20 million tons per annum (mtpa) with transport distances of 180 km to 1500 km in which the cost per ton of CO2 is compared between offshore pipelines, crewed/autonomous tanker ships, and SST. The results show that SSTs with cargo capacities 10,569 m3, 23,239 m3, and 40,730 m3 are technically feasible. Furthermore, the SSTs are competitive for short and intermediate distances of 180–750 km and smaller CO2 volumes of 1–2.5 mtpa. Lastly, it is mentioned that the SST design used the DNVGL Rules for Classification for Naval Vessels, Part 4 Sub-surface ships, Chapter 1 Submarine, DNVGL-RU-NAVAL-Pt4Ch1, which is primarily catered towards military submarine design. It is expected that a dedicated structural design code that is optimized for the SST would reduce the structural weight and corresponding capital expenditure (CAPEX).

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Longo, Cristina, Gillian Bartlett, Tibor Schuster, Francine M. Ducharme, Brenda MacGibbon, and Tracie A. Barnett. "Influence of weight status in the response to Step-2 maintenance therapies in children with asthma." BMJ Open Respiratory Research 6, no. 1 (April 2019): e000401. http://dx.doi.org/10.1136/bmjresp-2019-000401.

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IntroductionOverweight children with asthma may display impaired response to inhaled corticosteroids (ICS), possibly due to non-eosinophilic inflammation or weight-related lung compression; these mechanisms may differentially affect response to ICS and leukotriene receptor antagonists (LTRAs). We assessed whether weight status modified the response to low-dose ICS and LTRA Step-2 monotherapy.MethodsA historical cohort study from clinical data linked to administrative databases was conducted among children aged 2–18 years with specialist-diagnosed asthma who were initiating or continuing a Step-2 monotherapy from 2000 to 2007 at the Montreal Children’s Hospital Asthma Centre. The outcome was time-to-management failure defined as any step-up in therapy, acute care visit, hospitalisation or oral corticosteroids for asthma, whichever occurred first. The independent and joint effects of weight status (body mass index [BMI] percentile) and time-varying treatment on time-to-management failure were estimated with marginal structural Cox models. The likelihood ratio test (LRT) and relative excess risk due to interaction (RERI) were computed to assess treatment effect modification by weight status on the multiplicative and additive scales.ResultsOf the 433 and 85 visits with a low-dose ICS and LTRA prescription, respectively, 388 management failures occurred over 14 529 visit-weeks of follow-up. Children using LTRA compared with low-dose ICS tended to have an overall higher risk of early management failure (HR 1.52; 95% CI 0.72 to 3.22). Irrespective of treatment, the hazard of management failure increased by 5% (HR 1.05; 95% CI 1.01 to 1.10) for every 10-unit increase in BMI percentile. An additional hazard reduction of 17% (HR 0.83; 95% CI 0.70 to 0.99) was observed for every 10-unit increase in BMI percentile among LTRA users, but not for ICS (HR 0.95; 95% CI 0.86 to 1.04). The LRT indicated a departure from exact multiplicativity (p<0.0001), and the RERIs for ICS and LTRA were −0.05 (95% CI −0.14 to 0.05) and −0.52 (95% CI −1.76 to 0.71).ConclusionsWeight status was associated with earlier time-to-management failure in children prescribed Step-2 therapy. This hypothesis-generating study suggests that LTRA response increases in children with higher BMI percentiles, although further research is warranted to confirm findings.

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Honda, Toshio. "Estimation in additive cox models by marginal integration." Annals of the Institute of Statistical Mathematics 57, no. 3 (September 2005): 403–23. http://dx.doi.org/10.1007/bf02509232.

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Liu, Shao-Hsien, Stavroula A. Chrysanthopoulou, Qiuzhi Chang, Jacob N. Hunnicutt, and Kate L. Lapane. "Missing Data in Marginal Structural Models." Medical Care 57, no. 3 (March 2019): 237–43. http://dx.doi.org/10.1097/mlr.0000000000001063.

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Bryan, J. "Analysis of longitudinal marginal structural models." Biostatistics 5, no. 3 (July 1, 2004): 361–80. http://dx.doi.org/10.1093/biostatistics/kxg041.

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Smith, Madison M., Marika Holland, and Bonnie Light. "Arctic sea ice sensitivity to lateral melting representation in a coupled climate model." Cryosphere 16, no. 2 (February 4, 2022): 419–34. http://dx.doi.org/10.5194/tc-16-419-2022.

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Abstract. The melting of sea ice floes from the edges (lateral melting) results in open-water formation and subsequently increases absorption of solar shortwave energy. However, lateral melt plays a small role in the sea ice mass budget in both hemispheres in most climate models. This is likely influenced by the simple parameterization of lateral melting in sea ice models that are constrained by limited observations. Here we use a coupled climate model (CESM2.0) to assess the sensitivity of modeled sea ice state to the lateral melt parameterization in preindustrial and 2×CO2 runs. The runs explore the implications of how lateral melting is parameterized and structural changes in how it is applied. The results show that sea ice is sensitive both to the parameters determining the effective lateral melt rate and the nuances in how lateral melting is applied to the ice pack. Increasing the lateral melt rate is largely compensated for by decreases in the basal melt rate but still results in a significant decrease in sea ice concentration and thickness, particularly in the marginal ice zone. Our analysis suggests that this is tied to the increased efficiency of lateral melting at forming open water during the summer melt season, which drives the majority of the ice–albedo feedback. The more seasonal Southern Hemisphere ice cover undergoes larger relative reductions in sea ice concentration and thickness for the same relative increase in lateral melt rate, likely due to the hemispheric differences in the role of the sea-ice–upper-ocean coupling. Additionally, increasing the lateral melt rate under a 2×CO2 forcing, where sea ice is thinner, results in a smaller relative change in sea ice mean state but suggests that open-water-formation feedbacks are likely to steepen the decline to ice-free summer conditions. Overall, melt processes are more efficient at forming open water in thinner ice scenarios (as we are likely to see in the future), suggesting the importance of accurately representing thermodynamic evolution. Revisiting model parameterizations of lateral melting with observations will require finding new ways to represent salient physical processes.

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Saarela, Olli, David A. Stephens, Erica E. M. Moodie, and Marina B. Klein. "On Bayesian estimation of marginal structural models." Biometrics 71, no. 2 (February 10, 2015): 279–88. http://dx.doi.org/10.1111/biom.12269.

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VanderWeele, Tyler J., Stijn Vansteelandt, and James M. Robins. "Marginal Structural Models for Sufficient Cause Interactions." American Journal of Epidemiology 171, no. 4 (January 11, 2010): 506–14. http://dx.doi.org/10.1093/aje/kwp396.

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Chiba, Yasutaka, Kenichi Azuma, and Jiro Okumura. "Marginal Structural Models for Estimating Effect Modification." Annals of Epidemiology 19, no. 5 (May 2009): 298–303. http://dx.doi.org/10.1016/j.annepidem.2009.01.025.

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Vansteelandt, S., K. Mertens, C. Suetens, and E. Goetghebeur. "Marginal structural models for partial exposure regimes." Biostatistics 10, no. 1 (May 23, 2008): 46–59. http://dx.doi.org/10.1093/biostatistics/kxn012.

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Platt, Robert W., M. Alan Brookhart, Stephen R. Cole, Daniel Westreich, and Enrique F. Schisterman. "An information criterion for marginal structural models." Statistics in Medicine 32, no. 8 (September 12, 2012): 1383–93. http://dx.doi.org/10.1002/sim.5599.

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Medialdea, Adriana, José Miguel Angulo, and Jorge Mateu. "Structural Complexity and Informational Transfer in Spatial Log-Gaussian Cox Processes." Entropy 23, no. 9 (August 31, 2021): 1135. http://dx.doi.org/10.3390/e23091135.

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The doubly stochastic mechanism generating the realizations of spatial log-Gaussian Cox processes is empirically assessed in terms of generalized entropy, divergence and complexity measures. The aim is to characterize the contribution to stochasticity from the two phases involved, in relation to the transfer of information from the intensity field to the resulting point pattern, as well as regarding their marginal random structure. A number of scenarios are explored regarding the Matérn model for the covariance of the underlying log-intensity random field. Sensitivity with respect to varying values of the model parameters, as well as of the deformation parameters involved in the generalized informational measures, is analyzed on the basis of regular lattice partitionings. Both a marginal global assessment based on entropy and complexity measures, and a joint local assessment based on divergence and relative complexity measures, are addressed. A Poisson process and a log-Gaussian Cox process with white noise intensity, the first providing an upper bound for entropy, are considered as reference cases. Differences regarding the transfer of structural information from the intensity field to the subsequently generated point patterns, reflected by entropy, divergence and complexity estimates, are discussed according to the specifications considered. In particular, the magnitude of the decrease in marginal entropy estimates between the intensity random fields and the corresponding point patterns quantitatively discriminates the global effect of the additional source of variability involved in the second phase of the double stochasticity.

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Sato, Tosiya, and Yutaka Matsuyama. "Marginal Structural Models as a Tool for Standardization." Epidemiology 14, no. 6 (November 2003): 680–86. http://dx.doi.org/10.1097/01.ede.0000081989.82616.7d.

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Tan, Zhiqiang. "Marginal and Nested Structural Models Using Instrumental Variables." Journal of the American Statistical Association 105, no. 489 (March 1, 2010): 157–69. http://dx.doi.org/10.1198/jasa.2009.tm08299.

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Journal articles on the topic 'Marginal Structural Cox models'

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