Marginal Causal Sub-Group Analysis with Incomplete Covariate Data

Incomplete data arises frequently in health research studies designed to investigate the causal relationship between a treatment or exposure, and a response of interest. Statistical methods for conditional causal effect parameters in the setting of incomplete data have been developed, and we expand upon these methods for estimating marginal causal effect parameters. This thesis focuses on the estimation of marginal causal odds ratios, which are distinct from conditional causal odds ratios in logistic regression models; marginal causal odds ratios are frequently of interest in population studies. We introduce three methods for estimating the marginal causal odds ratio of a binary response for different levels of a subgroup variable, where the subgroup variable is incomplete. In each chapter, the subgroup variable, exposure variable and the response variable are binary and the subgroup variable is missing at random. In Chapter 2, we begin with an overview of inverse probability weighted methods for confounding in an observational setting where data are complete. We also briefly review methods to deal with incomplete data in a randomized setting. We then introduce a doubly inverse probability weighted estimating equation approach to estimate marginal causal odds ratios in an observational setting, where an important subgroup variable is incomplete. One inverse probability weight accounts for the incomplete data, and the other weight accounts for treatment selection. Only complete cases are included in the response model. Consistency results are derived, and a method to obtain estimates of the asymptotic standard error is introduced; the extra variability introduced by estimating two weights is incorporated in the estimation of the asymptotic standard error. We give a method for hypothesis testing and calculation of confidence intervals. Simulation studies show that the doubly weighted estimating equation approach is effective in a non-ignorable missingness setting with confounding, and it is straightforward to implement. It also performs well when the missing data process is ignorable, and/or when confounding is not present. In Chapter 3, we begin with an overview of an EM algorithm approach for estimating conditional causal effect parameters in the setting of incomplete covariate data, in both randomized and observational settings. We then propose the use of a doubly weighted EM-type algorithm approach to estimate the marginal causal odds ratio in the setting of missing subgroup data. In this method, instead of using complete case analysis in the response model, all available data is used and the incomplete subgroup variable is “filled in” using a maximum likelihood approach. Two inverse probability weights are used here as well, to account for confounding and incomplete data. The weight which accounts for the incomplete data is needed, even though an EM approach is being used, because the marginal causal odds ratio is of interest. A method to obtain asymptotic standard error estimates is given where the extra variability introduced by estimating the two inverse probability weights, as well as the variability introduced by estimating the conditional expectation of the incomplete subgroup variable, is incorporated. Simulation studies show that this method is effective in terms of obtaining consistent estimates of the parameters of interest; however it is difficult to implement, and in certain settings there is a loss of efficiency in comparison to the methods introduced in Chapter 2. In Chapter 4, we begin by reviewing multiple imputation methods in randomized and observational settings, where estimation of the conditional causal odds ratio is of interest. We then propose the use of multiple imputation with one inverse probability weight to account for confounding in an observational setting where the subgroup variable is incomplete. We discuss methods to correctly specify the imputation model in the setting where the conditional causal odds ratio is of interest, as well as in the setting where the marginal causal odds ratio is of interest. We use standard methods for combining the estimates of the marginal log odds ratios from each imputed dataset. We propose a method for estimating the asymptotic standard error of the estimates, which incorporates both the estimation of the parameters in the weight for confounding, and the multiply imputed datasets. We give a method for hypothesis testing and calculation of confidence intervals. Simulation studies show that this method is efficient and straightforward to implement, but correct specification of the imputation model is necessary. In Chapter 5, the three methods that have been introduced are used in an application to an observational cohort study of 418 colorectal cancer patients. We compare patients who received an experimental chemotherapy with patients who received standard chemotherapy; of interest is estimation of the marginal causal odds ratio of a thrombotic event during the course of treatment or 30 days after treatment is discontinued. The important subgroups are (i) patients receiving first line of treatment, and (ii) patients receiving second line of treatment. In Chapter 6, we compare and contrast the three methods proposed. We also discuss extensions to different response models, models for missing response data, and weighted models in the longitudinal data setting

Effect of Colchicine on the Risk of Perioperative Acute Kidney Injury: Clinical Protocol of a Substudy of the Colchicine for the Prevention of Perioperative Atrial Fibrillation Randomized Clinical Trial

Acute kidney injury; Colchicine; Noncardiac surgeryLesión renal aguda; Colchicina; Cirugía no cardiacaLesión renal aguda; Colchicina; Cirugía no cardiacaBackground: Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Objective: Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Design and Setting: Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients: Patients (~3200) aged 55 years and older having major thoracic surgery. Intervention: Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Methods: Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2. Limitations: The substudy will be underpowered to detect small effects on more severe forms of acute kidney injury treated with dialysis. Results: Substudy results will be reported in 2024. Conclusions: This substudy will estimate the effect of colchicine on the risk of perioperative acute kidney injury in older adults undergoing major thoracic surgery.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Canadian Institutes of Health Research provided an operating grant for the main COP-AF trial. General Research Fund (14121720), Research Grants Council, Hong Kong Special Administrative Region, China. The Department of Medicine at Western University provided additional financial support for this substudy. In addition, the authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: AXG is supported by the Dr Adam Linton Chair in Kidney Health Analytics. PJ Devereaux is supported by a Tier 1 Canada Research Chair in Perioperative Medicine. CP is a member of the advisory board and owns equity in RenalytixAI. He also serves as a consultant for Genfit and is supported by NIH grants R01HL085757, U01DK114866, U01DK106962, U01DK129984, R01DK093770, and P30DK079310. EP is supported by a research grant from Generalitat de Catalunya (PERIS SLT017/20/000089). MKW is supported by the PSI Foundation—Research Trainee Award. D Conen received speaker fees from Servier Canada and BMS/Pfizer, and he received consulting fees from Trimedics and Roche Diagnostics, all outside of the current work. No funding entity had a role in data collection, statistical analysis, article writing, or the decision to publish

Effects of accelerated versus standard care surgery on the risk of acute kidney injury in patients with a hip fracture: a substudy protocol of the hip fracture accelerated surgical treatment and care track (HIP ATTACK) international randomised controlled trial

Accelerated surgery; Acute kidney injury; Hip fractureCirugía acelerada; Lesión renal aguda; Fractura de caderaCirurgia accelerada; Lesions renals agudes; Fractura de malucIntroduction: Inflammation, dehydration, hypotension and bleeding may all contribute to the development of acute kidney injury (AKI). Accelerated surgery after a hip fracture can decrease the exposure time to such contributors and may reduce the risk of AKI. Methods and analysis: Hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) is a multicentre, international, parallel-group randomised controlled trial (RCT). Patients who suffer a hip fracture are randomly allocated to either accelerated medical assessment and surgical repair with a goal of surgery within 6 hours of diagnosis or standard care where a repair typically occurs 24 to 48 hours after diagnosis. The primary outcome of this substudy is the development of AKI within 7 days of randomisation. We anticipate at least 1998 patients will participate in this substudy. Ethics and dissemination: We obtained ethics approval for additional serum creatinine recordings in consecutive patients enrolled at 70 participating centres. All patients provide consent before randomisation. We anticipate reporting substudy results by 2021. Trial registration number: NCT02027896; Pre-results.This work was supported by the following grants: Canadian Institute of Health and Research (CIHR) Foundation Award, CIHR’s Strategy for Patient Oriented Research (SPOR), through the Ontario SPOR Support Unit, which is supported by the CIHR and the Province of Ontario, as well as the Ontario Ministry of Health and Long-Term Care, and a grant from Smith & Nephew to recruit 300 patients in Spain. Grants to support this substudy were provided by the Department of Medicine at Western University. Dr Devereaux was supported by a Tier 1 Canada Research Chair in Perioperative Medicine. Dr Amit Garg was supported by the Dr Adam Linton Chair in Kidney Health Analytics and a CIHR Clinician Investigator Award

Effects of accelerated versus standard care surgery on the risk of acute kidney injury in patients with a hip fracture: A substudy protocol of the hip fracture accelerated surgical treatment and care track (hip attack) international randomised controlled trial

Introduction: Inflammation, dehydration, hypotension and bleeding may all contribute to the development of acute kidney injury (AKI). Accelerated surgery after a hip fracture can decrease the exposure time to such contributors and may reduce the risk of AKI.Methods and analysis: Hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) is a multicentre, international, parallel-group randomised controlled trial (RCT). Patients who suffer a hip fracture are randomly allocated to either accelerated medical assessment and surgical repair with a goal of surgery within 6 hours of diagnosis or standard care where a repair typically occurs 24 to 48 hours after diagnosis. The primary outcome of this substudy is the development of AKI within 7 days of randomisation. We anticipate at least 1998 patients will participate in this substudy.Ethics and dissemination: We obtained ethics approval for additional serum creatinine recordings in consecutive patients enrolled at 70 participating centres. All patients provide consent before randomisation. We anticipate reporting substudy results by 2021.Trial registration number: NCT02027896; Pre-results

Evaluating the impact of MEDLINE filters on evidence retrieval: study protocol

<p>Abstract</p> <p>Background</p> <p>Rather than searching the entire MEDLINE database, clinicians can perform searches on a filtered set of articles where relevant information is more likely to be found. Members of our team previously developed two types of MEDLINE filters. The 'methods' filters help identify clinical research of high methodological merit. The 'content' filters help identify articles in the discipline of renal medicine. We will now test the utility of these filters for physician MEDLINE searching.</p> <p>Hypothesis</p> <p>When a physician searches MEDLINE, we hypothesize the use of filters will increase the number of relevant articles retrieved (increase 'recall,' also called sensitivity) and decrease the number of non-relevant articles retrieved (increase 'precision,' also called positive predictive value), compared to the performance of a physician's search unaided by filters.</p> <p>Methods</p> <p>We will survey a random sample of 100 nephrologists in Canada to obtain the MEDLINE search that they would first perform themselves for a focused clinical question. Each question we provide to a nephrologist will be based on the topic of a recently published, well-conducted systematic review. We will examine the performance of a physician's unaided MEDLINE search. We will then apply a total of eight filter combinations to the search (filters used in isolation or in combination). We will calculate the recall and precision of each search. The filter combinations that most improve on unaided physician searches will be identified and characterized.</p> <p>Discussion</p> <p>If these filters improve search performance, physicians will be able to search MEDLINE for renal evidence more effectively, in less time, and with less frustration. Additionally, our methodology can be used as a proof of concept for the evaluation of search filters in other disciplines.</p

Aspirin and clonidine in non-cardiac surgery: acute kidney injury substudy protocol of the Perioperative Ischaemic Evaluation (POISE) 2 randomised controlled trial

IntroductionPerioperative Ischaemic Evaluation-2 (POISE-2) is an international 2×2 factorial randomised controlled trial of low-dose aspirin versus placebo and low-dose clonidine versus placebo in patients who undergo non-cardiac surgery. Perioperative aspirin (and possibly clonidine) may reduce the risk of postoperative acute kidney injury (AKI).Methods and analysisAfter receipt of grant funding, serial postoperative serum creatinine measurements began to be recorded in consecutive patients enrolled at substudy participating centres. With respect to the study schedule, the last of over 6500 substudy patients from 82 centres in 21 countries were randomised in December 2013. The authors will use logistic regression to estimate the adjusted OR of AKI following surgery (compared with the preoperative serum creatinine value, a postoperative increase ≥26.5 μmol/L in the 2 days following surgery or an increase of ≥50% in the 7 days following surgery) comparing each intervention to placebo, and will report the adjusted relative risk reduction. Alternate definitions of AKI will also be considered, as will the outcome of AKI in subgroups defined by the presence of preoperative chronic kidney disease and preoperative chronic aspirin use. At the time of randomisation, a subpopulation agreed to a single measurement of serum creatinine between 3 and 12 months after surgery, and the authors will examine intervention effects on this outcome.Ethics and disseminationThe authors were competitively awarded a grant from the Canadian Institutes of Health Research for this POISE-2 AKI substudy. Ethics approval was obtained for additional kidney data collection in consecutive patients enrolled at participating centres, which first began for patients enrolled after January 2011. In patients who provided consent, the remaining longer term serum creatinine data will be collected throughout 2014. The results of this study will be reported no later than 2015.Clinical Trial Registration NumberNCT01082874

Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease-1: Study Protocol for a Multicenter Clinical Trial

Background: The progression to end-stage renal disease (ESRD) is the most important complication of chronic kidney disease (CKD). Patients with ESRD require dialysis or transplantation to survive, incur numerous complications, and have high mortality rates. Slowing the progression of CKD is an important goal. Unfortunately, even when current treatments are appropriately applied, patients with CKD still progress to ESRD. Current treatments do not address the inflammation and fibrosis that mediate progression to ESRD, but micro-particle curcumin, a natural health product, has both anti-inflammatory and anti-fibrotic properties and may be an effective treatment for patients with CKD. Objective: Micro-particle curcumin for the treatment of CKD-1 (MPAC-CKD-1) will measure the effect of micro-particle curcumin on 2 important markers of CKD progression: albuminuria and estimated glomerular filtration rate (eGFR). Efficacy in either of these markers will justify a larger, international trial to investigate micro-particle curcumin’s ability to lower the risk of ESRD in patients with CKD. Design: MPAC-CKD-1 is a multicenter, double-blind prospective randomized controlled trial. Setting: Four kidney disease clinics in Ontario, Canada (3 in London and 1 in Hamilton). Patients: We will enroll patients with CKD, defined by an eGFR between 15 and 60 mL/min/1.73 m 2 and a daily albumin excretion of more than 300 mg (or a random urine sample albumin-to-creatinine ratio more than 30 mg/mmol). Measurements: We will measure changes in the co-primary outcomes of urinary albumin-to-creatinine ratio and eGFR at 3 months and 6 months. We will also measure compliance, safety parameters, and changes in health-related quality of life. Methods: Participants will be randomly assigned to receive micro-particle curcumin 90 mg once daily or matching placebo for 6 months. We will enroll at least 500 patients to exclude clinically meaningful 6-month changes in these 2 co-primary outcomes (16% difference in albuminuria, and a 2.3 mL/min/1.73 m 2 between-group difference in the 6-month change in eGFR, at a two-tailed alpha of 0.025, power of 0.80). Results: Patient enrollment began on October 1, 2015, with 414 participants randomized as of July 2018. We expect to report the results in 2020. Limitations: MPAC-CKD-1 is not powered to assess outcomes such as the need for renal replacement therapy or death. Conclusions: MPAC-CKD-1 is a multicenter, double-blind prospective randomized controlled trial designed to test whether micro-particle curcumin reduces albuminuria and slows eGFR decline in patients with albuminuric CKD. MPAC-CKD-1 will also test the feasibility of this intervention and inform the need for a future larger scale trial (MPAC-CKD-2). Trial registration: MPAC-CKD-1 is registered with U.S. National Institutes of Health at clinicaltrials.gov (NCT02369549). Protocol version 2.0, December 6, 2014