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Covariate-based linkage analysis: application of a propensity score as the single covariate consistently improves power to detect linkage.

Successful identification of genetic risk loci for complex diseases has relied on the ability to minimize disease and genetic heterogeneity to increase the power to detect linkage. One means to account for disease heterogeneity is by incorporating covariate data. However, the inclusion of each covariate will add one degree of freedom to the allele sharing based linkage test, which may in fact decrease power. We explore the application of a propensity score, which is typically used in causal inference to combine multiple covariates into a single variable, as a means of allowing for multiple covariates with the addition of only one degree of freedom. In this study, binary trait data, simulated under various models involving genetic and environmental effects, were analyzed using a nonparametric linkage statistic implemented in LODPAL. Power and type I error rates were evaluated. Results suggest that the use of the propensity score to combine multiple covariates as a single covariate consistently improves the power compared to an analysis including no covariates, each covariate individually, or all covariates simultaneously. Type I error rates were inflated for analyses with covariates and increased with increasing number of covariates, but reduced to nominal rates with sample sizes of 1000 families. Therefore, we recommend using the propensity score as a single covariate in the linkage analysis of a trait suspected to be influenced by multiple covariates because of its potential to increase the power to detect linkage, while controlling for the increase in the type I error.

Algorithms↗

Reduction of sampling bias of odds ratios for vertebral fractures using propensity scores.

INTRODUCTION: Assessment of the predictive power of a newly introduced diagnostic technique with regard to fracture risk is frequently limited by the enormous costs and long time periods required for prospective studies. A preliminary estimate of predictive power usually relies on cross-sectional case-control studies in which bone measurements of normal and fractured subjects are compared. The measured discriminatory power is taken as an estimate of predictive power. Because of possible sample selection bias, study participants may have different bone mineral density (BMD) values, and fractured patients may have fractures of different severity levels. The same diagnostic techniques for the measured discriminatory power, expressed as odds ratios, will differ among studies with different patient and control populations. METHODS: In this paper, we propose a weighted logistic regression approach to adjust the odds ratio in order to reduce the effect of sampling bias. The weight is derived from age, deformity severity, BMD, and the interactions of these, using the propensity score theory and reference population data. RESULTS: Simulation examples using data from the Osteoporosis and Ultrasound Study (OPUS) demonstrate that such a procedure can effectively reduce the estimation bias of odds ratios introduced by sampling differences, such as for dual x-ray absorptiometry (DXA) scans of the spine and hip as well as various quantitative ultrasound techniques. The derived estimated odds ratios are substantially less biased, and the corresponding 95% confidence intervals contain the true odds ratios from the population data. CONCLUSIONS: We conclude that a statistical correction procedure based on propensity scores and weighted logistic regression can effectively reduce the effect of sampling bias on the odds ratios calculated from cross-sectional case-control studies. For a new diagnostic technique, hip BMD and deformity severity information are necessary and likely sufficient to derive the propensity scores required to adjust the measured standardized odds ratios.

Adult↗

Propensity score analysis of vascular complications after diagnostic cardiac catheterization and percutaneous coronary intervention 1998-2003.

OBJECTIVES: To evaluate the adjusted risk of vascular complications after manual compression and vascular closure devices for femoral artery access site management in a large contemporary cohort, using propensity score analysis. BACKGROUND: Vascular closure devices (VCD) allow early ambulation after cardiac procedures involving femoral artery access, but whether the benefit of use of vascular closure devices (VCD) is offset by reduced safety in contemporary practice remains uncertain. METHODS: Twenty one thousand eight hundred and forty one consecutive diagnostic cardiac catheterization (n = 13,124) and percutaneous coronary intervention procedures (n = 8,717) performed via a femoral access at a single site (WFUBMC) between 1998 and 2003 were evaluated. VCD's were used based on operator preference. Propensity to receive a vascular closure device (VCD) was calculated. The relative incidence of vascular complications was evaluated by logistic regression models, using the propensity score as a covariate. RESULTS: Overall, the unadjusted incidence of any vascular complication was 1.3% for VCD use and 1.4% for manual compression, p = NS. The propensity score-adjusted odds ratio for any vascular complication comparing VCD (n = 8,707) to manual compression (n = 13,034) was 0.86 (0.67-1.11) for all procedures, 0.80 (0.53-1.21) for diagnostic procedure, and 0.90 (0.65-1.26) for interventional procedures. CONCLUSIONS: In this large single-center, contemporary observational study, the risk-adjusted occurrence of vascular complications following VCD use for femoral artery access management is not increased by VCD use. Thus, in the current era, the benefit of VCD use is not offset by reduced safety.

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Variable selection and raking in propensity scoring.

This paper discusses some practical issues in applying propensity scoring in the context of endpoint analysis in a pre-/posttest longitudinal design with an ordinal measure of treatment intensity and a high-dimensional potential covariate space: how many covariates to include in propensity models; how to evaluate the adequacy of tentative propensity models; and how to tailor models to provide hypercontrol on a limited subset of covariates. These issues arose in the evaluation of a health communication program.

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Application of the propensity score in a covariate-based linkage analysis of the Collaborative Study on the Genetics of Alcoholism.

BACKGROUND: Covariate-based linkage analyses using a conditional logistic model as implemented in LODPAL can increase the power to detect linkage by minimizing disease heterogeneity. However, each additional covariate analyzed will increase the degrees of freedom for the linkage test, and therefore can also increase the type I error rate. Use of a propensity score (PS) has been shown to improve consistently the statistical power to detect linkage in simulation studies. Defined as the conditional probability of being affected given the observed covariate data, the PS collapses multiple covariates into a single variable. This study evaluates the performance of the PS to detect linkage evidence in a genome-wide linkage analysis of microsatellite marker data from the Collaborative Study on the Genetics of Alcoholism. Analytical methods included nonparametric linkage analysis without covariates, with one covariate at a time including multiple PS definitions, and with multiple covariates simultaneously that corresponded to the PS definitions. Several definitions of the PS were calculated, each with increasing number of covariates up to a maximum of five. To account for the potential inflation in the type I error rates, permutation based p-values were calculated. RESULTS: Results suggest that the use of individual covariates may not necessarily increase the power to detect linkage. However the use of a PS can lead to an increase when compared to using all covariates simultaneously. Specifically, PS3, which combines age at interview, sex, and smoking status, resulted in the greatest number of significant markers identified. All methods consistently identified several chromosomal regions as significant, including loci on chromosome 2, 6, 7, and 12. CONCLUSION: These results suggest that the use of a propensity score can increase the power to detect linkage for a complex disease such as alcoholism, especially when multiple important covariates can be used to predict risk and thereby minimize linkage heterogeneity. However, because the PS is calculated as a conditional probability of being affected, it does require the presence of observed covariate data on both affected and unaffected individuals, which may not always be available in real data sets.

Alcoholism↗

Does receiving an earnings supplement affect union formation? Estimating effects for program participants using propensity score matching.

This article demonstrates a novel application of propensity score matching techniques: to estimate nonexperimental impacts on program participants within the context of an experimental research design. The author examines the relationship between program participation, defined as qualifying for an earnings supplement by working full-time, and marital union formation among low-income mothers in two Canadian provinces. The author finds that receipt of an earnings supplement substantially increased union formation in one province but not the other. A subgroup analysis based on propensities of program participation revealed that the positive effect on unions was concentrated among relatively disadvantaged participants. The techniques demonstrated in the article are broadly applicable to studies in which take-up is less than 100% among those randomly assigned to a program group.

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Propensity score matching with time-dependent covariates.

In observational studies with a time-dependent treatment and time-dependent covariates, it is desirable to balance the distribution of the covariates at every time point. A time-dependent propensity score based on the Cox proportional hazards model is proposed and used in risk set matching. Matching on this propensity score is shown to achieve a balanced distribution of the covariates in both treated and control groups. Optimal matching with various designs is conducted and compared in a study of a surgical treatment, cystoscopy and hydrodistention, given in response to a chronic bladder disease, interstitial cystitis. Simulation studies also suggest that the statistical analysis after matching outperforms the analysis without matching in terms of both point and interval estimations.

Cohort Studies↗

Early and medium-term results after on-pump and off-pump coronary artery surgery: a propensity score analysis.

BACKGROUND: Comparative publications on beating-heart off-pump coronary artery bypass grafting (OPCAB) surgery versus conventional coronary artery bypass grafting (CCAB) surgery frequently do not offer conclusive information because of investigator bias. METHODS: Trying to eliminate this problem, a propensity score analysis of the data of all CCAB patients (n = 517) and OPCAB patients (n = 133) operated on by the same surgeons during the same time period (1998 to 2001) was applied. After matching patients with similar propensity score values, 97 CCAB patients and 72 OPCAB patients entered the final analysis. RESULTS: Early results were similar in both groups: the 30-day mortality reached 1.4% in the CCAB group and 2.8% in the OPCAB group; strokes did not happen. Perioperative myocardial infarctions occurred in 4.1% of the CCAB patients and 4.3% of the OPCAB patients. Drainage blood loss in the first 24 hours after surgery (830 +/- 687 mL, CCAB group; and 909 +/- 678 mL, OPCAB group) was similar (p = 0.06) in both groups. Medium term results (freedom from percutaneous transluminal coronary angioplasty or reoperation, freedom from myocardial infarction, freedom from stroke, and the quality of life) also were not significantly different between the off-pump and on-pump groups after a mean follow-up of 27 +/- 11 months. CONCLUSIONS: Our results suggest that elective-surgery patients with coronary artery disease can be operated on either on-pump or off-pump with the same early and late mortality and morbidity.

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Outcomes in ambulatory chronic systolic and diastolic heart failure: a propensity score analysis.

BACKGROUND: Prior studies demonstrating significant difference in outcomes in systolic and diastolic heart failure (HF) are often limited to hospitalized acute HF patients, and may be confounded by residual bias. In this analysis, we examined long-term mortality and hospitalization in a propensity score matched cohort of ambulatory chronic systolic and diastolic HF patients. METHODS: Of the 7788 patients in the Digitalis Investigation Group trial, 6800 had systolic HF (ejection fraction >45%) and 988 had diastolic HF (ejection fraction >45%). We restricted our analysis to 7617 patients without valvular heart disease: 916 diastolic HF and 6701 systolic HF. Propensity scores for diastolic HF, calculated for each patient by a non-parsimonious multivariable logistic regression model, were used to match 697 diastolic HF with 2091 systolic HF patients. Matched Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for outcomes in diastolic (versus systolic) HF. RESULTS: During a median 38-month follow-up, compared with 32% mortality in systolic HF, 23% of diastolic HF patients died (HR=0.70; 95% CI=0.59-0.84; P<.0001). Respective HR (95%CI) for cardiovascular and HF mortality were 0.60 (0.48-0.74; P<.0001) and 0.56 (0.39-0.79; P=.001). All-cause hospitalizations occurred in 64% of systolic and 67% of diastolic HF patients (HR=0.99; 95% CI=0.87-1.11; P=0.801). Respective HR (95%CI) for cardiovascular and HF hospitalizations were 0.84 (0.73-0.96; P=.011) and 0.63 (0.51-0.77; P<.0001). CONCLUSIONS: Despite lower mortality and cardiovascular morbidity, diastolic HF patients had similar overall hospitalizations as in systolic HF. Ejection fraction should be assessed in all HF patients to guide therapy, with special attention to non-cardiovascular morbidity in diastolic HF.

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Adjusting effect estimates for unmeasured confounding with validation data using propensity score calibration.

Often, data on important confounders are not available in cohort studies. Sensitivity analyses based on the relation of single, but not multiple, unmeasured confounders with an exposure of interest in a separate validation study have been proposed. In this paper, the authors controlled for measured confounding in the main cohort using propensity scores (PS's) and addressed unmeasured confounding by estimating two additional PS's in a validation study. The "error-prone" PS exclusively used information available in the main cohort. The "gold standard" PS additionally included data on covariates available only in the validation study. Based on these two PS's in the validation study, regression calibration was applied to adjust regression coefficients. This propensity score calibration (PSC) adjusts for unmeasured confounding in cohort studies with validation data under certain, usually untestable, assumptions. The authors used PSC to assess the relation between nonsteroidal antiinflammatory drugs (NSAIDs) and 1-year mortality in a large cohort of elderly persons. "Traditional" adjustment resulted in a hazard ratio for NSAID users of 0.80 (95% confidence interval (CI): 0.77, 0.83) as compared with an unadjusted hazard ratio of 0.68 (95% CI: 0.66, 0.71). Application of PSC resulted in a more plausible hazard ratio of 1.06 (95% CI: 1.00, 1.12). Until the validity and limitations of PSC have been assessed in different settings, the method should be seen as a sensitivity analysis.

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The impact of subsidized health insurance for the poor: evaluating the Colombian experience using propensity score matching.

This paper evaluates the impact of Colombia's subsidized health insurance program (SUBS) on medical care utilization. Colombia's SUBS program is a demand-side subsidy intended for low-income families, where the screening of beneficiaries takes place in decentralized locations across the country. Due to the self-selection problems associated with non-experimental data, we implement Propensity Score Matching (PSM) methods to measure the impact of this subsidy on medical care utilization. By combining unique household survey data with community and regional data, we are able to compute propensity scores in a way that is consistent with both the local government's decision to offer the subsidy, and with the individual's decision to accept the subsidy. Although the application of PSM using these rich datasets helps to achieve a balance between the treatment and control groups along observable dimensions, we also present instrumental variable estimates to control for the potential endogeneity of program participation. Using both methods, we find that Colombia's subsidized insurance program greatly increased medical care utilization among the country's poor and uninsured. This evidence supports the case for other Latin American countries implementing similar subsidy programs for health insurance for the poor.

Adolescent↗

Impact of an entertainment-education television drama on health knowledge and behavior in Bangladesh: an application of propensity score matching.

Shabuj Chaya is a weekly television drama broadcast during a 13-week period in Bangladesh in 2000. It used an entertainment-education format to increase health knowledge and to promote visits to health clinic and modern contraceptive use. The purpose of this article is to demonstrate how a relatively new statistical technique, propensity score matching in conjunction with structural equation modeling, can be used to obtain an unbiased estimate of changes in health outcomes that can be attributed to exposure to the drama. The analysis is conducted with data from an after-only, cross-sectional survey of 4,492 men and women from the intended audience. The results from propensity score matching approximate what would be expected from a randomized control group design.

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[Analysis with the propensity score of the association between likelihood of treatment and event of interest in observational studies. An example with myocardial reperfusion].

INTRODUCTION AND OBJECTIVES: Analysis of the effect of treatment in observational studies is complex due to differences between treated and nontreated patients. Calculating the probability of receiving treatment conditioned on relevant covariates (propensity score [PS]) has been proposed as a method to control for these differences. We report an application of PS to assess the association between reperfusion treatment and 28-day case fatality in patients with acute myocardial infarction (AMI). METHOD: We describe the procedure used to calculate PS for receiving reperfusion treatment, and different strategies to analyze the association between PS and case fatality with regression modeling and matching. Data were from a population-based registry of 6307 patients with AMI in Spain during 1997-98. RESULTS: The PS for reperfusion was calculated in 5622 patients. In the multivariate analysis, reperfusion was associated with lower case fatality (OR = 0.59; 95% confidence interval [95% CI]: 0.46-0.77). When PS was included as a covariate, this association became non- significant (OR = 0.76; 95% CI: 0.57-1.01). In the subgroup of matched patients with a similar PS (n = 3138), treatment was not associated with case fatality (OR = 0.95; 95% CI: 0.72-1.26). When the influence of cases with missing data on PS was controlled for, reperfusion treatment was associated with lower fatality (OR = 0.66; 95% CI: 0.55-0.80). CONCLUSIONS: Calculating propensity score is a method that controls for differences between treated and nontreated patients. This score has limitations when matching is incomplete and when data are missing. Results of the present example suggest that reperfusion treatment reduces AMI case fatality.

Adult↗

Using propensity scores to estimate the cost-effectiveness of medical therapies.

The cost-effectiveness ratio is a popular statistic that is used by policy makers to decide which programs are cost-effective in the public health sector. Recently, the net monetary benefit has been proposed as an alternative statistical summary measure to overcome the limitations associated with the cost-effectiveness ratio. Research on using the net monetary benefit to assess the cost-effectiveness of therapies in non-randomized studies has yet to be done. Propensity scores are useful in estimating adjusted effectiveness of programs that have non-randomized or quasi-experimental designs. This article introduces the use of propensity score adjustment in cost-effectiveness analyses to estimate net monetary benefits for non-randomized studies. The uncertainty associated with the net monetary benefit estimate is evaluated using cost-effectiveness acceptability curves. Our method is illustrated by applying it to SEER-Medicare data for muscle invasive bladder cancer to determine the most cost-effective treatment protocol.

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Outcomes in off-pump vs. on-pump coronary artery bypass grafting stratified by pre-operative risk profile: an assessment using propensity score.

AIMS: To assess the benefit of off-pump coronary surgery stratified by the pre-operative risk profile. METHODS AND RESULTS: Prospective and multicentric cohort study. All consecutive patients undergoing a first coronary bypass procedure between November 2001 and November 2003 were potentially eligible. Pre-operative EuroSCORE and in-hospital outcomes were prospectively collected using strictly standardized criteria. To ensure optimal adjustment, a propensity score was constructed using clinically relevant variables and incorporating individual centres. Of 1602 patients who underwent a first coronary bypass, EuroSCORE could be calculated in 1585: 787 were of moderate/high pre-operative risk profile (EuroSCORE > 3), of which 347 underwent off-pump procedures, and 798 were of low pre-operative risk profile (EuroSCORE < or = 3), of which 349 underwent off-pump procedures. After risk adjusting for propensity score, off-pump patients had less major events (post-operative death, myocardial infarction, and need for reoperation). This benefit was higher in the low-risk stratum (OR ranged between 0.27 and 0.4; P = 0.02-0.07) than in the high-risk stratum (OR between 0.4 and 0.7; P, not significant). CONCLUSION: In real-life conditions, off-pump coronary surgery may be more effective than on-pump surgery. In contrast with previous reports, our results suggest that this benefit may be higher in patients with low pre-operative risk.

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Inability to perform maximal stair climbing test before lung resection: a propensity score analysis on early outcome.

OBJECTIVE: The objective of the present study was to assess whether patients unable to perform a preoperative maximal stair climbing test had an increased incidence of morbidity and mortality after major lung resection compared to patients who were able to exercise. METHODS: Three hundred and ninety one patients submitted to pulmonary lobectomy or pneumonectomy for lung cancer were analyzed. Forty-five of these patients were unable to perform a preoperative maximal stair climbing test for underlying comorbidities. Unadjusted and propensity score case matched comparisons were performed between patients who could and who could not perform a preoperative stair climbing test. Multi-variable analyses were then performed to identify predictors of morbidity and mortality, and were validated by bootstrap bagging. RESULTS: Patients who could not perform the stair climbing test had similar morbidity rates (31.1 vs. 35.6%, respectively, P=0.7), but higher mortality rates (15.6 vs. 4.4%, respectively, P=0.08) and deaths among complicated patients (50 vs. 12.5%, respectively, P=0.025), compared to propensity score matched patients who could perform the stair climbing test. Logistic regression analyses showed that the inability to perform the stair climbing test was an independent and reliable predictor of mortality (P=0.005) but not of morbidity (P=0.2). CONCLUSIONS: Patients unable to perform a preoperative maximal exercise test had an increased risk of mortality after major lung resection. Half of these patients did not survive postoperative complications, due to their decreased aerobic reserve caused by physical inactivity which made them unable to cope with the increased oxygen demand.

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A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass may result in excessive fibrinolysis and platelet (PLT) dysfunction, resulting in impaired hemostasis and excessive blood loss. Prophylactic use of the antifibrinolytic drugs aprotinin and tranexamic acid is thought to prevent these hemostatic defects. Their relative clinical utility and safety in high-transfusion-risk cardiac surgery, however, is not known. STUDY DESIGN AND METHODS: Using propensity scores, 449 patients who received aprotinin for high-transfusion-risk cardiac surgery were matched to 449 patients who received tranexamic acid from a pool of 10,870 consecutive patients who underwent cardiac surgery at a single center, 586 of whom received aprotinin and the remainder of whom received tranexamic acid. RESULTS: The two matched groups were well balanced in terms of measured perioperative variables. Blood product transfusion rates were similar in the aprotinin and tranexamic acid groups: red blood cells, 79 percent versus 76 percent (p = 0.3); PLTs, 56 percent versus 50 percent (p = 0.06); and plasma, 66 percent versus 61 percent (p = 0.1). Adverse events rates were comparable in the two groups, except for renal dysfunction (defined as a greater than 50% increase in creatinine concentration during the first postoperative week to >100 micromol/L in women and >110 micromol/L in men or a new requirement for dialysis support), which occurred in 24 percent (107/449) of aprotinin patients and 17 percent (75/449) of tranexamic acid patients (p = 0.01). CONCLUSIONS: Aprotinin and tranexamic acid have similar hemostatic effectiveness in high-transfusion-risk cardiac surgery. Within the confines of propensity score matching, our results suggest that aprotinin may be associated with renal dysfunction.

Adult↗

Effect of avoiding cardiopulmonary bypass in non-elective coronary artery bypass surgery: a propensity score analysis.

OBJECTIVE: Non-elective coronary artery surgery (emergent/salvage or urgent) carries an increased risk in most risk-stratification models. Off-pump coronary surgery is increasingly used in non-elective cases. We aimed to investigate the effect of avoiding cardiopulmonary bypass on outcomes following non-elective coronary surgery. METHODS: Of the 3771 consecutive coronary artery bypass procedures performed by five surgeons between April 1997 and March 2002, 828 (22%) were non-elective and 417 (50.4%) of these patients had off-pump surgery. Multivariate logistic regression was used to assess the effect of off-pump on in-hospital outcomes, while adjusting for treatment selection bias. Treatment selection bias was controlled for by constructing a propensity score from core patient characteristics, which was the probability of avoiding cardiopulmonary bypass. The C statistic for this model was 0.8. RESULTS: Off-pump patients were more likely to be hypertensive, stable, had less extensive disease and better left ventricular function. The left internal mammary artery was used in 91.8% (n=383) of off-pump patients compared to 79.3% (n=326) of on-pump cases (P<0.001). After adjusting for the propensity score, no difference in in-hospital mortality was observed between off-pump and on-pump (adjusted odds ratio (OR) 0.83 (95% confidence intervals (CI) 0.36-1.93); P=0.667). Off-pump patients were less likely to require intra-aortic balloon pump support (adjusted OR 0.44 (95% CI 0.21-0.96); P=0.039), less likely to have renal failure (adjusted OR 0.44 (95% CI 0.22-0.90); P=0.025), and have shorter lengths of stay (adjusted OR 0.51 (95% CI 0.37-0.70); P<0.001). Other morbidity outcomes were similar in both groups. CONCLUSIONS: In this experience, off-pump coronary surgery in non-elective patients is safe with acceptable results. Non-elective off-pump patients have a significantly reduced incidence of renal failure, and shorter post-operative stays compared to on-pump coronary artery bypass surgery.

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