Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies

Mendelian randomization studies estimate causal effects using genetic variants as instruments. Instrumental variable methods are straightforward for linear models, but epidemiologists often use odds ratios to quantify effects. Also, odds ratios are often the quantities reported in meta‐analyses. Many applications of Mendelian randomization dichotomize genotype and estimate the population causal log odds ratio for unit increase in exposure by dividing the genotype‐disease log odds ratio by the difference in mean exposure between genotypes. This ‘Wald‐type’ estimator is biased even in large samples, but whether the magnitude of bias is of practical importance is unclear. We study the large‐sample bias of this estimator in a simple model with a continuous normally distributed exposure, a single unobserved confounder that is not an effect modifier, and interpretable parameters. We focus on parameter values that reflect scenarios in which we apply Mendelian randomization, including realistic values for the degree of confounding and strength of the causal effect. We evaluate this estimator and the causal odds ratio using numerical integration and obtain approximate analytic expressions to check results and gain insight. A small simulation study examines finite sample bias and mild violations of the normality assumption. For our simple data‐generating model, we find that the Wald estimator is asymptotically biased with a bias of around 10% in fairly typical Mendelian randomization scenarios but which can be larger in more extreme situations. Recently developed methods such as structural mean models require fewer untestable assumptions and we recommend their use when the individual‐level data they require are available. The Wald‐type estimator may retain a role as an approximate method for meta‐analysis based on summary data. Copyright © 2012 John Wiley & Sons, Ltd.     

Transitional Care for Patients With Congestive Heart Failure: A Systematic Review and Meta-Analysis

PURPOSE

We aimed to determine the impact of transitional care interventions (TCIs) on acute health service use by patients with congestive heart failure in primary care and to identify the most effective TCIs and their optimal duration.

METHODS

We conducted a systematic review and meta-analysis of randomized controlled trials, searching the Medline, PsycInfo, EMBASE, and Cochrane Library databases. We performed a meta-analysis to assess the impact of TCI on all-cause hospital readmissions and emergency department (ED) visits. We developed a taxonomy of TCIs based on intensity and assessed the methodologic quality of the trials. We calculated the relative risk (RR) and a 95% confidence interval for each outcome. We conducted a stratified analysis to identify the most effective TCIs and their optimal duration.

RESULTS

We identified 41 randomized controlled trials. TCIs significantly reduced risks of readmission and ED visits by 8% and 29%, respectively (relative risk = 0.92; 95% CI, 0.87–0.98; P = .006 and relative risk = 0.71; 95% CI, 0.51–0.98; P = .04). High-intensity TCIs (combining home visits with telephone followup, clinic visits, or both) reduced readmission risk regardless of the duration of follow-up. Moderate-intensity TCIs were efficacious if implemented for a longer duration (at least 6 months). In contrast, low-intensity TCIs, entailing only followup in outpatient clinics or telephone follow-up, were not efficacious.

CONCLUSIONS

Clinicians and managers who implement TCIs in primary care can incorporate these results with their own health care context to determine the optimal balance between intensity and duration of TCIs. High-intensity interventions seem to be the best option. Moderate-intensity interventions implemented for 6 months or longer may be another option.     

Impact of Anemia on Hospitalization Time, Charges, and Mortality in Patients with Heart Failure

OBJECTIVES: Although anemia is known to influence clinical outcomes in heart failure (HF) patients, little is known about its impact on economic outcomes. A retrospective analysis was performed to determine the impact of hemoglobin (Hb) level on hospital length of stay (LOS), total charges, and hospital mortality in HF patients. METHODS: Claims data were drawn from 21 teaching and nonteaching hospitals for patients hospitalized between October 1, 2000 and September 30, 2001. The impact of Hb on LOS, charges, and hospital mortality was determined using multivariate analyses. Two-stage least squares regression methods were used to assess the potential endogeneity of the economic outcomes (LOS and total charges) and Hb level. RESULTS: Of the 8569 patients in the analysis, 40.2% had Hb < 12 g/dl and 73.8% were > or = 70 years of age. Hemoglobin had significant independent effects on all three outcomes. A 1 g/dl increase in Hb was associated with a 5.1% reduction in LOS (P < 0.001), a 4.3% decrease in charges (P < 0.001), and an 8.7% reduction in mortality risk (P < 0.001). The impact of Hb on all outcomes was greatest in younger HF patients. CONCLUSIONS: This analysis demonstrates that higher Hb is associated with reductions in LOS, charges, and mortality in hospitalized HF patients. Further clinical studies are necessary to validate the cost effectiveness of pharmacologic intervention in anemic HF patients and its impact on patient care.     

卡托普利与美托洛尔共同治疗慢性心力衰竭临床研究观察

目的观察并详细记录在卡托普利与美托洛尔共同作用下慢性心力衰竭的临床治疗效果。方法选取符合标准的70位慢性心力衰竭患者,任意组成数量相等的Ⅰ、Ⅱ两组。保证Ⅰ、Ⅱ两组患者的基本资料差异不影响临床研究结果。对Ⅰ组应用卡托普利/利尿剂/洋地黄制剂的常规治疗基础之上辅助服用美托洛尔。而Ⅱ组仅仅应用卡托普利/利尿剂/洋地黄制剂等进行常规治疗。跟踪观察患者15周,详细准确记录慢性心力衰竭患者在治疗始末病情改善状况以及可能发生的不良反应。记录项目包括左右室舒张末内径/左右室收缩末内径等。并且对患者追踪观察8个月。结果Ⅰ、Ⅱ两组在心功能/超声心电图/8min步行实验/等项目上记录的数据差异有统计学意义(P﹤0.05):Ⅰ组总有效率是82.85%,而Ⅱ组只有60%。Ⅰ组比Ⅱ组LVEDD/LVESD明显减小而LVEF则变大了(P﹤0.05)。结论在美托洛尔和卡托普利常规治疗的共同作用下,慢性心力衰竭患者病情疗效显著改善,减少了患者突然死亡几率降低了再次住院几率提高了患者的生活质量。     

The relationship between low back magnetic resonance imaging, surgery, and spending: impact of physician self-referral status

Objective. To examine the relationship between use of magnetic resonance imaging (MRI) and receipt of surgery for patients with low back pain. Data Sources. Medicare claims for a 20 percent sample of beneficiaries from 1998 to 2005. Study Design. We identify nonradiologist physicians who appear to begin self‐referral arrangements for MRI between 1999 and 2005, as well as their patients who have a new episode of low back pain care during this time. We focus on regression models that identify the relationship between receipt of MRI and subsequent use of back surgery and health care spending. Receipt of MRI may be endogenous, so we use physician acquisition of MRI as an instrument for receipt of MRI. The models adjust for demographic and socioeconomic covariates as well as month, year, and physician fixed effects. Data Collection/Extraction Methods. We include traditional, fee‐for‐service Medicare beneficiaries with a visit to an orthopedist or primary care physician for nonspecific low back pain, and no claims for low back pain in the year prior. Principal Findings. In the first stage, acquisition of MRI equipment is a strongly correlated with patients receiving MRI scans. Among patients of orthopedists, receipt of an MRI scan increases the probability of having surgery by 34 percentage points. Among patients of primary care physicians, receiving a low back MRI is not statistically significantly associated with subsequent surgery receipt. Conclusions. Orthopedists and primary care physicians who begin billing for the performance of MRI procedures, rather than referring patients outside of their practice for MRI, appear to change their practice patterns such that they use more MRI for their patients with low back pain. These increases in MRI use appear to lead to increases in low back surgery receipt and health care spending among patients of orthopedic surgeons, but not of primary care physicians.     

黄芪注射液治疗慢性充血性心力衰竭56例疗效观察

目的观察黄芪注射液配合西药常规治疗慢性充血性心力衰竭的疗效及安全性。方法110例患者随机分成对照组和治疗组,对照组54例给予西医常规抗心力衰竭治疗,治疗组56例在常规抗心力衰竭的基础上加用黄芪注射液40ml,1次／d,两组均连续用药2周。结果临床疗效总有效率治疗组为91．07％,对照组为72．22％;心电图改善总有效率治疗组为87．50％,对照组为62．96％。两组在临床疗效和心电图改善方面均有显著差异（P〈0．05）,治疗组明显优于对照组。结论黄芪注射液配合西医常规抗心力衰竭治疗慢性充血性心力衰竭,比单纯西医常规治疗效果好,是非常有前景的治疗心力衰竭药物。     

Rater bias in a blinded randomized placebo-controlled psychiatry trial

Rater bias occurs when rater knowledge of treatment assignment modifies the outcome assessment. Raters may be unconsciously influenced by inclinations for or against a particular treatment and consequently may give a more or less generous assessment depending upon these biases. Blinding of raters by keeping raters unaware of treatment assignment is one way to limit bias influencing assessment due to knowledge of treatment assignment. Unblinding may be particularly problematic in efficacy studies comparing placebo to drugs and/or non-drug psychotherapy treatments where subjects may reveal drug side-effects or mention their therapist by name, thus unblinding their treatment assignment. We present a new instrumental variable statistical approach for assessing the association between success in blinding and its impact on efficacy estimates of active drug and/or cognitive behavioural psychotherapy versus placebo in the multicentre comparative treatment study of panic disorder. Despite the uncertainty involved in assessing bias that may be unobserved and unconscious, we will show how to derive a bound for the impact of rater bias.     

The staffing-outcomes relationship in nursing homes

OBJECTIVE: To assess longitudinally whether a change in registered nurse (RN) staffing and skill mix leads to a change in nursing home resident outcomes while controlling for the potential endogeneity of staffing. DATA SOURCES: Minimum Data Set (MDS) nursing home resident assessment data from five states merged with Online Survey Certification and Reporting (OSCAR) data from 1996 through 2000. STUDY DESIGN: Resident-level longitudinal analysis with facility fixed effects and instrumental variables. Outcomes studied are incidence of pressure sores and urinary tract infections. RN staffing was measured as the care hours per resident-day and skill mix was measured as RN staffing hours as a proportion of total staffing hours. DATA EXTRACTION METHOD: We use all quarterly MDS assessments that fall within 120 days of an annual OSCAR data point, resulting in 399,206 resident-level observations. PRINCIPAL FINDINGS: Controlling for endogeneity of staffing increases the estimated impact of staffing on outcomes in nursing homes. Greater RN staffing significantly decreases the likelihood of both adverse outcomes. Increasing skill mix only reduces the incidence of urinary tract infections. CONCLUSIONS: Research that fails to account for endogeneity of the staffing-outcomes relationship may underestimate the benefit from increased RN staffing. Increases in RN staffing are likely to reduce adverse outcomes in some nursing homes. More research using a broader array of instruments and a national sample would be beneficial.     

Two-stage instrumental variable methods for estimating the causal odds ratio: analysis of bias

We present closed-form expressions of asymptotic bias for the causal odds ratio from two estimation approaches of instrumental variable logistic regression: (i) the two-stage predictor substitution (2SPS) method and (ii) the two-stage residual inclusion (2SRI) approach. Under the 2SPS approach, the first stage model yields the predicted value of treatment as a function of an instrument and covariates, and in the second stage model for the outcome, this predicted value replaces the observed value of treatment as a covariate. Under the 2SRI approach, the first stage is the same, but the residual term of the first stage regression is included in the second stage regression, retaining the observed treatment as a covariate. Our bias assessment is for a different context from that of Terza (J. Health Econ. 2008; 27(3):531-543), who focused on the causal odds ratio conditional on the unmeasured confounder, whereas we focus on the causal odds ratio among compliers under the principal stratification framework. Our closed-form bias results show that the 2SPS logistic regression generates asymptotically biased estimates of this causal odds ratio when there is no unmeasured confounding and that this bias increases with increasing unmeasured confounding. The 2SRI logistic regression is asymptotically unbiased when there is no unmeasured confounding, but when there is unmeasured confounding, there is bias and it increases with increasing unmeasured confounding. The closed-form bias results provide guidance for using these IV logistic regression methods. Our simulation results are consistent with our closed-form analytic results under different combinations of parameter settings.     

替米沙坦在慢性充血性心力衰竭中的疗效分析

目的观察联合血管紧张素Ⅱ受体拮抗剂替米沙坦治疗慢性充血性心力衰竭（CHF）的临床疗效及安全性。方法选择慢性充血性心力衰竭患者34例,根据治疗情况随机分成两组,常规治疗组14例给予内科常规抗心力衰竭治疗,试验组20例在常规治疗的基础上加用替米沙坦治疗。治疗前后观察静息心率（HR）、收缩压（SBP）、舒张压（DBP）、心功能级别、左室舒张末内径（LVEDD）、左室射血分数（LVEF）及心脏指数（CI）。结果两组患者的各项指标在治疗后均较治疗前有明显改善,但试验组较常规治疗组改善更为显著,其临床疗效优于常规治疗组（P〈0．05）。结论在常规抗心衰治疗基础上加用替米沙坦可明显改善患者心功能,是一种安全有效的临床治疗方法。     

卡维地洛治疗老年充血性心力衰竭72例疗效观察及安全性评价

目的 探讨卡维地洛治疗老年充血性心力衰的疗效及安全性.方法 将2009年7月～2011年9月于某院进行常规治疗的72例老年充血性心力衰竭患者设为对照组,同期的72例加用卡维地洛进行治疗的患者为观察组,后将两组患者的治疗总有效率、不良反应发生率及治疗前、治疗后1个月、2个月的心功能、血清BNP、hs-CRP水平进行对比.结果 观察组不仅治疗总有效率及不良反应发生率明显好于对照组,且其治疗后的心功能、血清BNP、hs-CRP水平改善幅度也明显大于对照组,P均＜ 0.05,差异有统计学意义.结论 卡维地洛治疗老年充血性心力衰的临床疗效及安全性均受肯定,心功能及相关血清因子也从多个方面肯定了其疗效.     

An exploratory instrumental variable analysis of the outcomes of localized breast cancer treatments in a medicare population

This study is motivated by the potential problem of using observational data to draw inferences about treatment outcomes when experimental data are not available. We compare two statistical approaches, ordinary least-squares (OLS) and instrumental variables (IV) regression analysis, to estimate the outcomes (three-year post-treatment survival) of three treatments for early stage breast cancer in elderly women: mastectomy (MST), breast conserving surgery with radiation therapy (BCSRT), and breast conserving surgery only (BCSO). The primary data source was Medicare claims for a national random sample of 2907 women (age 67 or older) with localized breast cancer who were treated between 1992 and 1994.Contrary to randomized clinical trial (RCT) results, analysis with the observational data found highly significant differences in survival among the three treatment alternatives: 79.2% survival for BCSO, 85.3% for MST, and 93.0% for BCSRT. Using OLS to control for the effects of observable characteristics narrowed the estimated survival rate differences, which remained statistically significant. In contrast, the IV analysis estimated survival rate differences that were not significantly different from 0. However, the IV-point estimates of the treatment effects were quantitatively larger than the OLS estimates, unstable, and not significantly different from the OLS results. In addition, both sets of estimates were in the same quantitative range as the RCT results.We conclude that unadjusted observational data on health outcomes of alternative treatments for localized breast cancer should not be used for cost-effectiveness studies. Our comparisons suggest that whether one places greater confidence in the OLS or the IV results depends on at least three factors: (1) the extent of observable health information that can be used as controls in OLS estimation, (2) the outcomes of statistical tests of the validity of the instrumental variable method, and (3) the similarity of the OLS and IV estimates. In this particular analysis, the OLS estimates appear to be preferable because of the instability of the IV estimates.     

Correcting for bias when estimating the cost of hospital-acquired infection: an analysis of lower respiratory tract infections in non-surgical patients

Hospital acquired infections (HAI) are costly but many are avoidable. Evaluating prevention programmes requires data on their costs and benefits. Estimating the actual costs of HAI (a measure of the cost savings due to prevention) is difficult as HAI changes cost by extending patient length of stay, yet, length of stay is a major risk factor for HAI. This endogeneity bias can confound attempts to measure accurately the cost of HAI. We propose a two-stage instrumental variables estimation strategy that explicitly controls for the endogeneity between risk of HAI and length of stay. We find that a 10% reduction in ex ante risk of HAI results in an expected savings of pound 693 ($ US 984).     

卡托普利治疗慢性心力衰竭长期疗效分析

目的 观察应用血管紧张素转换酶抑制剂卡托普利协同治疗慢性心力衰竭(CHF)的预后。方法 65例CHF 患者分为对照组24例,采用地高辛、利尿剂、硝酸酯类及β-受体阻滞剂等综合疗法;治疗组41例,在上述基础上加用卡托普 利。结果 5年观察期间,对照组和治疗组因心力衰竭加重再住院率分别为75.0％和26.8％(P<0.001),病死率分别为 29.17％和7.32％(P<0.01);在观察期满时对心功能NYHAⅡ-Ⅲ级患者复查,与治疗前相比,治疗组心功能、最大运动功 率、运动持续时间及6min步行距离均明显提高(P<0.01),心脏超声测定心搏量(SV)、心输出量(CO)及射血分数(LVEF) 结果示均明显改善(P<0.01);而对照组各项指标无明显改善。结论 协同其他治疗CHF的基本药物。卡托普利可显著改 善CHF患者的长期预后。     

Estimating the Efficacy of Receiving Treatment in Randomized Clinical Trials with Noncompliance

Analysis of a randomized trial is problematic when there is noncompliance with the treatment assignment. An intent-to-treat (ITT) analysis estimates the effect of randomization rather than the effect for those who actually receive the treatment. An alternative to the ITT is the as treated analysis, in which subjects are classified by the treatment actually received. However, the as treated analysis is also flawed since confounders are likely to be associated with switching treatment.We propose the use of an instrumental variable estimate (using the randomization as the instrument) in combination with propensity score adjustment. In addition, we consider the assumptions implicit in the instrumental variable methodology.These methods are illustrated with data from the Multimodal Treatment of ADHD (MTA) Study of treatment efficacy for children with attention deficit hyperactivity disorder. We show how the addition of the propensity score adjustment to the instrumental variable analysis uncovers some surprising results concerning the children who were assigned to behavioral therapy only but switched to medication.     

慢性充血性心力衰竭的中医分型与血清尿酸的关系

目的观察慢性充血性心力衰竭的中医分型与血清尿酸的关系。方法慢性充血性心力衰竭中医辩证分型分为气阴两虚、气虚血瘀、阳虚水泛3型,对87例病人均测定血清尿酸,并把各型的血清尿酸水平进行比较。结果中医症型不同高尿酸血症的发生率和尿酸水平有明显不同,气阴两虚型〈气虚血瘀型〈阳虚水泛。结论慢性充血性心力衰竭病人血尿酸水平升高对判断中医症型有一定意义。     

A critical review of anti-adrenergic therapy in patients with heart failure and diabetes mellitus

Anti-adrenergic therapy has been widely accepted as an important therapeutic intervention in patients with chronic heart failure. However, there has been continuing controversy regarding the risks and clinical significance of metabolic effects of different anti-adrenergic drugs. This review summarizes what has been learned from clinical trial evidence regarding the benefits of anti-adrenergic drugs in diabetic patients with chronic heart failure.     

A general approach to evaluating the bias of 2‐stage instrumental variable estimators

Unmeasured confounding is a common concern when researchers attempt to estimate a treatment effect using observational data or randomized studies with nonperfect compliance. To address this concern, instrumental variable methods, such as 2‐stage predictor substitution (2SPS) and 2‐stage residual inclusion (2SRI), have been widely adopted. In many clinical studies of binary and survival outcomes, 2SRI has been accepted as the method of choice over 2SPS, but a compelling theoretical rationale has not been postulated. We evaluate the bias and consistency in estimating the conditional treatment effect for both 2SPS and 2SRI when the outcome is binary, count, or time to event. We demonstrate analytically that the bias in 2SPS and 2SRI estimators can be reframed to mirror the problem of omitted variables in nonlinear models and that there is a direct relationship with the collapsibility of effect measures. In contrast to conclusions made by previous studies (Terza et al, 2008), we demonstrate that the consistency of 2SRI estimators only holds under the following conditions: (1) when the null hypothesis is true; (2) when the outcome model is collapsible; or (3) when estimating the nonnull causal effect from Cox or logistic regression models, the strong and unrealistic assumption that the effect of the unmeasured covariates on the treatment is proportional to their effect on the outcome needs to hold. We propose a novel dissimilarity metric to provide an intuitive explanation of the bias of 2SRI estimators in noncollapsible models and demonstrate that with increasing dissimilarity between the effects of the unmeasured covariates on the treatment versus outcome, the bias of 2SRI increases in magnitude.     

运动自我效能在慢性心力衰竭患者运动恐惧与运动康复依从性间的中介效应

目的 探讨运动自我效能在慢性心力衰竭患者运动恐惧与运动康复依从性间的中介效应。方法 采用便利抽样法,于2021年2月—10月选取南京某三甲医院就诊的慢性心力衰竭患者,使用心脏病患者运动恐惧量表、运动自我效能量表、运动依从性量表对其进行调查。结果 慢性心力衰竭患者运动恐惧与运动自我效能呈负相关（r = - 0.315,P＜0.01）,与运动康复依从性呈负相关（r = - 0.197,P＜0.01）,运动自我效能与运动康复依从性呈正相关（r = 0.375;P＜0.01）。中介模型显示,运动恐惧对运动康复依从性的直接效应不显著（β = - 0.087,P＞0.05）,运动自我效能在运动恐惧与运动康复依从性中起完全中介作用（β = 0.347,P＜0.01）,中介效应占总效应的56.25%。结论 运动恐惧主要通过运动自我效能影响慢性心衰患者运动康复依从性,提示医护人员可以从运动自我效能出发,引导患者改善心理品质,增强其运动自我效能,以减轻运动恐惧,提高运动康复依从性。     

普伐他汀和缬沙坦联合应用对慢性心功能不全患者阵发性心房颤动的影响

目的 探讨他汀类药物及血管紧张素受体拮抗剂对慢性心功能不全患者阵发性心房颤动的影响.方法 145例伴有阵发性心房颤动的慢性心功能不全患者随机分为四组:胺碘酮组(Ⅰ组)、胺碘酮+缬沙坦组(Ⅱ组)、胺碘酮+普伐他汀组(Ⅲ组)、胺碘酮+缬沙坦+普伐他汀组(Ⅳ组),治疗随访2年,比较四组治疗前后左心房内径、C反应蛋白(CRP)水平变化及窦性心律维持率.结果 治疗后,Ⅰ、Ⅱ、Ⅲ、Ⅳ组的左心房内径分别为(44.1±2.1)、(41.7±2.8)、(44.4±3.1)、(40.1±2.5)mm.Ⅰ组和Ⅲ组左心房内径均大于Ⅱ组和Ⅳ组(P<0.05),而Ⅰ组和Ⅲ组,Ⅱ组和Ⅳ组比较差异无统计学意义;Ⅰ、Ⅱ、Ⅲ、Ⅳ组的CRP水平分别为(4.56 ±0.24)、(4.47±0.45)、(2.87±0.53)、(2.54 ±0.42)mg/L Ⅰ组和Ⅱ组CRP水平高于Ⅲ组和Ⅳ组(P<0.05),I组和Ⅱ组、Ⅲ组和Ⅳ组比较差异无统计学意义;Ⅰ、Ⅱ、Ⅲ、Ⅳ组的窦性心律维持率分别为57.9%、79.4%、77.1%、85.3%,Ⅰ组窦性心律维持率低于Ⅱ、Ⅲ和Ⅳ组(P<0.05).结论 缬沙坦和普伐他汀联合应用能减少慢性心力衰竭患者阵发性心房颤动的复发.缬沙坦能抑制左心房的扩大.而普伐他汀能有效降低血中CRP的水平.