John M. Brooks

Estimation of Cachexia among Cancer Patients Based on Four Definitions.

Objectives. Estimate and compare the proportion of cancer patients with cachexia using different definitions from available clinical data. Methods. Electronic medical records were examined to estimate the proportion of cancer patients with cachexia using 4 definitions: (1) ICD-9 diagnostic code of 799.4 (cachexia), (2) ICD-9 diagnosis of cachexia, anorexia, abnormal weight loss, or feeding difficulties, (3) prescription for megestrol acetate, oxandrolone, somatropin, or dronabinol, and (4) ≥5% weight loss. Patients with cancer of the stomach, pancreas, lung, colon/rectum, head/neck, esophagus, prostate, breast, or liver diagnosed between 1999 and 2004 were followed for cachexia. Results. Of 8541 cancer patients (60% men and 55% Caucasian), cachexia was observed in 2.4% of patients using the cachexia diagnostic code, 5.5% expanded diagnoses, 6.4% prescription medication definition, and 14.7% with ≥5% weight loss. Conclusions. The proportion of patients with cachexia varied considerably depending upon the definition employed, indicating that a standard operational definition is needed.

Squeezing the Balloon: Propensity Scores and Unmeasured Covariate Balance

OBJECTIVE To assess the covariate balancing properties of propensity score-based algorithms in which covariates affecting treatment choice are both measured and unmeasured. DATA SOURCES/STUDY SETTING A simulation model of treatment choice and outcome. STUDY DESIGN Simulation. DATA COLLECTION/EXTRACTION METHODS Eight simulation scenarios varied with the values placed on measured and unmeasured covariates and the strength of the relationships between the measured and unmeasured covariates. The balance of both measured and unmeasured covariates was compared across patients either grouped or reweighted by propensity scores methods. PRINCIPAL FINDINGS Propensity score algorithms require unmeasured covariate variation that is unrelated to measured covariates, and they exacerbate the imbalance in this variation between treated and untreated patients relative to the full unweighted sample. CONCLUSIONS The balance of measured covariates between treated and untreated patients has opposite implications for unmeasured covariates in randomized and observational studies. Measured covariate balance between treated and untreated patients in randomized studies reinforces the notion that all covariates are balanced. In contrast, forced balance of measured covariates using propensity score methods in observational studies exacerbates the imbalance in the independent portion of the variation in the unmeasured covariates, which can be likened to squeezing a balloon. If the unmeasured covariates affecting treatment choice are confounders, propensity score methods can exacerbate the bias in treatment effect estimates.

Population-based assessment of hospitalizations for neutropenia from chemotherapy in older adults with non-Hodgkin's lymphoma (United States).

ObjectiveTo study neutropenia hospitalization (NH) incidence and risk factors in a population-based sample of older adults with non-Hodgkin’s lymphoma (NHL) and evaluate the validity of inferences from Surveillance, Epidemiology and End Results (SEER)-Medicare linked databases.MethodsNHL cases receiving first-course chemotherapy were identified from Iowa SEER-Medicare. Survival methods evaluated NH risk factors. Medical record and Medicare claims data on chemotherapy and NH were compared.ResultsOf 761 subjects, 165 (21.7%, 95% CI: 18.8, 24.6) were hospitalized for neutropenia. Of those hospitalized, 41% were hospitalized in cycle 1 and 22% in cycle 2. Significant multivariable risk factors for NH were diffuse large cell histology, renal disease, Charlson comorbidity index, and anthracycline chemotherapy but not patient age. Medicare and medical records agreed on month of chemotherapy initiation 95% of the time and chemotherapy type 95% of the time. ICD-9 code 288.0 sensitivity for NH was 80%.ConclusionsNeutropenia hospitalizations were common in the first 2 chemotherapy cycles, especially among older adults with comorbidity. Findings conflict with a prior medical records study in which age was a risk factor for NH and dose intensity a negative confounder. Valid inferences about age effects on chemotherapy toxicity require more clinical detail than is available in administrative data.

Translating Research into Practice Intervention Improves Management of Acute Pain in Older Hip Fracture Patients

OBJECTIVE To test an interdisciplinary, multifaceted, translating research into practice (TRIP) intervention to (a) promote adoption, by physicians and nurses, of evidence-based (EB) acute pain management practices in hospitalized older adults, (b) decrease barriers to use of EB acute pain management practices, and (c) decrease pain intensity of older hospitalized adults. STUDY DESIGN Experimental design with the hospital as the unit of randomization. STUDY SETTING Twelve acute care hospitals in the Midwest. DATA SOURCES (a) Medical records (MRs) of patients > or =65 years or older with a hip fracture admitted before and following implementation of the TRIP intervention and (b) physicians and nurses who care for those patients. DATA COLLECTION Data were abstracted from MRs and questions distributed to nurses and physicians. PRINCIPAL FINDINGS The Summative Index for Quality of Acute Pain Care (0-18 scale) was significantly higher for the experimental (10.1) than comparison group (8.4) at the end of the TRIP implementation phase. At the end of the TRIP implementation phase, patients in the experimental group had a lower mean pain intensity rating than those in the comparison group ( p<.0001). CONCLUSION The TRIP intervention improved quality of acute pain management of older adults hospitalized with a hip fracture.

Heterogeneity and the interpretation of treatment effect estimates from risk adjustment and instrumental variable methods.

Objectives:To contrast the interpretations of treatment effect estimates using risk adjustment and instrumental variable (IV) estimation methods using observational data when the effects of treatment are heterogeneous across patients. We demonstrate these contrasts by examining the effect of breast conserving surgery plus irradiation (BCSI) relative to mastectomy on early stage breast cancer (ESBC) survival. Methods:We estimated discrete time survival models for 6185 ESBC patients in the 1989–1994 Iowa Cancer Registry via IV estimation using 2 distinct instruments (distance of the patients residence from the nearest radiation center, and local area BCSI rate) and controlling for cancer stage, grade, and location; age; comorbidity; hospital access; payer; diagnosis year; and area poverty level. We then estimated comparable risk adjustment survival models using linear probability methods with robust standard errors. Results:Risk adjustment models yielded average survival estimates similar to trial results. With favorable BCSI selection, these estimates represent an upper bound of the true effect for patients receiving BCSI. IV estimates showed a BCSI survival risk for patients whose surgery choices were affected by the instruments and these estimates varied with the instrument specification. Conclusions:When treatment benefits are heterogeneous across patients, treatment effect estimates from observational data can still be useful to policymakers, but they must be interpreted correctly. Risk adjustment methods yield estimates that can assess whether the patients who received treatment benefited from the treatment, but the direction of bias must be considered. In contrast, IV estimates can assess the effect of treatment rate changes, but characteristics of patients whose choices were affected by the instruments must be considered when making such inferences.

Information Gained From Linking Seer Cancer Registry Data to State-level Hospital Discharge Abstracts

Objectives.Our goal was to link patients from the Iowa Surveillance, Epidemiology, and End Results (SEER) Registry to their respective inpatient discharge abstracts from an Iowa Health Care Cost and Utilization Project (HCUP)–formatted database and evaluate whether this linkage provides information related to cancer treatment variation. Methods.Computer algorithms linked patients from the Iowa SEER Registry to discharge abstracts using 5 variables consistently defined between the databases (hospital identification, date of birth, admission date, discharge date, and zip code). Abstracts were reviewed for validity, and links not passing face validity were excluded. Subjects.Our sample contained 7,296 patients with early-stage breast cancer (I, IIa, IIb) with surgery from the Iowa SEER Registry from 1989 through 1994 with contacts only with Iowa hospitals. Results.Inpatient discharges abstracts were linked to 86.4% of the patients in our sample. More than 96% of the linked discharges for Medicare patients had a corresponding Medicare claim. Over 45% of the linked patients were not covered by Medicare. Comorbidity indexes were comparable to other published sources. Significant differences in diagnosis, comorbidities, and treatment were found across third-party payers. Conclusions.This linkage provides a valuable source of comorbidity and insurance data and perhaps the only source of secondary clinical information for the uninsured. This linkage is best suited for cancers requiring inpatient stays for treatment and for those states where border crossing for treatment is low.

Comparison of Instrumental Variable Analysis Using a New Instrument With Risk Adjustment Methods to Reduce Confounding by Indication

Confounding by indication is a vexing problem, especially in evaluating treatment effects using observational data, since treatment decisions are often related to disease severity, prognosis, and frailty. To compare the ability of the instrumental variable (IV) approach with a new instrument based on the local-area practice style and risk adjustment methods, including conventional multivariate regression and propensity score adjustment, to reduce confounding by indication, the authors investigated the effects of long-term control (LTC) therapy on the occurrence of acute asthma exacerbation events among children and young adults with incident and uncontrolled persistent asthma, using Iowa Medicaid claims files from 1997-1999. Established evidence from clinical trials has demonstrated the protective benefits of LTC therapy for persistent asthma. Among patients identified (n = 4,275), those with higher asthma severity at baseline were more likely to receive LTC therapy. The multivariate regression and propensity score adjustment methods suggested that LTC therapy had no effect on the occurrence of acute exacerbation events. Estimates from the new IV approach showed that LTC therapy significantly decreased the occurrence of acute exacerbation events, which is consistent with established clinical evidence. The authors discuss how to interpret estimates from the risk adjustment and IV methods when the treatment effect is heterogeneous.

Diffuse large B-cell lymphoma in the elderly: diffusion of treatment with rituximab and survival advances with and without anthracyclines

Anthracycline-based chemotherapy (ABC) is the most effective therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to ABC in controlled trials has demonstrated superior survival, yet ABC is inconsistently utilized in elderly patients, and little is known about the penetrance or impact of rituximab with other treatments. We analyzed the treatment and survival patterns of 7559 patients with DLBCL over age 66 diagnosed from 1992 to 2002 using a linked Surveillance, Epidemiology and End Results (SEER)–Medicare database. Rituximab use was first detected in 1999 and by 2002 was incorporated in 79% of ABC-treated patients and 71% of patients treated with non-anthracycline chemotherapy, but only 12% of patients not receiving cytotoxic chemotherapy. ABC rates remained constant across time as did rates of no therapy, which were highest among the very old. Rituximab-associated survival improvements were seen among elderly treated with or without anthracyclines. Patients treated with rituximab but not anthracyclines had comparable survival to those treated with anthracycline but not rituximab.

Apples and Oranges? Interpretations of Risk Adjustment and Instrumental Variable Estimates of Intended Treatment Effects Using Observational Data

Instrumental variable (IV) and risk adjustment (RA) estimators, including propensity score adjustments, are both used to alleviate confounding problems in nonexperimental studies on treatment effects, but it is not clear how estimates based on these 2 approaches compare. Methodological considerations have shown that IV and RA estimators yield estimates of distinct types of causal treatment effects regardless of confounding problems. Many investigators have neglected these distinctions. In this paper, the authors use 3 schematic models to explain visually the relations between IV and RA estimates of intended treatment effects as demonstrated in the methodological studies. When treatment effects are homogeneous across a study population or when treatment effects are heterogeneous across the study population but treatment decisions are unrelated to the treatment effects, RA and IV estimates should be equivalent when the respective assumptions are met. In contrast, when treatment effects are heterogeneous and treatment decisions are related to the treatment effects, RA estimates of treatment effect can asymptotically differ from IV estimates, but both are correct even when the respective assumptions are met. Appropriate interpretations of IV or RA estimates can be facilitated by developing conceptual models related to treatment choice and treatment effect heterogeneity prior to analyses.

Survival Implications Associated with Variation in Mastectomy Rates for Early-Staged Breast Cancer

Despite a 20-year-old guideline from the National Institutes of Health (NIH) Consensus Development Conference recommending breast conserving surgery with radiation (BCSR) over mastectomy for woman with early-stage breast cancer (ESBC) because it preserves the breast, recent evidence shows mastectomy rates increasing and higher-staged ESBC patients are more likely to receive mastectomy. These observations suggest that some patients and their providers believe that mastectomy has advantages over BCSR and these advantages increase with stage. These beliefs may persist because the randomized controlled trials (RCTs) that served as the basis for the NIH guideline were populated mainly with lower-staged patients. Our objective is to assess the survival implications associated with mastectomy choice by patient alignment with the RCT populations. We used instrumental variable methods to estimate the relationship between surgery choice and survival for ESBC patients based on variation in local area surgery styles. We find results consistent with the RCTs for patients closely aligned to the RCT populations. However, for patients unlike those in the RCTs, our results suggest that higher mastectomy rates are associated with reduced survival. We are careful to interpret our estimates in terms of limitations of our estimation approach.