Who should code cause of death in a clinical trial?
Abstract
Clinical trials of intervention in chronic disease often use cause-specific mortality as a principal outcome variable. Surprisingly, there has been little standardization of the approach to determining cause of death. Some studies use standard nosological coding based on the International Statistical Classification of Diseases while others rely on panels of physicians. Some studies utilize autopsy findings; others do not. There is a clear need for standardization, and a unified approach is suggested. In this approach, panels of physicians prepare death certificates and are trained and standardized to generate reproducible information. A system for adjudication of differences is a part of the trial's design. Death certificates are then transmitted to panels of nosologists who assign cause of death. Again, the nosologists are standardized, and an adjudication system for resolving differences is developed. This two-stage system takes advantage of strengths of the two types of cause of death coding now in use in clinical trials and should produce results permitting cross-trial and cross-time comparisons.
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Cited by (15)
Comparing classifications of death in the Mode Selection Trial: Agreement and disagreement among site investigators and a clinical events committee
2006, Contemporary Clinical TrialsClinical events committees (CECs) are the current standard for endpoint adjudication in clinical trials. However, little data exist with which to compare CEC and site investigator determinations or to evaluate internal agreement among CEC members.
Using data from the Mode Selection Trial in Sinus Node Dysfunction (MOST), we analyzed classifications of death in order to compare internal agreement among CEC physician reviewers and agreement between the CEC and site investigators. Death was classified at 2 levels: by major cause (cardiac, noncardiac, or unknown) and by minor subclassification of the major classifications. Reviewer agreement was tabulated at the major and minor levels, and standard and weighted κ statistics were calculated. Disagreement at both levels was also determined. Individual decision-making was tabulated in terms of frequency in classifying death as unknown.
All 404 deaths were classified by the CEC. Site investigators determined major classifications in 382 cases and minor classification in 379 cases. The CEC and the site investigators disagreed in classifying 41 cases (10.7%) at the major level and 117 (30.9%) at the minor level. CEC reviewers disagreed internally at the major level in 64 cases (15.8%), at the minor level in 63 cases (15.6%), and at any level in 127 cases (31.4%) (κ = 0.60, 95% confidence interval (CI) [0.55, 0.66]; weighted κ = 0.66, 95% CI [0.62, 0.75]). In resolving internal disagreements, the full CEC agreed with 1 of 2 CEC reviewers in 85.9% of cases.
Disagreements occurred between site investigators and CEC reviewers in classifying deaths. Endpoint determination and decision-making varied among individual CEC reviewers, but second-tier reviews by the full CEC resolved all disagreements. These findings support continued use of CECs for endpoint adjudication in clinical trials.
Cause-specific mortality coding: Methods in the Collaborative Ocular Melanoma Study COMS Report No. 14
2001, Controlled Clinical TrialsAscertainment of cause of death is often sought in clinical trials in which mortality is an outcome of interest. Standardized methods of coding all-cause and disease-specific mortality were developed and evaluated in the Collaborative Ocular Melanoma Study randomized trial of pre-enucleation radiation of large choroidal melanoma. All available clinical and pathologic materials documenting events prior to each reported death were reviewed systematically by a Mortality Coding Committee (MCC) to determine whether melanoma metastasis or local recurrence was present at the time of death. A level of certainty was assigned based on availability of local or central review of pathology materials. The outcome of the mortality coding protocol was evaluated both by assessing agreement between the judgment of the MCC and the presumed cause of death reported by the clinical center and, for a subset of patients, by assessing agreement between the MCC classification and the cause of death reported on the death certificate. As of July 31, 1997 (the cutoff date for the initial mortality report), 435 (95%) of 457 deceased patient files had been reviewed. The MCC classified 269 patients (62%) as dead with melanoma metastasis, 22 (5%) as dead with another malignant tumor, and 92 (21%) as dead with a malignant tumor of uncertain origin. Thirty-eight patients (9%) died with no evidence of malignancy; in 14 cases (3%), the presence or absence of malignancy could not be established due to lack of clinical information. Fair agreement (kappa = 0.34) was observed between the determinations of the MCC based on detailed review of materials and the cause of death reported on the death certificate, but death certificates alone underestimated the proportion of deaths due to metastatic choroidal melanoma. Detailed mortality coding identified difficulties associated with accurate reporting of cause-specific mortality in patients with choroidal melanoma. Control Clin Trials 2001;22:248–262
The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre- enucleation radiation of large choroidal melanoma II: Initial mortality findings COMS report no. 10
1998, American Journal of OphthalmologyPurpose: To report initial mortality findings from the Collaborative Ocular Melanoma Study (COMS) randomized clinical trial of pre-enucleation radiation of large choroidal melanoma.
Methods: Patients were evaluated for eligibility at one of 43 participating centers in the United States and Canada. Eligible consenting patients were assigned randomly at the time of enrollment to standard enucleation or to external radiation of the orbit and globe prior to enucleation. Eligibility was confirmed at the COMS Coordinating Center, Echography Center, and Photograph Reading Center. Adherence to the radiotherapy protocol was monitored at the Radiological Physics Center. The diagnosis of choroidal melanoma was confirmed following enucleation by a three-member Pathology Review Committee. Patient accrual began in November 1986 and was completed in December 1994; 1,003 patients enrolled. Patients have been followed at annual clinical examinations. Cause of death was coded by a Mortality Coding Committee whose members were not involved in the care of COMS patients; the clinical trial was monitored by an independent Data and Safety Monitoring Committee.
Results: A total of 1,003 patients were enrolled; 506 were assigned to enucleation alone and 497 to pre-enucleation radiation. Treatment groups were well balanced on baseline characteristics. Only nine patients were found to be ineligible after enrollment, seven in the interval between randomization and enucleation and two after enucleation based on histopathology. All but nine patients were treated as assigned; in only six of 491 eyes treated with pre-enucleation radiation was there a major deviation from the radiotherapy protocol. With 5-year outcome known for 801 patients enrolled (80%), the estimated 5-year survival rates and 95% confidence intervals (CIs) were 57% (95% CI, 52% to 62%) for enucleation alone and 62% (95% CI, 57% to 66%) for pre-enucleation radiation. Among the baseline covariates evaluated, only age and longest basal diameter of the melanoma affected the prognosis for survival to a statistically significant degree. The risk of death among patients treated with pre-enucleation radiation relative to those treated with enucleation alone after adjustment for baseline characteristics of patients, eyes, and tumors was 1.03 (95% CI, 0.85 to 1.25). Of 435 deaths classified by the Mortality Coding Committee, 269 patients had histologically confirmed melanoma metastases at the time of death. Estimated 5-year survival rates for this secondary outcome were 72% (95% CI, 68% to 76%) for enucleation alone and 74% (95% CI, 69% to 78%) for pre-enucleation radiation.
Conclusions: No survival difference attributable to pre-enucleation radiation of large choroidal melanoma, using the COMS fractionation schedule, has been demonstrated to date in this randomized trial. The trial had statistical power of 90% to detect a relative difference in mortality rates between the two treatment arms of 20% or larger. A smaller difference is possible, but a clinically meaningful difference in mortality rates, whether from all causes or from metastatic melanoma, is unlikely.
A framework for evaluating and conducting prognostic studies: An application to cirrhosis of the liver
1989, Journal of Clinical EpidemiologyA framework for evaluating and conducting prognostic studies is proposed. Recently published studies on prognosis of cirrhosis of the liver are evaluated according to the proposed framework. It was found that appropriate statistical techniques were often used to analyze the results of prognostic studies of cirrhosis of the liver. On the other hand, the studies performed poorly with regards to study design, the determination of the usefulness of the data, the validity of the collected information, and the analytic strategy. It is hoped that the criteria suggested in this paper will improve the planning and the reporting of prognostic studies.
Standardized physician preparation of death certificates
1987, Controlled Clinical TrialsOne method for determining cause of death in a clinical trial is to use standard nosological coding of death certificates. In order to look at an alternative approach, the Hypertension Detection and Follow-up Program (HDFP) assessed underlying causes of death through the use of three physicians. These physicians were trained and standardized in the proper recording of cause of death on death certificates. Each physician completed a death certificate for each of the 768 deaths in the HDFP, utilizing all available information, including HDFP records, plus any additional hospital and autopsy records. The new standardized death certificates were then transmitted to a panel of three nosologists who coded the cause of death. The physician preparation procedure was compared with a procedure wherein a panel of three nosologist coded the original death certificate for the underlying cause of death. The procedures agreed on the three-digit International Classification of Disease, Adapted code in 60.1% of the cases. The agreement rate improved to 72.5% when disease codes were collapsed into broad disease categories utilized in the HDFP.