Distinct problems in the analysis of failure times with competing causes of failure include the estimation of treatment or exposure effects on specific failure types, the study of interrelations among failure types, and the estimation of failure rates for some causes given the removal of certain other failure types. The usual formation of these problems is in terms of conceptual or latent failure times for each failure type. This approach is criticized on the basis of unwarranted assumptions, lack of physical interpretation and identifiability problems. An alternative approach utilizing cause-specific hazard functions for observable quantities, including time-dependent covariates, is proposed. Cause-specific hazard functions are shown to be the basic estimable quantities in the competing risks framework. A method, involving the estimation of parameters that relate time-dependent risk indicators for some causes to cause-specific hazard functions for other causes, is proposed for the study of interrelations among failure types. Further, it is argued that the problem of estimation of failure rates under the removal of certain causes is not well posed until a mechanism for cause removal is specified. Following such a specification, one will sometimes be in a position to make sensible extrapolations from available data to situations involving cause removal. A clinical program in bone marrow transplantation for leukemia provides a setting for discussion and illustration of each of these ideas. Failure due to censoring in a survivorship study leads to further discussion.
We treated 93 patients who had acute nonlymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate postgrafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival.
LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN.
The study highlights the role of human factors in negative surgical outcomes. Even in the most eventful circumstances, however, appropriate human factors defense mechanisms can lead to a successful outcome.
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