Additive hazards Markov regression models illustrated with bone marrow transplant data

Goodness-of-fit tests for Cox's proportional hazards model and Aalen's additive risk model, in which each model is compared on an equal footing with the best fitting fully nonparametric model, are developed. The goodness-of-fit statistics are based on differences each model, with a fully nonparametric estimator of d recently introduced by the authors. Here A( , z) denotes the conditional hazard function of the survival time of an individual with covariate vector z. Comparison of the results of the tests makes it possible to decide whether Cox's proportional hazards or Aalen's additive risk model gives a better fit to the data. In addition, a goodness-of-fit test for Cox's model within the family of all proportional hazards models A(t, z) = AO(t)r(z), where AO is a baseline hazard function and r is a general relative risk function, is developed. Additive hazards and proportional hazards regression models used in the analysis of censored survival data can give substantially different results. For instance, in connection with a study of cancer mortality among Japanese atomic bomb survivors, Muirhead & Darby (1987) have noted that the two models give substantially different estimates of the age-spe- cific probability that an individual will develop radiation induced cancer. Muirhead & Darby (see also Aranda-Ordaz, 1983) introduced a generalized parametric model which contains parametric additive hazards and proportional hazards models as special cases. The goodness- of-fit of each model is then obtained by comparing with the best fitting model within the generalized family, allowing the two special models to be treated on an equal footing. Beyond the parametric setting, much effort has been devoted to the development of goodness-of-fit tests for Cox's (1972) proportional hazards model

Comparison of Outcomes after Transplantation of G-CSF–Stimulated Bone Marrow Grafts versus Bone Marrow or Peripheral Blood Grafts from HLA-Matched Sibling Donors for Patients with Severe Aplastic Anemia

Background:Survival rates for breast cancer (BC) are often based on the outcomes of this disease. The aim of this study was to compare the performance of three survival models, namely Cox regression, Aalen's, and Lin and Ying's additive hazards (AH) models for identifying the prognostic factors regarding the survival time of BC patients.Materials and Methods:This study was a historical cohort study which used 1025 females' medical records that underwent modified radical mastectomy or breast saving. These patients were admitted to Besat and Chamran Hospitals, Tehran, Iran, during 2010–2015 and followed until 2017. The Aalen's and Lin and Ying's AH models and also traditional Cox model were applied for analysis of time to death of BC patients using R 3.5.1 software.Results:In Aalen's and also Lin and Ying's AH models, age at diagnosis, history of disease, number of lymph nodes, metastasis, hormonal therapy, and evacuation lymph nodes were prognostic factors for the survival of BC patients (P < 0.05). In addition, in the Lin and Ying's AH model tumor size (P = 0.048) was also identified as a significant factor. According to Aalen's plot, metastasis, age at diagnosis, and number of lymph nodes had a time-varying effect on survival time. These variables had a different slope as the times go on.Conclusion:AH model may yield new insights in prognostic studies of survival time of patients with BC over time. Because of the positive slope of estimated cumulative regression function in Aalen's plot, metastasis, higher age at diagnosis, and high number of lymph nodes are important factors in reducing the survival BC, and then based on these factors, the therapists should consider a special therapeutic protocol for BC patients.

Systemic lupus erythematosus in a 15-year-old with graft-versus-host disease following liver transplant and unexpected full hematopoietic engraftment

Under the case-cohort design introduced by Prentice (Biometrica 73:1-11, 1986), the covariate histories are ascertained only for the subjects who experience the event of interest (i.e., the cases) during the follow-up period and for a relatively small random sample from the original cohort (i.e., the subcohort). The case-cohort design has been widely used in clinical and epidemiological studies to assess the effects of covariates on failure times. Most statistical methods developed for the case-cohort design use the proportional hazards model, and few methods allow for time-varying regression coefficients. In addition, most methods disregard data from subjects outside of the subcohort, which can result in inefficient inference. Addressing these issues, this paper proposes an estimation procedure for the semiparametric additive hazards model with case-cohort/two-phase sampling data, allowing the covariates of interest to be missing for cases as well as for non-cases. A more flexible form of the additive model is considered that allows the effects of some covariates to be time varying while specifying the effects of others to be constant. An augmented inverse probability weighted estimation procedure is proposed. The proposed method allows utilizing the auxiliary information that correlates with the phase-two covariates to improve efficiency. The asymptotic properties of the proposed estimators are established. An extensive simulation study shows that the augmented inverse probability weighted estimation is more efficient than the widely adopted inverse probability weighted complete-case estimation method. The method is applied to analyze data from a preventive HIV vaccine efficacy trial.

Additive time-dependent hazard model with doubly truncated data

Establishment of complete and mixed donor chimerism after allogeneic lymphohematopoietic transplantation: recommendations from a workshop at the 2001 Tandem Meetings of the International Bone Marrow Transplant Registry and the American Society of Blood and Marrow Transplantation.

Wilford Hall Medical Center (WHMC), at Lackland Air Force Base in San Antonio, Texas, is the only center within the U.S. Department of Defense at which allogeneic bone marrow transplantation (BMT) is performed. From the inception of the BMT program in 1987 through February 1999, 286 military health care beneficiaries have undergone human leukocyte antigen-matched related donor allogeneic bone marrow transplantation for hematologic disorders. We conducted a retrospective chart review to analyze the outcomes of all allogeneic BMT procedures performed at WHMC through February 1999. Our analysis revealed that allogeneic BMT outcomes compared favorably with those reported by the International Bone Marrow Transplant Registry. The results of this study support the continued designation of the Fisher Bone Marrow Transplant Center at WHMC as a specialty treatment service within the Department of Defense.

Aplastic anemia is caused by several diverse factors, including a lack of or defective hematopoietic stem cells, immune abnormalities, and disorders of the bone marrow microenvironment. The outcome of transplanting bone marrow from genetically identical twins into patients with aplastic anemia may help define how frequently these factors play a role in this condition. To determine the outcome of transplanting bone marrow from genetically identical twins into patients with aplastic anemia. Observational study. 31 centers participating in the international Bone Marrow Transplant Registry. 40 patients with aplastic anemia who received bone marrow transplants from their genetically identical twins between 1964 and 1992. 23 patients received their first bone marrow transplant without pretransplantation conditioning; 17 received it after pretransplantation conditioning with cyclophosphamide alone or combined with other drugs or radiation. Six patients received post-transplantation immunosuppressive therapy with methotrexate, cyclosporine, and corticosteroids, alone or in combination. Outcomes of transplantation, including hematologic recovery and survival. Seven of 23 patients who received their first transplant without receiving conditioning had sustained complete hematologic recovery. One of 16 patients who did not have complete recovery after the first transplantation recovered after a second transplantation, which was not preceded by conditioning. The other 15 patients had two to five transplantations that were preceded by conditioning; in 13 patients, sustained bone marrow function was recovered. Twelve of 17 patients whose first transplantation was preceded by conditioning had sustained complete hematologic recovery. The likelihood of hematologic recovery was greater in patients who had conditioning before the first transplantation (P = 0.033). The actuarial 10-year survival rate for the 40 patients was 78% (95% CI, 59% to 92%). The survival rate was higher in patients who did not have conditioning before the first transplantation (patients without conditioning, 87% [range, 65% to 99%]; patients with conditioning, 70% [range, 47% to 89%]; P = 0.037). Most patients with aplastic anemia recover bone marrow function after receiving a transplant from a genetically identical twin. Pretransplantation conditioning may increase the chance of bone marrow recovery but does not seem to improve survival.

Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers? [see comments

Bone marrow transplants from HLA-identical siblings are increasingly used to treat acute leukemia including acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL). We review transplant results in 3710 persons with AML and ALL reported to the International Bone Marrow Transplant Registry (IBMTR) between 1984 and 1989.KeywordsAcute Lymphoblastic LeukemiaBone Marrow TransplantAcute LeukemiaRemission StateImmune PhenotypeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Treatment with busulphan and/or hydroxyurea rarely produces remission in patients with chronic myelogenous leukaemia (CML) in chronic phase. HLA-identical sibling transplants almost always produce remission, and only about 20% of patients relapse post-transplant. The increased anti-leukaemic efficacy of transplants results from intensive pretransplant treatment and immune-mediated anti-leukaemia effects. We studied 433 patients surviving > or = 2 years after diagnosis of CML to determine if patients who have relapsed after a transplant in chronic phase have longer survival from diagnosis than comparable subjects receiving chemotherapy. The chemotherapy cohort included 344 adults < 50 years of age treated on consecutive trials of the Italian Cooperative Study Group on CML between 1973 and 1986. The transplant cohort included 89 patients reported to the International Bone Marrow Transplant Registry who relapsed after an HLA-identical sibling bone marrow transplant carried out between 1978 and 1992. Survivals in the two groups were compared using Cox proportional hazards regression to adjust for prognostic variables. Median survival was 65 months in the chemotherapy cohort and 86 months in the transplant cohort. The 7-year probability (95% confidence interval) of survival was 34% (28-39%) in the chemotherapy cohort and 57% (43-70%) in the transplant cohort (P=0003). There was no difference in survival of patients relapsing after T-cell depleted and non-T-cell-depleted transplants. We conclude that patients who relapse after an HLA-identical sibling bone marrow transplant for CML in chronic phase have longer survival from diagnosis than comparable patients receiving chemotherapy. This effect is most likely to be the result of intensive chemotherapy and/or radiation given for pretransplant conditioning.

<h3>To the Editor.</h3> —Ringdén et al¹conclude that among patients with leukemia who are older than 30 years at the time of allogeneic bone marrow transplantation, increasing age into the fifth decade does not adversely affect outcome after transplants from HLA-identical siblings. This conclusion is based on results obtained in 2180 patients, only 80 of whom were older than 50 years. Ringdén et al admit that the patients were highly selected, since only data on transplanted patients reported to the International Bone Marrow Transplant Registry were analyzed. Despite this, their main conclusion is made without reservation. From Table 2 in the article it is clear that the leukemia-free survival rate in 45- to 49-year-old patients at 2 years with advanced leukemia was 3%, and the treatment-related mortality rate was 94%. Results in patients 50 years or older with advanced disease were not evaluated. For patients with an intermediate state

Therapeutic results for patients with acute myelogenous leukemia have improved dramatically over the past decade. The effective use of cytosine arabinoside (Ara-C) combined with anthracycline antibiotics as induction therapy has resulted in complete remission rates of 60–75% (1–3). Several series of patients from individual institutions or collaborating institutions testing novel chemotherapy strategies have demonstrated that up to 50% of their patient populations can achieve prolonged disease free survival (4–8). Among the strategies reported to be successful in prolonging remission duration are the use of prolonged intensive cytotoxic therapy (4), brief intensive therapy using multiple non-cross resistant drugs (8), consolidation with high dose Ara-C (7), intensive timed sequential therapy with daunorubicin and Ara-C (6), and consolidation with intensive chemoradiotherapy followed by allogeneic or syngeneic bone marrow transplantation (9–14). When the data is viewed in the aggregate, allogeneic bone marrow transplantation during first remission has resulted in a higher proportion and a greater number of long term survivors than any other treatment strategy. A recent update from the International Bone Marrow Transplantation Registry indicates that 45% of 418 patients transplanted in first remission, or 188 patients have a probability of being alive at 3 and 4 years (15).

The International Bone Marrow Transplant Registry (IBMTR) and the Autologous Blood and Marrow Transplant Registry (ABMTR) are international research organizations that collect and analyze data on recipients of allogeneic and autologous hematopoietic stem cell transplants, respectively. Over 300 institutions in 47 countries contribute data to the IBMTR and over 150 institutions in North and South America contribute data to the ABMTR. The IBMTR and ABMTR database have information on more than 65,000 transplant recipients, about 40% of allogeneic transplantations performed since 1964, and about half of all autotransplantations in North and South America since 1989. Current transplant activity, as reported to the IBMTR and ABMTR, is summarized in this article as well as key findings from recent IBMTR and ABMTR studies.