Alfred A. Rimm

Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data.

Although the association between malignancy and thromboembolic disease is well established, the relative risk of developing initial and recurrent deep vein thrombosis (DVT) or pulmonary embolism (PE) among patients with malignancy versus those without malignancy has not been clearly defined. The Medicare Provider Analysis and Review Record (MEDPAR) database was used for this analysis. Patients hospitalized during 1988-1990 with DVT/PE alone, DVT/PE and malignancy, malignancy alone, or 1 of several nonmalignant diseases (other than DVT/PE) were studied. The association of malignancy and nonmalignant disease with an initial episode of DVT/PE, recurrent DVT/PE, and mortality were analyzed. The percentage of patients with DVT/PE at the initial hospitalization was higher for those with malignancy compared with those with nonmalignant disease (0.6% versus 0.57%, p = 0.001). The probability of readmission within 183 days of initial hospitalization with recurrent thromboembolic disease was 0.22 for patients with prior DVT/PE and malignancy compared with 0.065 for patients with prior DVT/PE and no malignancy (p = 0.001). Among those patients with DVT/PE and malignant disease, the probability of death within 183 days of initial hospitalization was 0.94 versus 0.29 among those with DVT/PE and no malignancy (p = 0.001). The relative risk of DVT/PE among patients with specific types of malignancy is described. This study demonstrates that patients with concurrent DVT/PE and malignancy have a more than threefold higher risk of recurrent thromboembolic disease and death (from and cause) than patients with DVT/PE without malignancy. An alternative management strategy may be indicated for such patients.

Interstitial Pneumonitis After Bone Marrow Transplantation: Assessment of Risk Factors

Data from 932 patients with leukemia who received bone marrow transplants were analyzed to determine factors associated with an increased risk of developing interstitial pneumonitis. Interstitial pneumonitis developed in 268 patients for a 2-year actuarial incidence of 35 +/- 4% (SD) and with a mortality rate of 24%. Six factors were associated with an increased risk: use of methotrexate rather than cyclosporine after transplantation (relative risk, 2.3; p less than 0.0002); older age (relative risk, 2.1; p less than 0.0001); presence of severe graft-versus-host disease (relative risk, 1.9; p less than 0.003); long interval from diagnosis to transplantation (relative risk, 1.6; p less than 0.002); performance ratings before transplantation of less than 100% (relative risk, 2.1; p less than 0.0001); and high dose-rates of irradiation in patients given methotrexate after transplantation (relative risk, 3.2; p less than 0.03). The risk of developing interstitial pneumonitis ranged from 8% in patients with none of these adverse risk factors to 94% in patients with all six. These findings may help to identify patients at high risk for this complication.

Identical-twin bone marrow transplants for leukemia

Bone marrow transplants are increasingly used to treat leukemias including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). Approximately 4000 allogeneic transplants are done annually worldwide [1]. Most transplants are from HLA-identical siblings; few persons with leukemia receive transplants from identical twins. Consequently, analyses of results of twin transplants are limited by the small number of participants and diverse remission states. We analyzed the results of identical-twin transplants for leukemia in 103 persons reported to the International Bone Marrow Transplant Registry between 1978 and 1990. Transplant outcomes were compared with those of concurrent HLA-identical sibling transplants for leukemia. Methods The study population included 103 patients with ALL or AML in first remission or CML in first chronic phase receiving bone marrow transplants from identical twins between 1978 and 1990 and reported to the International Bone Marrow Transplant Registry by 66 centers. During the same period, 3214 recipients of non-T-cell-depleted HLA-identical sibling transplants for these indications were reported to the International Bone Marrow Transplant Registry by 163 centers: 581 for ALL in first remission, 1394 for AML in first remission, and 1240 for CML in first chronic phase. Assessing Comparability of Twin and HLA-identical Sibling Transplant Recipients For each disease, prognostic factors for transplant outcome were compared between twin and HLA-identical sibling transplant recipients using chi-square for categorical variables and the Mann-Whitney test [2] for continuous variables. Factors considered were those associated with HLA-identical sibling transplant outcome in previous International Bone Marrow Transplant Registry studies [3-7]. These included the following: for ALL, age, leukocytes at diagnosis, immune phenotype, and time to achieve first remission [3, 4]; for AML, age, leukocytes at diagnosis, FAB type, and Karnofsky performance score [5]; and for CML, age, previous splenectomy, interval between diagnosis and transplant, and previous treatment with busulfan [6, 7]. Conditioning regimens were also compared. For each twin transplant, 10 controls were selected from among 3214 HLA-identical sibling transplants matched for disease and any prognostic factors differing between the two cohorts with P < 0.1. For ALL, pairs were matched for age within 5 years; for AML, pairs were matched for FAB type and Karnofsky score; for CML, pairs were matched for age, interval between diagnosis and transplant, and use of busulfan before transplantation. Statistical Methods Actuarial probabilities of relapse, treatment-related mortality [8], and leukemia-free survival were calculated in the twins and matched HLA-identical sibling controls using life-table methods. Relapse was defined as hematologic recurrence in any site; patients in continuous complete remission were censored at death or, for survivors, at last contact. Treatment-related mortality was defined as death in continuous complete remission; patients were censored at time of relapse or at last follow-up. Leukemia-free survival was defined as survival in continuous complete remission. Relapse and death from causes other than leukemia were considered failures; patients alive and in remission were censored at time of last follow-up. Univariate comparisons of survival distributions were done using the matched log-rank test [9]. To compare relapse risks after adjusting for the effect of graft-versus-host disease, we used Cox proportional-hazards regression with acute and chronic graft-versus-host disease entered as time-dependent covariates [10, 11]. The International Bone Marrow Transplant Registry The Registry is a voluntary working group of more than 200 transplant teams worldwide that contribute detailed data on their allogeneic and identical-twin bone marrow transplants to a statistical center [12, 13]. The program is primarily funded by a program project grant from the U.S. National Institutes of Health. Participants are required to report all consecutive transplants; compliance is monitored by on-site audits. Approximately two thirds of all active allogeneic transplant centers report their data to the Registry. The Registry database includes 40% to 45% of all allogeneic transplant recipients since 1970. Patients are followed longitudinally. Computerized error checks, physician review of submitted data, and on-site audits of participating centers ensure data quality. Transplant outcomes estimated using Registry data are similar to those reported by large nonparticipating centers for comparable patients. Results Differences were found in patient-, disease- and treatment-related variables between the 103 recipients of identical-twin transplants and the 3214 recipients of HLA-identical sibling transplants reported to the International Bone Marrow Transplant Registry during the same interval. Some were intrinsic to the study design. For example, identical-twin donors and recipients were always of the same sex compared with only about one half of HLA-identical sibling donor-recipient pairs. Also, only eight (8%) twin recipients received immune suppression after transplantation compared with 100% of HLA-identical sibling transplant recipients. It was not possible to match or otherwise control for potential effects of these differences. Other differences were as follows: for ALL, younger median age in twins compared with HLA-identical siblings (17 compared with 22 years; P = 0.003); for AML, higher proportion of twins older than 40 years of age (22% compared with 8%; P = 0.002) and with Karnofsky performance scores at transplantation of less than 90% (15% compared with 10%; P < 0.001); and for CML in first chronic phase, shorter median interval from diagnosis to transplant in twins (6 compared with 13 months; P < 0.001) and fewer twins treated with busulfan before transplant (12% compared with 32%, P = 0.04). Ten HLA-identical sibling transplant controls were selected for each twin transplant, matching for diagnosis and for these variables. The resulting matched cohort was similar to the twin cohort for all variables considered, other than those intrinsic to twin transplants as indicated (Appendix Table 1). The median follow-up times of 6.3 years (range, 0.4 to 13.6 years) and 5.0 years (range, 0.3 to 14.8 years) were similar for twin and HLA-identical sibling transplant cohorts, respectively (P = 0.2). Appendix Table 1. Matched-Twin Compared with HLA-identical Sibling Cohorts* Transplant Outcome The two matched cohorts, twins and HLA-identical siblings, were compared for three transplant outcomes: relapse, treatment-related mortality, and leukemia-free survival. Cox regression analysis was used to compare relapse risk between the cohorts after adjusting for acute and chronic graft-versus-host disease. Acute Lymphoblastic Leukemia Ten of 24 twins had a relapse. The 3-year probability of relapse was 36% (CI, 17% to 55%) compared with 26% (CI, 20% to 32%) after 240 HLA-identical sibling transplants (P = 0.1; Figure 1). The 95% CI for the difference in relapse rates between twin and HLA-identical sibling transplants at 3 years was 10% to 30%. Regression analysis with adjustment for acute and chronic graft-versus-host disease showed no difference between identical-twin and HLA-identical sibling transplants in relapse risk (relative risk for twins compared with HLA-identical siblings, 1.4; CI, 0.6 to 2.8, P > 0.2). Figure 1. Outcome of transplants for acute lymphoblastic leukemia. top bottom Two recipients of twin transplants died in remission. The 3-year probability of treatment-related mortality in twins was 10% (CI, 3% to 30%) compared with 21% (CI, 16% to 26%) in HLA-identical sibling transplant recipients (P = 0.1). Twelve of 24 twins were alive in continuous complete remission between 1.2 and 9.5 years (median, 5.4 years) after transplantation. The 3-year probability of leukemia-free survival was 57% (CI, 37% to 77%) compared with 58% (CI, 52% to 64%) after HLA-identical sibling transplants (P > 0.2; Figure 1). Acute Myelogenous Leukemia Twenty-three of 45 twins had a relapse. The 3-year probability of relapse was 52% (CI, 37% to 67%) compared with 16% (CI, 12% to 20%) after 450 HLA-identical sibling transplants (P < 0.001; Figure 2). The 95% CI for the difference in relapse rates at 3 years was 20% to 52%. Regression analysis after adjustment for acute and chronic graft-versus-host disease also showed an increased relapse risk in twins (relative risk, 3.8; CI, 2.3 to 6.2, P < 0.001). Figure 2. Outcome of transplants for acute myelogenous leukemia. top bottom Five twins died of treatment-related causes. The 3-year probability of treatment-related mortality was 12% (CI, 1% to 23%) compared with 34% (CI, 29% to 39%) after HLA-identical sibling transplants (P = 0.004). Seventeen recipients of twin transplants were alive in continuous complete remission 5 months to 13.6 years (median, 6.3 years) after transplantation. The 3-year probability of leukemia-free survival was 42% (CI, 27% to 57%) compared with 55% (CI, 50% to 60%) after HLA-identical sibling transplants (P = 0.2; Figure 2). Chronic Myelogenous Leukemia Seventeen of 34 twins had a relapse. The 3-year probability of relapse was 40% (CI, 23% to 57%) compared with 7% (CI, 4% to 10%) after 340 HLA-identical sibling transplants (P < 0.001; Figure 3). The 95% CI for the difference in relapse rates at 3 years was 16% to 50%. Regression analysis after adjustment for acute and chronic graft-versus-host disease also showed increased relapse risk in twins (relative risk, 5.5; CI, 2.8 to 11.0, P < 0.001). Figure 3. Outcome of transplants for chronic myelogenous leukemia. top bottom One twin died of treatment-related causes. The 3-year probability of treatment-related mortality was 3% (CI, 0% to 16%) compared with 34% (CI, 29% to 39%) after HLA-ident

A Meta-Analysis of Controlled Studies Comparing Major Malformation Rates in IVF and ICSI Infants with Naturally Conceived Children

Purpose: To estimate the risk of major malformations in IVF and ICSI infants.Methods: Forty-four studies published in English since 1990 where the major malformation rate for IVF or ICSI cases was compared to an appropriate control group were reviewed. Nineteen studies met all selection criteria. In addition, a quality score was developed to assess each study based on sample size, timing of diagnosis, appropriateness of control group and other factors.Results: In 19 studies, the major malformation rates ranged from 0–9.5% for IVF; 1.1–9.7 for ICSI; and 0–6.9% in the control groups. When ICSI was compared to IVF, and multiple births compared to singleton, there were no statistically significant differences. When data from 16 studies involving 28,524 IVF infants and 2,520,988 spontaneously conceived controls and 7 studies involving 7234 ICSI infants and 978,078 controls were pooled, we found an overall odds ratio for the 19 studies of 1.29 (95% CI 1.01–1.67).Conclusions: The overall odds ratio of 1.29 was statistically significant at the 5% level. These results may be useful for counseling ART patients and properly designing the consent forms used for ART procedures. It is not clear whether this risk is due to the procedures used in ART. We found that some of these studies have design flaws. All of them lacked an appropriate control group, i.e. infertile patients conceiving spontaneously. These flaws may create biases that would in almost all instances increase the risk of major malformations in the study group. Further research with better designed studies will likely result in a better estimate of the risk of major malformations associated with IVF and ICSI.

Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission

BACKGROUND It is unclear how best to treat children with acute lymphoblastic leukemia who are in a second remission after a bone marrow relapse. For those with HLA-identical siblings, the question of whether to perform a bone marrow transplantation or to continue chemotherapy has not been answered. METHODS We compared the results of treatment with marrow transplants from HLA-identical siblings in 376 children, as reported to the International Bone Marrow Transplant Registry, with the results of chemotherapy in 540 children treated by the Pediatric Oncology Group. A preliminary analysis identified variables associated with treatment failure in both groups. We selected cohorts by matching these variables. A possible bias associated with differences in the interval between remission and treatment was controlled for by choosing matched pairs in which the duration of the second remission in the chemotherapy recipient was at least as long as the time between the second remission and transplantation in the transplant recipient. A total of 255 matched pairs were studied. RESULTS The mean (+/- SE) probability of a relapse at five years was significantly lower among the transplant recipients than among the chemotherapy recipients (45 +/- 4 percent vs. 80 +/- 3 percent, P < 0.001). At five years the probability of leukemia-free survival was higher after transplantation than after chemotherapy (40 +/- 3 percent vs. 17 +/- 3 percent, P < 0.001). The relative benefit of transplantation as compared with chemotherapy was similar in children with prognostic factors indicating a high or low risk of relapse (the duration of the first remission, age, leukocyte count at the time of the diagnosis, and phenotype of the leukemic cells). CONCLUSIONS For children with acute lymphoblastic leukemia in a second remission, bone marrow transplants from HLA-identical siblings result in fewer relapses and longer leukemia-free survival than does chemotherapy.

Surgery for colorectal cancer: Race-related differences in rates and survival among Medicare beneficiaries.

This study examined surgery for colorectal cancer among Medicare beneficiaries 65 years of age or older with an initial diagnosis in 1987 (n = 81 579). Black patients were less likely than White to undergo surgical resection (68% vs 78%), even after age, comorbidity, and location and extent of tumor were controlled for. Among those who underwent resection, Black patients were more likely to die (a 2-year mortality rate of 40.0% vs 33.5% in White patients); this disparity also remained after confounders had been controlled. The disparities were similar in teaching and nonteaching hospitals and in private and public hospitals. These data may indicate racially based differences among Medicare beneficiaries in access to and quality of care for colorectal cancer.

The Sensitivity of Medicare Claims Data for Case Ascertainment of Six Common Cancers

BACKGROUND Although Medicare claims data have been used to identify cases of cancer in older Americans, there are few data about their relative sensitivity. OBJECTIVES To investigate the sensitivity of diagnostic and procedural coding for case ascertainment of breast, colorectal, endometrial, lung, pancreatic, and prostate cancer. SUBJECTS Three hundred and eighty nine thousand and two hundred and thirty-six patients diagnosed with cancer between 1984 and 1993 resided in one of nine Surveillance Epidemiology and End Results (SEER) areas. MEASURES The sensitivity of inpatient and Part B diagnostic and cancer-specific procedural codes for case finding were compared with SEER. RESULTS The sensitivity of inpatient and inpatient plus Part B claims for the corresponding cancer diagnosis was 77.4% and 91.2%, respectively. The sensitivity of inpatient claims alone was highest for colorectal (86.1%) and endometrial (84.1%) cancer and lowest for prostate cancer (63.6%). However, when Part B claims were included, the sensitivity for diagnosis of breast cancer was greater than for other cancers (93.6%). Inpatient claim sensitivity was highest for earlier years of the study, and, because of more complete data and longer follow up, the highest sensitivity of combined inpatient and Part B claims was achieved in the late 1980s or early 1990s. CONCLUSIONS Medicare claims provide reasonably high sensitivity for the detection of cancer in the elderly, especially if inpatient and Part B claims are combined. Because the study did not measure other dimensions of accuracy, such as specificity and predictive value, the potential costs of including false positive cases need to be assessed.

Agreement of medicare claims and tumor registry data for assessment of cancer-related treatment

BACKGROUND Although health claims data are increasingly used in evaluating variations in patterns of cancer care and outcomes, little is known about the comparability of these data with tumor registry information. OBJECTIVES To evaluate the agreement between Medicare claims and tumor registry data in measuring patterns of diagnostic and therapeutic procedures for older cancer patients. RESEARCH DESIGN Analysis of a database linking Surveillance, Epidemiology and End Results (SEER) registry data and Medicare claims in patients aged > or =65 years with cancer. SUBJECTS 361,255 Medicare patients with invasive breast, colorectal, endometrial, lung, pancreatic, and prostate cancer diagnosed between 1984 and 1993. MEASURES Concordance of SEER files with corresponding Medicare claims. RESULTS Medicare claims generally identified patients who underwent resection and radical surgery according to SEER (ie, concordance > or =85%-90%) but less likely biopsy or local excision (ie, concordance < or =50%). In some instances, claims also categorized patients as having more invasive surgery than was listed in SEER and also provided incremental information about the use of surgical treatment after 4 months. SEER files and, to a lesser degree, Medicare claims identified radiation therapy not included in the other data source, and Medicare files also captured a significant number of patients with codes for chemotherapy. CONCLUSIONS Medicare files may be appropriate for studies of patterns of use of surgical treatment, but not for diagnostic procedures. The potential benefit of Medicare claims in identifying delayed surgical intervention and chemotherapy deserves further study.

The association between hospital type and mortality and length of stay: a study of 16.9 million hospitalized Medicare beneficiaries.

OBJECTIVES To examine the association between hospital type and mortality and length of stay using hospitalized Medicare beneficiaries for a 10-year period. METHODS The retrospective cohort study included 16.9 million hospitalized Medicare beneficiaries > or = 65 years of age admitted for 10 common medical conditions and 10 common surgical procedures from 1984 to 1993. A total of 5,127 acute-care hospitals in the United States were grouped into 6 mutually exclusive hospital types based on teaching status and financial structure (for-profit [FP], not-for-profit [NFP], osteopathic [OSTEO], public [PUB], teaching not-for-profit [TNFP], and teaching public [TPUB]) as reported in the 1988 American Hospital Association database. Logistic and linear regression methods were used to examine risk-adjusted 30-day and 6-month mortality and length of stay. RESULTS During the 10-year study period, 10.6 million patients were admitted with 1 of the 10 selected medical conditions, and 6.3 million patients were hospitalized for 1 of the 10 selected surgical procedures. Patients at TNFP hospitals had significantly lower risk-adjusted 30-day mortality rates than patients at other hospital types when all diagnoses or procedures were combined (combined diagnoses: RR(TNFP) = 1.00 [reference], RR(TPUB) = 1.40, RR(OSTEO) = 1.14, RR(PUB) = 1.07, RR(FP) = 1.03, RR(NFP) = 1.02; combined procedures: RR(TNFP) = 1.00 [reference], RR(OSTEO) = 1.36, RR(TPUB) = 1.30, RR(PUB) = 1.16, RR(FP) = 1.13, RR(NFP) = 1.08). The results were mostly consistent when diagnoses and procedures were examined separately. After adjustment for patient characteristics, patients at other hospital types had 10% to 20% shorter lengths of stay (LOS) than patients at TNFP hospitals for most diagnoses and procedures studied. CONCLUSION As measured by the risk-adjusted 30-day mortality, TNFP hospitals had an overall better performance than other hospital types. However, patients at TNFP hospitals had relatively longer LOS than patients at other hospital types, perhaps reflecting the medical education and research activities found at teaching institutions. Future research should examine the empirical evidence to help elucidate the adequate LOS for a given condition or procedure while maintaining the quality of care.

Air pollution and emergency department visits for asthma among Ohio Medicaid recipients, 1991-1996.

We examined the effects of nitrogen dioxide (NO(2)), ozone (O(3)), particulate matter of <10 microm aerodynamic diameter (PM(10)), and sulfur dioxide (SO(2)) on asthmatics ages 5-34 years enrolled in Medicaid in Cincinnati, Cleveland, and Columbus, OH (N=5416). Our study period was for the summer months, June-August, from July 1, 1991 to June 30, 1996. We preformed Poisson regression analyses for the number of daily emergency department (ED) visits for asthma in each city and on the aggregate data controlling for time trends and minimum temperature. We found a 12% increased likelihood of an asthma ED visit per 50 microg/m(3) increase in PM(10) in Cleveland [95% confidence interval (CI)=0-27%] and a 35% increase per 50 microg/m(3) increase in SO(2) in Cincinnati (95% CI=9-21%). When data were analyzed for all three cities combined, the risk of an ED visit increased for all pollutant increases and specifically by 12% (95% CI=1-23%) per 50 microg/m(3) increase in SO(2). Attributable risk estimates show a five times greater impact on Cleveland over Cincinnati or Columbus. Between 1991 and 1996, air pollutants in Cincinnati, Cleveland, and Columbus increased ED visits for asthmatics enrolled in Medicaid.