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Biomedical subjects

L A Kalish

Publications and source records attributed to L A Kalish.

71 records · Page 4Linked to original sources
PubMed1990

Efficient design for estimation of median lethal dose and quantal dose-response curves.

The results of quantal dose-response experiments are often summarized by an estimate of the "median lethal dose," denoted LD50, and many sequential designs have been proposed for efficient estimation of LD50. These designs strive to produce a sequence of trials at dose levels that get closer and closer to LD50. Consequently, they may not provide very good estimates of the overall shape of the dose-response curve. In this paper we propose guidelines for the design of experiments that estimate LD50 fairly efficiently and that also allow for efficient global estimation of the curve.

Animals↗
PubMed1990

Reducing mean squared error in the analysis of pair-matched case-control studies.

The standard estimator of the common odds ratio for pair-matched case-control studies, the stratified estimate, is consistent but it ignores all information from the concordant pairs. At the other extreme, the pooled estimator is more efficient as it uses all the data, but is not consistent. In order to trade between bias and precision, Liang and Zeger (1988, Biometrics 44, 1145-1156) proposed an estimator that is a compromise between the stratified and pooled estimates. In the current paper, the possibility of optimizing the trade-off is explored. Specifically, the family of weighted averages of the stratified and pooled estimates is considered, and the weight that minimizes an asymptotic approximation of mean squared error is derived. In practice, the optimal weight must be estimated from the data so that the estimator is only approximately optimal. Small-sample properties are evaluated via simulations.

Bias↗
PubMed1989

Psychosocial factors, curative therapies, and behavioral outcomes. A comparison of testis cancer survivors and a control group of healthy men.

In a retrospective study of 223 testis cancer survivors and 120 controls matched sociodemographically, we examined the relative impact of sociodemographic and clinical factors on long-term outcomes in the areas of sexual function, relationships, employment, and mental outlook. For most of the survivors, testis cancer did not lead to unemployment (4.5%), divorce (6.8%), or disabling psychological problems. Multivariate analysis results confirm that cancer survivors report significantly more infertility and sexual performance distress, but not more desire distress, than the control group. Survivors' sexual impairment varied according to treatment received (and therefore histologic factors) and sociodemographic variables. Parental status (not having children) and education (college or less) independently predict infertility distress, whereas education and lower occupational level independently predicted sexual performance distress. Adjusting for socioeconomic status (SES), the men with advanced testis cancer who received chemotherapy and standard retroperitoneal lymph node dissection (RPLND) had significantly more infertility and performance distress than those men who received other treatments. Neither the treatment or SES variables predicted disrupted relationships or a deteriorated mental outlook. However, men with sexual impairment distress were more likely to report strained relationships and a pessimistic mental outlook. These findings have implications for treatment decisions and can be used to identify subgroups of survivors who could benefit from counseling and sexual rehabilitation services.

Adolescent↗
PubMed1988

Stage I nonseminomatous germ cell testicular tumor: prediction of metastatic potential by primary histopathology.

A study of 60 patients with clinical stage I nonseminomatous germ cell testicular tumor (NSGCT) was conducted to identify prognostic factors that may predict the likelihood of metastasis. Clinical features and histopathologic features of the primary testicular tumor were examined and analyzed for correlations with the presence of retroperitoneal nodal metastasis documented by surgery (N+) and with development of relapse (R+). Pathologic tumor stage greater than or equal to 2, with tumor extension into the tunica albuginea, rete testis, epididymis, or spermatic cord, was correlated with an increased rate of N+ compared with pathologic tumor stage I (P = .001). Vascular invasion was correlated with a higher rate of N+ (P = .05) and had a similar association with R+ (P = .08). Tumors containing less than 50% teratoma were found to have a higher rate of N+ than tumors with greater than or equal to 50% teratoma (P = .02). Based on the identified prognostic factors, a model for predicting the probability of retroperitoneal nodal metastasis in clinical stage I patients is proposed. The risk factors for nodal metastasis are: pathologic tumor stage greater than or equal to 2, vascular invasion, and less than 50% teratoma. Patients with none of the risk factors are considered at low risk and may be offered orchiectomy alone with surveillance for initial treatment. Patients with all three risk factors are at high risk and should be treated with a retroperitoneal lymph node dissection (RPLND) or possibly chemotherapy. Patients with one or two risk factors are at intermediate risk; it is recommended that they undergo RPLND. This risk model facilitates a rational approach to the management of clinical stage I NSGCT.

Adult↗
PubMed1988

Efficiency of balanced treatment allocation for survival analysis.

We assess the efficiency of balanced treatment allocation methods in clinical trials for comparing treatments with respect to survival. We compare optimal designs for each of three standard survival analysis techniques (maximum partial likelihood estimation, log-rank test, exponential regression) with balanced designs, over a range of hypothetical trials. Although balanced designs are not optimal, we find them to be very efficient. In view of the high efficiency demonstrated in this and in a previous paper (Begg and Kalish, 1984, Biometrics 40, 409-420), and practical difficulties in implementing an optimal design, we recommend the use of balanced allocation methods in practice.

Clinical Trials as Topic↗
PubMed1987

Management of patients with clinical stage I or II nonseminomatous germ cell tumors of the testis. Evolving therapeutic options.

Eighty patients with clinical stage I or II nonseminomatous germ cell tumors of the testis were managed with modified protocols, including modified nerve-sparing retroperitoneal lymph node dissection for patients with stage I cancer, retroperitoneal lymph node dissection for patients with low-volume stage II cancer, and initial chemotherapy with or without subsequent retroperitoneal lymphadenectomy for patients with high-volume stage II cancer. Patients with low-stage disease (clinical stage I) were treated successfully with modified retroperitoneal lymph node dissection (relapse rate, three of 40 patients). Clinical understaging was evidenced in 14 of 48 patients with clinical stage I disease who were found to have pathologic involvement of the retroperitoneal lymph nodes, including six patients with extensive retroperitoneal nodal involvement (pathologic stage B2). Of nine patients with retroperitoneal tumors less than 3 cm in diameter, four patients were satisfactorily treated with retroperitoneal lymph node dissection alone while five patients required chemotherapy after retroperitoneal lymph node dissection. Of 26 patients with retroperitoneal tumors 3 to 5 cm in diameter, 17 patients were treated with chemotherapy alone. All patients remain free of disease after the completion of definitive therapy. We conclude that therapeutic options should be modified based on histologic factors in the primary tumor, extent of retroperitoneal disease as indicated on a computed tomographic scan, and presence or absence of elevated tumor markers. By consideration these factors, optimum therapy can be selected to achieve the highest long-term survival rate with the least morbidity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

The impact of treatment allocation procedures on nominal significance levels and bias.

Complete randomization, the simplest method for allocating treatments to patients in clinical trials, can serve as a basis for inferential procedures using standard permutation tests, because the method ensures that each sequence of allocations is equally likely. No other method of allocation possesses this property. However, many clinical trials employ allocation methods that force balance of covariates across treatment groups. With these methods, some allocation sequences are impossible or highly unlikely so that standard permutation tests are technically invalidated. In this article we investigate whether standard permutation tests for binary outcomes are likely to yield distorted nominal p values in practical applications of these alternative allocation methods. A sample of completed trials conducted by the Eastern Cooperative Oncology Group serves as a basis on which to construct simulations. Our results indicate that nominal p values can be conservative, but are not likely to be severely distorted if the analysis is stratified by important covariates used as allocation prompts. Moreover the inherent conservativeness of exact methods due to discreteness tends to dominate any additional conservativeness due to nonrandom designs. In addition, we investigate the relationship of treatment allocation methods with bias in estimates from a logistic model when important covariates are unknown. This bias is the same for all asymptotically balanced allocation methods and is significant but not disastrous.

Analysis of Variance↗
PubMed1987

Appropriate endpoints for superficial bladder cancer clinical trials.

Many protocols for treatment of superficial bladder cancer include periodic cystoscopic examinations with resection of visible lesions. This allows pathological restaging of the disease at each examination. For example, this type of follow-up is common in clinical trials evaluating intravesical therapies. In such trials, clinical outcome is typically summarized using end-points that measure failure to control superficial disease. Alternative endpoints measuring failure to prevent progression to invasive disease are often ignored. In this report, the rationale for ignoring the invasive disease endpoints is given and flaws in the rationale are described. Evidence from actual data sets support the view that superficial disease endpoints may not be appropriate surrogates for invasive disease endpoints. It is recommended that time to invasive disease should be considered a major endpoint when designing and analyzing trials in superficial bladder cancer.

Clinical Trials as Topic↗
PubMed1987

Evaluation of efficient designs for observational epidemiologic studies.

Recent research in the design of observational epidemiologic studies has been focused on determining which design is most efficient for controlling a potential confounding factor in the analysis of the disease-exposure relationship. Typically, only two candidate designs have been considered, the matched design and the random sample design. These are merely two of an infinite variety of potential designs in which the distributions of the confounder in the comparison groups and the ratio of group sample sizes are arbitrarily chosen. Only in special cases will either of the standard designs be the most efficient or "optimal" design. We construct optimal designs by minimizing the variance of the desired estimate of effect with respect to the controllable design parameters. Construction of an optimal design depends on unknown parameters, so that in practice only an approximately optimal design, perhaps constructed sequentially, is possible. We evaluate the potential usefulness of optimal designs by identifying circumstances in which an optimal design results in large efficiency gains relative to both the matched and random sample designs. We find that there can be substantial efficiency gains in follow-up studies when both the exposure and confounder are strong risk factors. Practical issues in the implementation of these designs are discussed.

Epidemiologic Methods↗
PubMed1985

A retrospective study of earliest indicators of recurrence in patients on Eastern Cooperative Oncology Group adjuvant chemotherapy trials for breast cancer. A preliminary report.

A retrospective review of the Eastern Cooperative Oncology Group adjuvant chemotherapy studies EST 5177 and EST 6177 was performed in order to ascertain the first indicator of relapse in women with breast cancer and pathologically positive axillary lymph nodes. Of 856 evaluable patients, 208 have relapsed. In 175 patients who relapsed, the first indicator could be clearly identified: symptoms, 36%; patient self-examination, 18.3%; physical examination by the physician, 19.4%; abnormal blood chemistries, 12%; bone scans, 8%; chest x-rays, 5.1%; and mammograms, 1.1%. Although 74% of recurrences are therefore detected clinically, in a sizable proportion (26%), the ancillary tests were the earliest indicators of relapse. The manner of detection was not influenced by nodal, estrogen receptor (ER), or menopausal status. These results suggest that the follow-up schedule currently employed by ECOG appears reasonable.

Breast Neoplasms↗
PubMed1985

Adjuvant CMFP versus CMFP plus tamoxifen versus observation alone in postmenopausal, node-positive breast cancer patients: three-year results of an Eastern Cooperative Oncology Group study.

After mastectomy, 265 postmenopausal patients with node-positive breast cancer were stratified according to pathologic nodal status and estrogen-receptor (ER) status and randomized to receive either 12 cycles of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP), or CMFP plus tamoxifen (CMFPT), or observation alone. Patients entered the study between March 1978 and July 1981. Cox regression analysis indicated that, compared to observation alone, chemotherapy (CMFP and CMFPT groups combined) led to a significant reduction in relapses by the end of the first year of study in every examined prognostic subgroup. However, after the first year the relapse-free survival curves of all treatment groups tended to merge, so that by three years 52% of the observation group and 51% of the chemotherapy groups remained disease free. Chemotherapy continued to show a significantly superior relapse-free survival rate for three years only in the subgroup of patients with ER-negative tumors (the subgroup with the largest relapse-free survival advantage at one year). The addition of tamoxifen produced no benefit or harm in any prognostic subcategory examined. ER status was prognostically important for predicting early relapse only in those patients not receiving chemotherapy, due to the greater effectiveness of this chemotherapy to prevent early relapse in the ER-negative subgroup. Treatment has had no early effect on survival. As breast cancer continues to recur even after ten or more years, later relapse patterns may alter these results.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Relationships of body size with breast cancer.

Three measures of body size (weight, height, and obesity) were compared with other patient characteristics in 852 operable node-positive breast cancer patients (age, 25-74 years) newly diagnosed in the United States. Weight and obesity were significantly associated with number of positive nodes. In postmenopausal women, weight and obesity were weakly associated with estrogen receptors. Observed weight and height distributions were compared with national averages and found to be highly aberrant in older women. There was an excess of tall woman (greater than or equal to 66 inches) among the study group in all age groups. An excess of heavy women (greater than or equal to 140 pounds) among the study group was observed only in the 55-74 years age group.

Adult↗
PubMed1984

Treatment allocation for nonlinear models in clinical trials: the logistic model.

Many clinical trials have a binary outcome variable. If covariate adjustment is necessary in the analysis, the logistic-regression model is frequently used. Optimal designs for allocating treatments for this model, or for any nonlinear or heteroscedastic model, are generally unbalanced with regard to overall treatment totals and totals within strata. However, all treatment-allocation methods that have been recommended for clinical trials in the literature are designed to balance treatments within strata, either directly or asymptotically. In this paper, the efficiencies of balanced sequential allocation schemes are measured relative to sequential Ds-optimal designs for the logistic model, using as examples completed trials conducted by the Eastern Cooperative Oncology Group and systematic simulations. The results demonstrate that stratified, balanced designs are quite efficient, in general. However, complete randomization is frequently inefficient, and will occasionally result in a trial that is very inefficient.

Biometry↗
PubMedDate not supplied

Treatment allocation methods in clinical trials: a review.

A comprehensive review of methods for allocation of treatments to patients in clinical trials is presented. Attention is restricted to controlled, prospective trials, as opposed to comparisons involving historical or other 'external' controls. We describe the features of each method and classify them according to whether their primary focus is randomization, efficiency, or balance with respect to prognostic factors. Methods which prevent bias, ensure an efficient treatment comparison and are simple to implement will contribute to the ability of clinical trials to provide precise and valid treatment comparisons. We assess critically the extent to which the methods achieve these goals, review the relationships of the allocation methods with subsequent analyses of the trial results, discuss current usage and provide guidelines for choice of method.

Biometry↗
PubMedDate not supplied

Long-term survival in Hodgkin's disease relative impact of mortality, second tumors, infection, and cardiovascular disease.

PURPOSE: Despite dramatic improvements in the survival of patients with Hodgkin's disease attributable to advances in treatment over the past 30 years, concern for the risk of treatment-related deaths has led to a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. We determined the causes of death in a group of patients with pathologically staged and intensively treated Hodgkin's disease who were followed for long intervals. MATERIALS AND METHODS: Between April 1969 and December 1988, 794 patients with laparotomy-staged IA to IIIB Hodgkin's disease were treated with radiation therapy alone or combined radiation therapy and chemotherapy. There were 8700 person-years of follow-up (average, 10.95 person-years/ patient). Causes of mortality were grouped into the categories Hodgkin's disease, second malignant tumors, cardiovascular, infection, and miscellaneous. Age- and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed-to-expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. RESULTS: Of 124 patients who died, 56 died of Hodgkin's disease, 36 of second malignant neoplasms, 15 of cardiac causes, 9 of infection, and 8 of miscellaneous causes. The 20-year actuarial survival rate for all patients in this study is 73%. Age 40 years or older, mixed cellularity/lymphocyte-depleted histologic type, and stage-III disease were adverse independent predictors of survival. The largest differences were seen by age. The 20-year actuarial rates of survival were 78%, 78%, and 46%, respectively, for patients aged 16 or less, 17 to 39, and 40 years or older at diagnosis. Hodgkin's disease diagnosed at age 40 or older was a significant risk factor for all causes of death. The use of combined chemotherapy/ radiotherapy was a significant risk factor for second tumor and infection-related mortality. The excess risk of death from all causes, including Hodgkin's disease, remained constant with time from treatment and was approximately 1.2% per year over the first 20 years. Deaths from Hodgkin's disease decreased with time from treatment, with no patients dying after 15 years. This decrease, combined with an increased excess mortality risk with time from other causes, especially second tumors, accounted for the constant excess mortality with time after Hodgkin's disease. CONCLUSIONS: Hodgkin's disease followed by second tumors, cardiac events, and infections remain the major causes of death after treatment of Hodgkin's disease. Our findings suggest the importance of both maintaining a high disease-free survival and reducing long-term complications in designing treatments of Hodgkin's disease.

Adolescent↗