Biomedical subjects

D Faraggi

Publications and source records attributed to D Faraggi.

At least 19 recordsLinked to original sources

PubMed2000

Methodological issues associated with tumor marker development. Biostatistical aspects.

The search for markers as potential prognostic factors for different stages of disease is becoming a major task in clinical research. Enormous amounts of information on the effectiveness of tumor markers are being published, and many of these results are conflicting and thus adding confusion to the area. In this paper we discuss the problem of multiplicity that we believe is one of the major statistical reasons for the conflicting results. We further review the ROC curve and the area under it as a popular statistical tool for evaluating the ability of a marker to distinguish between two populations. Finally we provide an extension to the ROC analysis when several markers are available.

Journal Article↗

PubMed2000

The effect of random measurement error on receiver operating characteristic (ROC) curves.

In this paper confidence intervals for the area under the ROC curve are adjusted for the presence of measurement error. A parametric normal model is assumed. The ratio of intra-individual to inter-individual variance provides a relative measure of the amount of measurement error. An exact adjusted confidence interval is developed for the equal variance case and an approximation is derived for the unequal variance case. We illustrate, using an example, the effect of ignoring the measurement error on the confidence interval for the area and show that the effect can be substantial on the decision as to the diagnostic effectiveness of the marker. We also examine, by means of a simulation study, the coverage probability of the unadjusted confidence interval and show that it can be far from its nominal value when measurement error is present.

Breast↗

PubMed2000

Hospitalizations due to falls in Jewish and Arab children in northern Israel.

In Israel, there are no epidemiological data regarding nonfatal childhood falls. A retrospective survey was conducted in order to find epidemiological characteristics of childhood falls among the different populations of northern Israel. During the years 1993 through 1995, 3082 children were hospitalized in Rambam Medical Center (RMC) due to injury. The children were subdivided into the four main populations: Jewish and Arab residents of Haifa region (the main metropolitan area) and Jewish and Arab residents of the Galilee region (the rural region). All of the children who suffered injury that required mechanical ventilation and careful assessment were admitted to the PICU. The charts of the children admitted to the PICU were then further studied. The demographic characteristics of all the cases of falls were statistically analyzed and the annual admission rates due to falls were calculated using the national statistical registrations of children in Israel. Falls were responsible for 1049 admissions due to injury, one third of the total number of children who were admitted due to an injury. Most of the children were five years of age or younger. Two thirds of the total childhood falls were of Arabs. The majority of the admissions were of two major sub-populations of northern Israel: Arab residents of Galilee region (66%) and Jewish residents of Haifa region (34%). Higher admission rate was found among Arab children of the Western Galilee district in comparison with Jewish children of the Haifa district. Most of the children who were admitted to the PICU were Arabs: nearly all of these children were from the rural region. More Arab than Jewish children who fell were admitted to the PICU and the majority of these cases were falls from buildings (private houses). Arab children of the rural region were responsible for 95% of the cases. These falls were mainly in staircases (46%) and from balconies (21%), roofs (11%) and windows (11%). The findings of the present study suggest that young Arab rural children in northern Israel are at high risk to a severe injury due to fall. Possible causes are discussed and a preventative intervention is suggested.

Accidental Falls↗

PubMed2000

Reproducibility of p53 immunohistochemistry in bladder tumors. National Cancer Institute, Bladder Tumor Marker Network.

The National Cancer Institute Bladder Tumor Marker Network conducted a study to evaluate the reproducibility of immunohistochemistry for measuring p53 expression in bladder tumors. Fifty paraffin blocks (10 from each of the five network institutions) were chosen at random from among high-grade invasive primary bladder tumors. Two sections from each block were sent to each laboratory for staining and scoring, and then all sections were randomly redistributed among the laboratories for a second scoring. Intra- and interlaboratory reproducibility was assessed with regard to both staining and scoring. For overall assessments of p53 positivity, the results demonstrated that intralaboratory reproducibility was quite good. Concordance across the five participating laboratories was high for specimens exhibiting no or minimal nuclear immunostaining of tumor cells or high percentages of tumor cells with nuclear immunoreactivities. However, there was a reduced level of concordance on specimens with percentages of stained tumor cells in an intermediate range. The discordancies were due mainly to staining differences in one of the five laboratories and scoring differences in another laboratory. These results indicate that some caution must be used in comparing results across studies from different groups. Standardization of staining protocols and selection of a uniform threshold for binary interpretation of results may improve assay reproducibility between laboratories.

Analysis of Variance↗

PubMed1999

Lymphocyte subpopulations in patients with multiple primary tumors.

BACKGROUND: Cancer patients with single tumors live longer today due to earlier detection and improved treatment methods. For this reason, the authors see more patients who develop a second primary tumor. The etiology of the second tumor can be the same as the first, whether treatment-induced or unknown. The prognoses of these patients usually depend on the behavior of the second tumor. METHODS: The authors investigated the lymphocyte subset in 88 of the more than 750 patients listed in the tumor registry at their treatment center who had at least one carcinoma of the breast or colon and a second primary of the same or another site. Mononuclear cells were obtained from heparinized blood by the standard fractionation Hypaque gradient centrifugation technique. Helper and suppressor cells were identified by using three murine monoclonal antibodies: CD3 for mature T lymphocytes, CD4 for helper inducer cells, and CD8 for suppressor cytotoxic cells. T-cell subset distribution was evaluated with flow cytometry. RESULTS: Most values of CD3, CD4, and CD4/CD8 were lower in patients than in healthy controls. The values of CD4 and CD4/CD8 were lower in patients who had a second tumor in the colon rather than in the breast. CONCLUSIONS: As tumors in patients with a second primary sometimes recur or the patient develops a third primary, the authors are prospectively following their patients to see whether those with immunosuppression have a greater tendency to develop recurrent disease or a third primary.

Adult↗

PubMed1999

Distribution of serum creatine kinase activity in young healthy persons.

The normal distribution of serum creatine kinase (CK) was determined in 428 men (mean age = 21.5) and 540 women (mean age = 20.2). The bootstrap method was employed to obtain statistical parameters of CK reference range and correlations with physical activity habits, BMI, cigarette smoking and alcohol consumption. CK distribution was non-Gaussian and skewed toward the higher values; 18.9% of the men and 4.6% of the women had values above the upper reference limits defined for the commercial assay kit. The median 97.5 percentile value was 532 u/l for men and 248 u/l for women (95% confidence interval of 384-738 u/l and 184-340 u/l, respectively). A significant correlation was found only between CK and alcohol consumption in men. Myoglobin level in a representative group of subjects correlated well with CK activity for both genders. Our findings define the range of CK values in a healthy, young, heterogeneous population. We suggest that only CK levels above the determined 97.5 percentile should warrant further clinical investigation.

Adult↗

PubMed1999

[Generalized ROC criteria in the evaluation of several tumor markers].

The main objective of this paper is to present a method of evaluating several tumor markers by using the generalized ROC criterion. This criterion finds the best linear combination of the tumor markers such that the area under the ROC curve is maximized. Confidence intervals for the generalized ROC criteria are also presented. This methodology is applied to 51 patients with advanced colorectal cancer for whom the ACE tumor markers were measured before and during chemotherapy treatment. Two populations were defined according to clinical response to chemotherapy. Each marker taken separately, whether on the raw scale or on the transformed scale, contained 0.5 in the confidence interval and was thus non significant. This was also true for both markers on the raw scale. However, the best linear combination on the logarithms of ACE before and at evaluation gave a significantly better area under the ROC curve. A weighted change in ACE measurements significantly distinguishes between responders and non responders in patients with advanced colorectal cancer. We propose that the methodology presented in this paper be used for the evaluation of several tumor markers.

Analysis of Variance↗

PubMed1998

Haptoglobin-related protein as a serum marker in malignant lymphoma.

A novel serum 21 kDa haptoglobin-related protein (Hpr) was investigated in patients with malignant lymphoma, to evaluate its correlation with clinical and histologic features at presentation and its possible role as a tumor marker for patient outcome. One hundred fifty eight serum samples were taken from 88 patients with non-Hodgkin's lymphoma (n=58) and Hodgkin's disease (n=30) at presentation and in the course of follow-up. Sera from 61 healthy volunteers served as normal controls. Serum Hpr levels in the lymphoma patients (median 430x10 u/ml, range 0-4000x10 ) were significantly higher than in the control group (median 68x10 u/ml, range 0-180x10 )(p=0.0001). Higher median Hpr values were detected in patients with advanced disease (p=0.013), "B" symptoms (p=0.029) and in males (p=0.053). There was also a significant correlation between Hpr and erythrocyte sedimentation rate (p=0.028). Serial determinations showed a significant decrease of the initial Hpr values obtained after treatment in 41 patients, 38 of whom achieved complete remission. In the follow-up period additional Hpr measurements were taken from 17 patients. Three of them eventually relapsed, and showed increased Hpr levels at the time of relapse. Hpr levels remained low in 11 of 14 patients who maintained complete remission, and increased in three. In conclusion, serum Hpr is a new serum tumor marker of potential use in the clinical setting of lymphoma.

Adolescent↗

PubMed1998

Biomarker study of primary nonmetastatic versus metastatic invasive bladder cancer. National Cancer Institute Bladder Tumor Marker Network.

A cohort of 109 patients with primary transitional cell carcinomas, stages T2-T3, grade 2 or higher, was identified and further divided into two groups based on lymphatic metastasis at the time of cystectomy (n = 57 cases) or absence of detectable metastatic disease over a minimum of 5 years of follow-up after cystectomy (n = 52). Blocks corresponding to the primary tumor lesions were sectioned and distributed to different laboratories to be analyzed. Immunohistochemistry on deparaffinized tissue sections was conducted for evaluation of p53 nuclear overexpression (monoclonal antibody PAb1801), assessment of proliferative index (Ki-67 antigen-monoclonal antibody MIB1), and microvascular counts (factor VIII-related antigen). DNA content/ploidy studies were performed on material obtained from thick sections. A double-blinded strategy was used for the evaluation of laboratory data versus clinical parameters. The cutoff value for p53 nuclear overexpression was > or =20% of tumor cells displaying nuclear staining. The median values for MIB1 (> or =18% of tumor nuclear cell staining) and microvascular counts (> or =40 microvessels/area screened) were used as cutoff points for these two variables. The assessment of DNA content was conducted by classifying cases as diploid, tetraploid, or aneuploid. Statistical analyses were performed using the Fisher's Exact Test (2-tailed). Results revealed that none of the markers studied had a statistically significant correlation with the end point of the study, i.e., the presence of lymph node metastatic disease, in the cohort of patients studied, although an obvious trend for p53 was noted. It is concluded that alterations of p53, Ki-67 proliferative index, microvascular counts, and ploidy are not strongly associated with lymph node status in patients affected with high-stage, high-grade bladder cancer.

Biomarkers, Tumor↗

PubMed1998

Bayesian variable selection method for censored survival data.

A Bayesian variable selection method for censored data is proposed in this paper. Based on the sufficiency and asymptotic normality of the maximum partial likelihood estimator, we approximate the posterior distribution of the parameters in a proportional hazards model. We consider a parsimonious model as the full model with some covariates unobserved and replaced by their conditional expected values. A loss function based on the posterior expected estimation error of the log-risk for the proportional hazards model is used to select a parsimonious model. We derive computational expressions for this loss function for both continuous and binary covariates. This approach provides an extension of Lindley's (1968, Journal of the Royal Statistical Society, Series B 30, 31-66) variable selection criterion for the linear case. Data from a randomized clinical trial of patients with primary biliary cirrhosis of the liver (PBC) (Fleming and Harrington, 1991, Counting Processes and Survival Analysis) is used to illustrate the proposed method and a simulation study compares it with the backward elimination procedure.

Bayes Theorem↗

PubMed1997

Large sample Bayesian inference on the parameters of the proportional hazard models.

This paper considers large sample Bayesian analysis of the proportional hazards model when interest is in inference on the parameters and estimation of the log relative risk for specified covariate vectors rather than on prediction of the survival function. We use a normal prior distribution for the parameters and make inferences based on the derived posterior distribution. The suggested approach is much simpler than alternative Bayesian analyses previously suggested for the proportional hazards models. Using simulated data we compare estimates obtained from the Bayesian analysis with those obtained from the full proportional hazards model and the reduced model after backwards elimination. We show that under a wider range of assumptions, the Bayesian analysis provides reduced estimation errors and improved rejection of noise variables. Finally, we illustrate the methodology using data from a large study of prognostic markers in breast cancer.

Bayes Theorem↗

PubMed1997

Dexamethasone, etoposide, ifosfamide, and cisplatin as second-line therapy in patients with aggressive non-Hodgkin's lymphoma.

BACKGROUND: This study analyzed the long term results of a combination of dexamethasone, etoposide, ifosfamide, and cisplatin (DVIP) used at the study center as standard second-line combination therapy in patients with aggressive non-Hodgkin's lymphoma (NHL) after prior exposure to doxorubicin. METHODS: All drugs were given intravenously for 4 consecutive days. The maximum daily doses of etoposide, ifosfamide, and cisplatin were 75 mg/m2, 1200 mg/m2, and 20 mg/m2, respectively. The dexamethasone dose was 20 mg twice daily. Cycles were repeated every 3 weeks. RESULTS: Fifty-six patients were included in the study. Partial response was noted in 18 patients (32%) and complete response (CR) in 18 patients (32%). Pretreatment factors that predicted CR were CR with prior therapy (CR in 17 of 34 in patients with a recurrence vs. 1 of 21 in patients with primary refractory NHL) and age (CR in 12 of 25 patients age < or = 65 years vs. 6 of 31 patients age > 65 years). Median time to treatment failure (TTF) and median survival were 11.5 months and 30 months, respectively, for patients with a CR and 3.5 months and 8 months, respectively, for all patients. Five patients (9%) remained disease free for > 24 months. By multivariate analysis, age was the only independent prognostic factor for TTF, whereas age, serum lactate dehydrogenase, and number of extranodal sites were independent predictors for survival. Myelosuppression (median granulocyte nadir and median platelet nadir of 350/mm3 and 77,000/mm3, respectively) was the major toxicity. There was one possible drug-related death associated with myelosuppression. CONCLUSIONS: DVIP is a relatively safe salvage combination therapy in patients with aggressive NHL. Response to first-line therapy and age are the most important predictors for prognosis after the administration of DVIP. This regimen is highly active in patients with recurrent NHL, but relatively ineffective in patients with primary refractory NHL.

Adult↗

PubMed1997

Confidence intervals for the generalized ROC criterion.

Receiver operating characteristic (ROC) curves are frequently used to assess the usefulness of diagnostic markers. When several diagnostic markers are available, they can be combined by a best linear combination: that is, when the area under the ROC curve of this combination is maximized among all possible linear combinations. This maximal area is the generalized ROC criterion, which provides a measure of how effective the combination of the markers is. This criterion needs to be estimated from the data, and is usually evaluated against single markers. In the present paper, we provide confidence intervals for the generalized ROC criterion under the assumption of homogeneous covariance matrices, derive an approximation for the heterogeneous covariance matrices case, and evaluate the approximation via a simulation study. Finally, we present an illustrative example.

Biomarkers↗

PubMed1996

A simulation study of cross-validation for selecting an optimal cutpoint in univariate survival analysis.

Continuous measurements are often dichotomized for classification of subjects. This paper evaluates two procedures for determining a best cutpoint for a continuous prognostic factor with right censored outcome data. One procedure selects the cutpoint that minimizes the significance level of a logrank test with comparison of the two groups defined by the cutpoint. This procedure adjusts the significance level for maximal selection. The other procedure uses a cross-validation approach. The latter easily extends to accommodate multiple other prognostic factors. We compare the methods in terms of statistical power and bias in estimation of the true relative risk associated with the prognostic factor. Both procedures produce approximately the correct type I error rate. Use of a maximally selected cutpoint without adjustment of the significance level, however, results in a substantially elevated type I error rate. The cross-validation procedure unbiasedly estimated the relative risk under the null hypothesis while the procedure based on the maximally selected test resulted in an upward bias. When the relative risk for the two groups defined by the covariate and true changepoint was small, the cross-validation procedure provided greater power than the maximally selected test. The cross-validation based estimate of relative risk was unbiased while the procedure based on the maximally selected test produced a biased estimate. As the true relative risk increased, the power of the maximally selected test was about 10 per cent greater than the power obtained using cross-validation. The maximally selected test overestimated the relative risk by about 10 per cent. The cross-validation procedure produced at most 5 per cent underestimation of the true relative risk. Finally, we report the effect of dichotomizing a continuous non-linear relationship between covariate and risk. We compare using a linear proportional hazard model to using models based on optimally selected cutpoints. Our simulation study indicates that we can have a substantial loss of statistical power when we use cutpoint models in cases where there is a continuous relationship between covariate and risk.

Humans↗

PubMed1995

A neural network model for survival data.

Neural networks have received considerable attention recently, mostly by non-statisticians. They are considered by many to be very promising tools for classification and prediction. In this paper we present an approach to modelling censored survival data using the input-output relationship associated with a simple feed-forward neural network as the basis for a non-linear proportional hazards model. This approach can be extended to other models used with censored survival data. The proportional hazards neural network parameters are estimated using the method of maximum likelihood. These maximum likelihood based models can be compared, using readily available techniques such as the likelihood ratio test and the Akaike criterion. The neural network models are illustrated using data on the survival of men with prostatic carcinoma. A method of interpreting the neural network predictions based on the factorial contrasts is presented.

Diethylstilbestrol↗

PubMed1995

Brain stem auditory evoked potentials: effects of ovarian steroids correlated with increased incidence of Bell's palsy in pregnancy.

To investigate the effect of ovarian steroids on the brain stem during changes of estrogen and progesterone blood levels, we recorded brain stem auditory evoked potentials with increased stimulus rates from 26 women treated for sterility by menotropins (Pergonal and Metrodin). These women were divided into three groups according to their estrogen and progesterone blood levels. The brain stem auditory evoked potential results revealed a significant delay of peak III only, with an increased stimulus rate in the group with the highest estrogen level. Estrogen may cause a brain stem synaptic impairment, presumably because of ischemic changes, and thus also may be responsible for a higher incidence of Bell's palsy during pregnancy.

Adult↗

PubMed1995

Full dose CHOP chemotherapy in elderly patients with non-Hodgkin's lymphoma.

Twenty-eight previously untreated elderly patients (median age 73 years, range 65-88) with aggressive non-Hodgkin's lymphoma were treated with full-dose CHOP chemotherapy between 1989 and 1992. The median of the average relative dose intensity (ARDI) was calculated for the initial cycles needed to achieve a maximal response or to determine progression of disease (1-6 cycles, median 4), as well as for the whole treatment course. For patients aged 65-74, both ARDIs were 0.89. A comparable group of 36 elderly patients who received reduced doses of CHOP from the start, served as a historical control. There was an increase of 11% and 29% in the ARDIs of the full-dose CHOP as compared with the reduced CHOP, in the initial cycles and for the whole treatment course respectively. Grade III-IV leukopenia was the main toxicity observed in 57% of the patients, and 7 patients were hospitalized for fever and leukopenia. There was no treatment-related death. It is concluded that CHOP chemotherapy without initial dose reduction is feasible in patients aged 65-74 years, resulting in high actual dose intensity with a reasonable degree of toxicity.

Aged↗

PubMed1995

Dynamic treatment allocation adjusting for prognostic factors for more than two treatments.

Methods of sequential allocation of one of K treatments to patients, while controlling for important prognostic factors, are developed and compared. We focus on methods that are based on optimality theory (Begg and Iglewicz, 1980, Biometrics 36, 81-90; Atkinson, 1982, Biometrika 69, 61-67), the permuted block procedure (Zelen, 1974, Journal of Chronic Diseases 27, 365-375), and the compromise method (Faraggi and Reiser, 1991, Communication in Statistics, Simulation and Computation 20, 243-254). These methods are extended to the K treatments case and are evaluated in terms of efficiency and balance. It is shown that each method achieved the best results in the criterion it was designed to optimize, i.e., within stratum balance for the permuted block allocation and efficiency for the allocations that are based on optimality theory, but did not do well with other criteria. The compromise method, on the other hand, has good overall properties in terms of both balance and efficiency.

Biometry↗