Biomedical subjects

D Faraggi

Publications and source records attributed to D Faraggi.

At least 19 recordsLinked to original sources

PubMed2001

Understanding neural networks using regression trees: an application to multiple myeloma survival data.

Neural networks are becoming very popular tools for analysing data. It is however quite difficult to understand the neural network output in terms of the original covariates or input variables. In this paper we provide, using readily available software, an easy way of understanding the output of the neural network using regression trees. We focus on the problem in the context of censored survival data for patients with multiple myeloma, where identifying groups of patients with different prognosis is an important aspect of clinical studies. The use of regression trees to help understand neural networks can be easily applied to uncensored situations.

Age Factors↗

PubMed2001

Statistical inference for the area under the receiver operating characteristic curve in the presence of random measurement error.

The area under the receiver operating characteristic curve is the most commonly used measure of the ability of a biomarker to distinguish between two populations. Some markers are subject to substantial measurement error. Under normality assumptions, the authors develop a confidence interval procedure for the area under the receiver operating characteristic curve that adjusts for measurement error. This procedure assumes the availability of data from a reliability study of the biomarker. A simulation study was used to check the validity of the proposed confidence interval. Furthermore, it was shown that not adjusting for measurement error could result in a serious understatement of the effectiveness of the biomarker.

Analysis of Variance↗

PubMed2001

mROC: a computer program for combining tumour markers in predicting disease states.

Receiver operating characteristic (ROC) curves are limited when several diagnostic tests are available, mainly due to the problems of multiplicity and inter-relationships between the different tests. The program presented in this paper uses the generalised ROC criteria, as well as its confidence interval, obtained from the non-central F distribution, as a possible solution to this problem. This criterion corresponds to the best linear combination of the test for which the area under the ROC curve is maximal. Quantified marker values are assumed to follow a multivariate normal distribution but not necessarily with equal variances for two populations. Other options include Box-Cox variable transformations, QQ-plots, interactive graphics associated with changes in sensitivity and specificity as a function of the cut-off. We provide an example to illustrate the usefulness of data transformation and of how linear combination of markers can significantly improve discriminative power. This finding highlights potential difficulties with methods that reject individual markers based on univariate analyses.

Biomarkers, Tumor↗

PubMed2001

TBARS and cardiovascular disease in a population-based sample.

BACKGROUND: Oxygen radicals might play a crucial role in the pathogenesis of various diseases, including atherosclerosis. Thiobarbituric acid reaction substances (TBARS), a biomarker of oxidative stress, have been proposed as a summary measure of total circulating oxidation. However, there is no strong indication that circulating levels of TBARS are increased in patients with atherosclerosis. DESIGN: We evaluated the relation between TBARS and cardiovascular disease (CVD) in a cross-sectional random sample of white men and women from Buffalo, New York. METHODS: Logistic regression was used to estimate the risk associated with high levels of TBARS. The area under the ROC curve was used to evaluate the discriminating power of TBARS. RESULTS: After adjusting for age and gender, TBARS levels were significantly higher in those with prevalent CVD (OR= 1.73, 95% CI=1.32-2.38), compared to those without a CVD diagnosis. These OR were almost 50% higher after correcting for measurement error (ME) (OR=1.93, 95% CI=1.07-3.40). The area under the ROC curve was 0.69 (95% CI=0.62-0.77) and when corrected for ME reached 0.80 (95% CI=0.65-0.89). CONCLUSIONS: Our results indicate that elevated levels of TBARS were associated with increase risk of the prevalence of CVD, but this effect was no longer significant after adjusting for glucose.

Adult↗

PubMed2001

[The chemotherapeutic treatment of advanced Hodgkin's disease].

Between 1972 and 1994, 121 adult patients with advanced Hodgkin's disease received MOPP (M) combination chemotherapy, MOPP alternating with ABVD (M-A) or MOPP and ABV hybrid (M/A). Radiation therapy was given to 1/3 of them. The median age was 35 years, 58% had stage III and 42% had stage IV disease. Failure-free survival at 10 years was 43.9%. It was 66.7%, 48.4% and 29.9% for patients treated by M/A, M-A and M, respectively. Overall survival at 10 years was 40.8%, and 78.2%, 48% and 27.7% for patients treated by M/A, M-A and M, respectively. Multivariate analysis found age (above or below 65 years) and combination chemotherapy (with or without adriamycin) to be significant prognostic factors. M/A combination was more myelotoxic, while M combination caused more second primaries. Today, 80% of patients with advanced Hodgkin's disease may be cured, with low rate of long-term toxicity.

Adolescent↗

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↗