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Biomedical subjects

A Tsiatis

Publications and source records attributed to A Tsiatis.

18 recordsLinked to original sources
PubMed1996

Complete remission induction with combined VBMCP chemotherapy and interferon (rIFN alpha 2b) in patients with multiple myeloma.

The purpose of this study was to evaluate a new regimen for the treatment of multiple myeloma based on alternating 3-week cycles of chemotherapy and interferon (rIFN alpha 2). In this prospective phase II clinical trial the Eastern Cooperative Oncology Group evaluated a regimen consisting of 2 cycles of VBMCP (Vincristine 1.2 mg/M(2) IV d1, BCNU 20 mg/M(2) IV d1, Melphalan 8 mg/M(2) PO dl-4, Cyclophosphamide 400 mg/M2 IV d1, Prednisone 40 mg/M(2) PO d1-7) followed by alternating 3-week cycles of VBMCP and rIFN alpha2 5 Mu/M(2) SC 3x/week. Treatment was administered for 2 years. Fifty-eight patients with previously untreated multiple myeloma were entered. Objective response (OR) required 50% decrease in M-protein with correction of severe anemia and no progression of skeletal disease. Complete remission (CR) was defined by disappearance of M-protein and normalization of the bone marrow morphology. Life table analysis was utilized to express survival and response duration. Fifty-four patients were evaluable. Objective response was seen in 80% of patients including CR in 30% (16 patients). The median response duration is 35 months, 46 months for patients with CR. The median survival is 42 months for all patients. Five year survival is 42%. Although 78% of patients had neutrophil nadirs <1000 x 10(9)/L, the incidence of severe infection was only 9%. These data demonstrate that VBMCP + interferon is an effective new regimen combining chemotherapy with a biological response modifier for the treatment of multiple myeloma. The incidence of CR is high, and the response and survival durations appear to be 1 year longer than usually seen with standard chemotherapy. A current ECOG randomized trial compares VBMCP + interferon with VBMCP alone.

Aged↗
PubMed1994

Exact permutational tests for group sequential clinical trials.

An efficient numerical algorithm is developed for computing stopping boundaries for group sequential clinical trials. Patients arrive in sequence, and are randomized to one of two treatments. The data are monitored at interim time points, with a fresh block of patients entering the study from one monitoring point to the next. The stopping boundaries are derived from the exact joint permutational distribution of the linear rank statistics observed across all the monitoring times. Specifically, the algorithm yields the exact boundary generating function, Pr(W1 < b1, W2 < b2, ..., Wi-1 < bi-1, Wi = wi), where Wj is the linear rank statistic at the jth interim time point. The distribution theory is based on assigning ranks after pooling all the patients who have entered the study, and then permuting the patients to the two treatments independently within each block of newly arrived patients. The methods are applicable for an arbitrary number of monitoring times, which need not be specified at the start of the study. The data may be continuous or categorical, and censored or uncensored. The randomization rule for treatment allocation can be adaptive. The algorithm is especially useful during the early stages of a clinical trial, when very little data have been gathered, and stopping boundaries are based on the extreme tails of the relevant boundary generating function. In that case the corresponding large-sample theory is not very reliable. To illustrate the techniques we present a group sequential analysis of a recently completed study by the Eastern Cooperative Oncology Group.

Algorithms↗
PubMed1993

Modeling the relationship between survival and CD4 lymphocytes in patients with AIDS and AIDS-related complex.

CD4 lymphocyte and survival data from two completed trials, a double-blind placebo-controlled trial of zidovudine in patients with advanced human immunodeficiency virus type 1 (HIV) disease (BW-02 study) and a randomized trial of two different doses of zidovudine in patients with advanced HIV disease (ACTG-002 study) were used to determine the degree to which CD4 lymphocyte counts reflect zidovudine-associated survival benefit. Proportional hazards models were used, and CD4 lymphocyte counts were smoothed by using empirical Bayes estimates. The geometric mean of the CD4 lymphocyte counts increased by 71 and 46 cells/mm3 for patients in the BW-02 and ACTG-002 studies, respectively, followed by a progressive decline. Higher pretreatment CD4 lymphocyte counts (p = 0.001), greater increases in CD4 lymphocytes at 8 weeks (p = 0.1), and smaller declines in the slope (p = 0.001) were associated with a lower risk of death. The most current CD4 lymphocyte count was most prognostic of death (p = 0.001). The risk of death was greater for patients with lower CD4 lymphocytes and this risk increased sharply when the CD4 lymphocyte counts fell below 50 cells/mm3. The hazard of death was higher for placebo recipients at all levels of CD4 lymphocytes compared with zidovudine recipients. Although higher CD4 lymphocyte counts are associated with improved survival, these increases account for only a small proportion of the survival benefit of zidovudine in these two studies.

AIDS-Related Complex↗
PubMed1991

Detection of mutations associated with zidovudine resistance in human immunodeficiency virus by use of the polymerase chain reaction.

A sensitive and specific polymerase chain reaction (PCR)-based assay was developed for four mutations in the reverse transcriptase gene of human immunodeficiency virus type 1 that have been associated with zidovudine resistance. These mutations were correlated in 366 specimens with zidovudine chemotherapy and resistance. Mutations at these four codons were detected only after zidovudine therapy. The usual sequence of appearance of mutations was codons 215, 70, 67, and 219, although individual variations occurred. The degree of resistance was proportional to the number of mutations present, although variable susceptibilities with identical patterns of mutations suggested the likelihood that additional mutations contribute to resistance. The existence of both phenotypic and genotypic mixtures was documented as was the occasional selection of subpopulations with passage of virus in vitro. The many complexities of zidovudine resistance render the assay of limited use for application to individual patients; however, it could prove useful for correlating disease or therapy with the emergence of resistance.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Robust estimation of the variance in moment methods for extra-binomial and extra-Poisson variation.

When faced with data in the form of overdispersed counts or proportions, moment methods allow consistent parameter estimation when only the form of the mean and variance is specified. If the variance form is misspecified, these methods still yield consistent parameter estimates, though with lower efficiency, and the variances of the estimates will be inconsistent. A variance correction is available that yields consistent variance estimates in these circumstances. The asymptotic and small-sample efficiencies of this correction are calculated, and its performance under variance misspecification is studied. A group-randomized breast self-examination prevention study that is now underway serves as a focal point for the study of these properties. The use of the variance correction in modelling is illustrated on a teratology data set.

Analysis of Variance↗
PubMed1984

Epidemiologic study of clinical and physiologic parameters in grain handlers of northern United States.

To study the effects of grain dust exposure, we compared respiratory parameters between 310 grain handlers and 237 city workers of comparable age, height, weight, and smoking habits. Both populations resided and worked in the same geographic area of the United States. Information was obtained by questionnaire, interview, and examination. Pulmonary function tests included FEV1, FVC, FEF25-75, Vmax50, CV, delta N2/L, and DLCO. The prevalence of acute work-related and chronic respiratory symptoms, of auscultatory bronchi, and of airways obstruction (FEV1/FVC less than 0.7) were significantly higher (p less than 0.05) in grain handlers than in control subjects. The mean values of all lung functions except CV, delta N2/L, and DLCO were significantly lower in grain workers than in control subjects. The effects of smoking and grain handling on symptom prevalence and lung functions adjusted for age and height, analyzed by logistic regression model, were highly significant (p values ranged from 0.00001 to 0.5) and independent. The odds of having chronic bronchitis or wheezing at work were, respectively, increased 4.4-fold and 4.8-fold by grain handling and by 2.9-fold and 1.9-fold by smoking. Grain handling increased the odds of having airways obstruction 2.6-fold and smoking increased it 2.7-fold. We conclude that grain handlers have a higher prevalence of chronic bronchitis and other respiratory symptoms than do comparable workers who do not handle grain. The effect of grain dust exposure on symptom prevalence is usually greater than that of smoking. Grain handling has an adverse effect on lung function that is of the same or smaller magnitude than that of smoking.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Incorporating extra information in experimental design for bioassay.

In a bioassay, under certain experimental circumstances, information on concentration (dose rate) and time to response for some subjects can be combined in a single analysis. An underlying logistic random variable is assumed and the resulting mixed- (continuous-quantal) response model is analyzed by likelihood methods. The estimation procedure for the mean and the variance is described, and expressions for asymptotic variances are obtained. A comparison of results from the mixed model and from the standard quantal-response model shows that there is a substantial reduction in the variance of the estimators for the mixed model. On the basis of the table of asymptotic variances, some design implications are discussed. An example from insect pheromone research is used to illustrate the main ideas.

Analysis of Variance↗
PubMed1982

Anaphylactoid reactions to Escherichia coli and Erwinia asparaginase in children with leukemia and lymphoma.

The incidence and clinical characteristics of anaphylactoid reactions to intravenous asparaginase were assessed in 196 patients given E. coli asparaginase and 49 patients given Erwinia asparaginase. All patients were given a 50 IU intravenous test dose followed in 30 min by the full dosage (10,000 IU/m2), if no reaction occurred to the test dose. Twenty-nine of 196 patients (14.8%) given E. coli asparaginase had an anaphylactoid reaction, occurring after their first through 12th doses. The probability of an anaphylactoid reaction was significantly greater in those patients not receiving concomitant prednisone-vincristine and patients with a hiatus between courses of asparaginase therapy. By logistic regression analysis, other variables such as age, sex, race, diagnosis, total number of doses and concurrent methotrexate or arabinosylcytosine did not contribute significantly to the probability of a reaction. Twenty-three of the patients who had reacted to E. coli asparaginase and 26 patients who had not reacted to E. coli asparaginase were subsequently given Erwinia asparaginase. Seven of these 49 patients (14%) had an anaphylactoid reaction. The probability of a reaction to Erwinia asparaginase was significantly related to a prior reaction to E. coli asparaginase, concomitant prednisone-vincristine therapy, total number of asparaginase doses, number of prior E. coli asparaginase doses, and diagnosis, when assessed by a logistic regression model. However, after adjusting for prior reaction to E. coli asparaginase and the total number of asparaginase doses given, the other variables did not contribute significantly to the probability of a reaction. Only 5/29 patients reacting to E. coli asparaginase and 1/7 reacting to Erwinia asparaginase had a reaction to the test dose. None of the reactions were fatal.

Adolescent↗
PubMed1982

Pharmacokinetic modeling of cisplatin disposition in children and adolescents with cancer.

A flow-limited physiologic pharmacokinetic model using volume terms, flow rates, distribution ratios, metabolic rate constants, and clearance terms restricted to physiologic or measured values was used to simulate the disposition of cisplatin in children and adolescents. Physiologic model simulations of parent cisplatin and total platinum serum concentrations were not statistically different from concentrations of these platinum species measured in 14 patients. A simplified first-order multicompartment operational model was also developed, and produced comparable simulations of parent cisplatin disposition but less accurate simulations of total platinum serum concentrations. These data provide further clarification of cisplatin disposition in humans and provide the basis for previously observed changes in the renal clearance of total platinum.

Adolescent↗
PubMed1982

Prognostic importance of chromosome number in 136 untreated children with acute lymphoblastic leukemia.

Leukemia cell karyotypes were determined at diagnosis for 136 of 159 consecutive patients with acute lymphoblastic leukemia (ALL) who were followed for up to 35 mo. Ninety patients (67%) had abnormal karyotypes. Five chromosome categories were designated, based on the distribution of modal numbers: hyperdiploid greater than 50 (n = 41), hyperdiploid 47-50 (n = 18), pseudodiploid (n = 28), normal (n = 46), and hypodiploid (n = 3). Treatment response was assessed for the categories in terms of time to failure (induction failure, first relapse, or death). Children in the hyperdiploid greater than 50 category had the best responses to treatment, with only 2 failures, and those in the pseudodiploid category had the poorest (p less than 0.001). The remaining 3 chromosome categories had intermediate responses and formed a third prognostic group. This same influence of chromosome number on time to failure was evident within the 2 clinical prognostic groups: high risk, signified by a leukocyte count greater than 100 X 10(9)/liter, meningeal leukemia, mediastinal mass, or the presence of blasts that formed rosettes with sheep erythrocytes at 37 degrees C, and standard risk, indicated by the absence of these features. The influence of chromosome number on time to failure was also the same within the historically favorable prognostic group that had common ALL. Results of a multivariate analysis indicated that chromosome number was the strongest single predictor of outcome (p less than 0.001) and was the only variable that added significant prognostic information to leukocyte count (p less than 0.001). The combination of chromosome number and leukocyte count should more clearly distinguish patients with ALL at low or high risk of relapse.

Asparaginase↗
PubMed1981

Pharmacokinetics of sustained serum methotrexate concentrations secondary to gastrointestinal obstruction.

A physiological pharmacokinetic model for methotrexate was refined and used to simulate serum methotrexate concentrations after high dose (5000 mg/m2) intravenous infusions with fixed normal values for all model parameters except the GI transit rate. There was good agreement between simulated and measured values when model simulations with the normal GI transit rate were compared to values measured following 109 doses administered to 27 patients with normal GI function. When model simulations were performed using GI transit rates representing 75, 50 and 10% of normal, there was a marked prolongation of the terminal serum methotrexate half-life, which was directly related to the reduction in the transit rate. When simulations were performed with GI transit reduced by 50%, the maximum amount of methotrexate in the GI lumen was 25% higher and occurred 4 hr later. Model simulations of serum methotrexate concentrations, using a GI transit rate reduced by 50%, were also in good agreement with serum concentrations measured in two patients with partial GI obstruction. These data establish a pharmacokinetic basis for previous clinical observations indicating sustained serum methotrexate concentrations in patients with GI obstructions and exemplify the utility of physiological pharmacokinetic models in assessing the potential effects of clinical variables on drug disposition.

Half-Life↗
PubMed1979

Farmer's lung disease: long-term clinical and physiologic outcome.

To determine the long-term effects of farmer's lung disease and the factors influening the outcome, 141 patients with farmer's lung disease were evaluated. At the time of the last follow-up, 29 patients had died and 92 (mean age, 54 years) were studied clinically, physiologically, and radiologically. The mean length of disease was 14.8 years (range, 2.25 to 40 years). Symptoms at the time of the last follow-up included complaints of cough (33 per cent of the patients), breathlessness while walking on the level (20 per cent), breathlessness on minor exertion (14 per cent), and breathlessness while at rest (3 per cent). Twenty-eight per cent had chronic bronchitis. Thirty-nine per cent (36 of 92 patients) had some evidence of interstitial changes on roentgenogram. Abnormal vital capacity was present in 11 patients (12 per cent), abnormal total lung capacity in 11 (12 per cent), and abnormal CO difussing capacity in 27 (30 per cent). The ratio of one-sec forced expiratory volume to forced vital capacity was abnormal in 23 patients (25 per cent), and arterial PO2 was abnormal in 39 (40 per cent). Patients with a history of 5 or more symptomatic recurrences had significantly smaller values (P less than 0.05) for vital capacity, total lung capacity, and CO diffusing capacity than did those patients with less than 5 recurrences. There was no significant relation between continued farming or length of disease and lung function. On the basis of several measurements of airway function, 34 of the patients (58 per cent) were found to have some abnormality, It is concluded that symptomatic recurrences may be the most important factor in determining the danger of progressive disease. Persistently positive precipitins were correlated with decreased CO diffusing capacity. Moreover, airway disease is relatively uncommon but does occur, and in some cases it is a possible consequence of farmer's lung disease.

Adult↗
PubMed1979

Pulmonary abnormalities in art glassblowers.

Art glassblowing is a profession bringing the lung in close contact with many potential hazards. Forty-seven art glassblowers with a mean age of 34.5 years answered a questionnaire and had pulmonary function studies performed. While this was generally a young, healthy population, 21% had "usual cough" and 31% had wheezing. Pulmonary functions were most often normal. However, using multiple linear regression analysis, the functions associated with volume, VC and FEV1 showed a significant drop with increase in the total lifetime hours exposed to glassblowing. Both the presence of a cough and the production of phlegm were related to hours of exposure. Thus it seems there may be some unknown toxic effect of art glassblowing which in the future may prove to be hazardous to health.

Adult↗
PubMed1977

Respiratory abnormalities among grain handlers: a clinical, physiologic, and immunologic study.

A survey of 300 grain elevator workers revealed that 77 per cent complained of eye symptoms; 64 per cent, of nasal symptoms; and 88 per cent, of one or more respiratory symptoms on exposure to airborne grain dust. Symptoms on exposure were independent of age and length of employment. Cough and wheezing on exposure were more common among smokers than nonsmokers (P less than 0.025). Nineteen per cent of the workers had had episodes of grain fever. The prevalence of chronic bronchitis was 37 per cent (42 per cent of smokers and 30 per cent of nonsmokers). Wheezes on auscultation were found in 23 per cent. Measurements of lung ventilatory function, as well as diffusing capacity, correlated significantly with age and smoking habits, but not with length of employment. Thirty-seven per cent of the workers had an abnormal mean forced expiratory flow during the middle half of the forced vital capacity (47 per cent of smokers and 13 per cent of nonsmokers), and 34 per cent had an abnormal maximal expiratory flow after exhalation of 50 per cent of the forced vital capacity (40 per cent of smokers and 13 per cent of nonsmokers), whereas only 13 per cent had an abnormal ratio of 1-sec forced expiratory volume to forced vital capacity. There was no correlation between precipitins to fungi, bacteria, grain, or grain dust antigens and acute or chronic respiratory symptoms, lung function, or grain fever. There was, however, a significant correlation between cutaneous reactivity to grain dust and wheezing on exposure (P less than 0.02). Abnormal flows at low lung volumes were more common among cutaneous reactors to common allergens. We concluded that exposure to airborne grain dust can cause acute inflammatory reaction to the exposed mucosa, and it is highly probable that grain dust contributes and, in some cases, causes chronic airway disease.

Adult↗
PubMed1975

A nonidentifiability aspect of the problem of competing risks.

For an experimental animal exposed to k greater than 1 possible risks of death R1, R2, ..., Rk, the term i-th potential survival time designates a random variable Yi supposed to represent the age at death of the animal in hypothetical conditions in which Ri is the only possible risk. The probability that Yi will exceed a preassigned t is called the i-th net survival probability. The results of a survival experiment are represented by k "crude" survival functions, empirical counterparts of the probabilities Qi(t) that an animal will survive at least up to the age t and eventually die from Ri. The analysis of a survival experiment aims at estimating the k net survival probabilities using the empirical data on those termed crude. Therorems 1 and 2 establish the relationship between the net and the crude probabilities of survival. In particular, Theorem 2 shows that, without the not directly verifiable assumption that in their joint distribution the variables Y1, Y2, ..., Yk are mutually independent, a given set of crude survival probabilities Qi(t) does not identify the corresponding net probabilities. An example shows that the results of a customary method of analysis, based on the assumption that Y1, Y2, ..., Yk are independent, may have no resemblance to reality.

Animals↗