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M H Zweig

Publications and source records attributed to M H Zweig.

At least 19 recordsLinked to original sources
PubMed1999

Prevalence-value-accuracy plots: a new method for comparing diagnostic tests based on misclassification costs.

The clinical accuracy of diagnostic tests commonly is assessed by ROC analysis. ROC plots, however, do not directly incorporate the effect of prevalence or the value of the possible test outcomes on test performance, which are two important factors in the practical utility of a diagnostic test. We describe a new graphical method, referred to as a prevalence-value-accuracy (PVA) plot analysis, which includes, in addition to accuracy, the effect of prevalence and the cost of misclassifications (false positives and false negatives) in the comparison of diagnostic test performance. PVA plots are contour plots that display the minimum cost attributable to misclassifications (z-axis) at various optimum decision thresholds over a range of possible values for prevalence (x-axis) and the unit cost ratio (UCR; y-axis), which is an index of the cost of a false-positive vs a false-negative test result. Another index based on the cost of misclassifications can be derived from PVA plots for the quantitative comparison of test performance. Depending on the region of the PVA plot that is used to calculate the misclassification cost index, it can potentially lead to a different interpretation than the ROC area index on the relative value of different tests. A PVA-threshold plot, which is a variation of a PVA plot, is also described for readily identifying the optimum decision threshold at any given prevalence and UCR. In summary, the advantages of PVA plot analysis are the following: (a) it directly incorporates the effect of prevalence and misclassification costs in the analysis of test performance; (b) it yields a quantitative index based on the costs of misclassifications for comparing diagnostic tests; (c) it provides a way to restrict the comparison of diagnostic test performance to a clinically relevant range of prevalence and UCR; and (d) it can be used to directly identify an optimum decision threshold based on prevalence and misclassification costs.

Apolipoprotein A-I↗
PubMed1997

Linear regression estimation of minimal detectable concentration. Thyrotropin as an example.

BACKGROUND: Minimal detectable concentration is an important analytic feature of certain clinical immunoassays. We believe that accuracy is an important component of the minimal detectable concentration; for a given observed concentration to be meaningful, it should reflect a consistent linear relationship with the amount of analyte actually present. METHODS: To evaluate the minimal detectable concentration, we developed a linearity regression protocol based on accuracy and also accounting for between-run variability. Using serial twofold dilutions of serum samples, we regressed the log of concentration (x) and of dilution (y) with linear, second-, and third-order polynomials. Initially, we evaluated two elements to find the linear region of the dataset, establishing the statistical significance of the beta coefficients with a t test and the reduction of the sum of square of the residuals between the linear regression and the higher-order regressions by means of an F test. As needed, we successively eliminated the lowest point until the linear regression was the best fit. Once we found the best fit, we added the most recently removed point back and calculated the difference between the value predicted by the first-order regression and the observed value. If the difference was not analytically significant, then we considered the point to be part of the linear set; otherwise, it was not included. In either case, the lowest included point was considered to be the minimal detectable concentration. RESULTS: We applied the technique in evaluating two automated systems for serum thyrotropin. One system appeared linear and accurate down to 0.02 mU/L, or better, approximately 77% of the time, and to 0.01 mU/L 68% of the time. The second system was linear infrequently and appeared to be useful down to 0.02 mU/L, or better, only about 20% of the time. CONCLUSIONS: This accuracy-based approach to determining the minimal detectable concentration is an attractive alternative to current empiric approaches, which are based only on interassay variability.

Humans↗
PubMed1994

Apolipoproteins and lipids in coronary artery disease. Analysis of diagnostic accuracy using receiver operating characteristic plots and areas.

Identification of clinically important coronary artery disease is a current goal in patient treatment. Serum lipid and apolipoprotein concentrations are commonly used to identify individuals who may have significant disease. With data published earlier from 304 men classified by coronary angiography, this study used receiver operating characteristic plots and analysis to examine the ability of 10 lipid or lipoprotein measures to discriminate between subjects with and without coronary artery disease. The analysis illustrated the simple elegance of receiver operating characteristic plots and demonstrated that all 10 measures are, at best, only moderately accurate.

Apolipoproteins↗
PubMed1993

Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine.

The clinical performance of a laboratory test can be described in terms of diagnostic accuracy, or the ability to correctly classify subjects into clinically relevant subgroups. Diagnostic accuracy refers to the quality of the information provided by the classification device and should be distinguished from the usefulness, or actual practical value, of the information. Receiver-operating characteristic (ROC) plots provide a pure index of accuracy by demonstrating the limits of a test's ability to discriminate between alternative states of health over the complete spectrum of operating conditions. Furthermore, ROC plots occupy a central or unifying position in the process of assessing and using diagnostic tools. Once the plot is generated, a user can readily go on to many other activities such as performing quantitative ROC analysis and comparisons of tests, using likelihood ratio to revise the probability of disease in individual subjects, selecting decision thresholds, using logistic-regression analysis, using discriminant-function analysis, or incorporating the tool into a clinical strategy by using decision analysis.

Chemistry, Clinical↗
PubMed1992

Urine free cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome.

OBJECTIVE: To develop criteria for interpreting the high-dose dexamethasone suppression test using urine free cortisol as an end point for the differential diagnosis of the Cushing syndrome. DESIGN: Retrospective review. SETTING: Inpatient research ward. PATIENTS: Patients (118) with surgically confirmed causes of the Cushing syndrome: 94 with pituitary disease, 14 with primary adrenal disease, and 10 with ectopic adrenocorticotropic hormone (ACTH) secretion. MAIN OUTCOME MEASURES: The sensitivity, specificity, and diagnostic accuracy were determined for the high-dose dexamethasone suppression test using urine free cortisol and using 17-hydroxysteroid excretion. For each analysis, patients with pituitary disease were considered to be "diseased" and patients with nonpituitary disease were considered to be "non-diseased". The level of suppression that gave 100% specificity was determined for each steroid. RESULTS: The accuracy of urine free cortisol when used as an end point in the high-dose dexamethasone suppression test was equivalent to that of 17-hydroxysteroid excretion. At all levels of sensitivity and specificity, however, the degree of suppression of urine free cortisol used for the diagnosis of pituitary disease was greater than that of 17-hydroxysteroid excretion. The likelihood ratios for pituitary disease based on urine free cortisol suppression of greater than 50%, of greater than 80%, and of greater than 90% were 4.2, 10.1, and "infinite," respectively. Suppression of urine free cortisol greater than 90% or suppression of 17-hydroxysteroid excretion greater than 64% was associated with 100% specificity. When these criteria were combined, the percentage of correct predictions (102 of 118 [86%; 95% CI, 78% to 92%]) was higher than that obtained using either steroid alone (89 of 118 [75%; CI, 65% to 83%]) (P = 0.009) and higher than that obtained using the traditional criterion of 50% suppression for 17-hydroxysteroid excretion (95 of 118 [80%; CI, 71% to 87%]) (P = 0.016). CONCLUSIONS: In the high-dose dexamethasone suppression test, the degree of suppression of urine free cortisol used for the diagnosis of pituitary disease is greater than that traditionally used for 17-hydroxysteroid excretion. The diagnostic performance of the test is improved by measuring both urine free cortisol and 17-hydroxysteroid excretion and by requiring greater suppression of both steroids.

17-Hydroxycorticosteroids↗
PubMed1992

New automated nonisotopic immunoassays for free thyroxin: effect of albumin and thyroxin-binding globulin concentrations.

Recently, nonisotopic (often automated) immunoassays for measuring serum free thyroxin (FT4) have become available. Though more costly than radioimmunoassays, they are considerably more convenient. We studied the influence of endogenous albumin and thyroxin-binding globulin concentration on five automated, nonisotopic methods of measuring FT4 [Enzymun on ES300 (one-step), Stratus I and II (essentially two-step), Delfia (two-step), and IMx (two-step)] in a mixed patient population. We observed that they (a) are influenced very little by endogenous serum binding proteins and (b) seem to have sufficient within-run precision to justify performing single measurements on patients' specimens.

Autoanalysis↗
PubMed1992

ROC curve analysis: an example showing the relationships among serum lipid and apolipoprotein concentrations in identifying patients with coronary artery disease.

Clinical accuracy, defined as the ability to discriminate between states of health, is the fundamental property of any diagnostic test or system. It is readily expressed as clinical sensitivity and specificity, and elegantly represented by the receiver operating characteristic (ROC) curve. To demonstrate the use of ROC curves, we reexamine a study of the ability of serum lipid and apolipoprotein measures to discriminate among degrees of coronary artery disease in patients undergoing coronary angiography. ROC curve analysis reveals that none of these indexes is highly accurate, but demonstrates a modest increase in the accuracy of apolipoprotein over lipid indexes.

Apolipoproteins↗
PubMed1991

Thyroid dysfunction associated with immunotherapy for patients with cancer.

The authors performed a prospective study to evaluate thyroid dysfunction in 130 patients with cancer who were receiving interleukin-2 (IL-2)-based immunotherapy. Primary hypothyroidism was the most common abnormality, occurring in 12% of patients before, 38% during, and 23% after immunotherapy. Hyperthyroidism occurred in 1%, 4%, and 7% of patients at those time intervals. Among patients initially euthyroid (n = 111), primary hypothyroidism developed in 32% during and 14% after immunotherapy, persisting a median of 54 days. Three patients required levothyroxine. Hyperthyroidism developed in 2% of patients during immunotherapy and 6% after. Thyroid dysfunction was not a function of sex, diagnosis, type of treatment, or response to immunotherapy. Elevated titers of antithyroglobulin and antithyroid microsomal antibodies were detected after treatment in 9% and 7%, respectively, of all patients without prior antibody abnormalities and did not correlate with response to therapy. The high incidence of therapy-induced thyroid dysfunction suggests that thyroid function should be carefully monitored in all patients receiving IL-2-based immunotherapy.

Adolescent↗
PubMed1991

Interference by iatrogenically induced anti-mouse IgG antibodies in a two-site immunometric assay for thyrotropin.

Two-site immunometric assays using mouse monoclonal antibodies are gaining increasingly widespread popularity and use. Patients with circulating antimurine immunoglobulin antibodies capable of interfering in these assays have been encountered and described sporadically. Parenteral administration of murine monoclonal antibodies for imaging and therapeutic purposes is increasing and is known to induce human anti-murine antibodies frequently. We examined 60 serum samples from 48 individuals who received such murine immunoglobulin to determine whether iatrogenically induced anti-murine antibodies could interfere in a two-site (sandwich) immunoradiometric assay for serum thyrotropin. We found that these circulating antibodies can indeed interfere in an "unblocked" assay, but that the interference appears to be suppressed by including nonspecific IgG in the commercial version of the assay kit.

Animals↗
PubMed1990

Direct and indirect techniques for free thyroxin compared in patients with nonthyroidal illness. III. Analysis of interference variables by stepwise regression.

We applied stepwise regression for multivariate analysis of data for free thyroxin (FT4) in serum and for other laboratory tests of thyroid function in patients with nonthyroidal illness. Using the maximum R2 improvement and backward elimination methods to test five variables [prealbumin, albumin, T4-binding globulin (TBG), free fatty acids (FFA), and FFA/albumin molar ratio], we found that the variables with the greatest predictive power clustered according to the methodology of FT4 measurement. Thus, we best predicted the FT4 results obtained by 16 techniques as follows: FT4 measured by one-step (analog) RIAs, with albumin; FT4 determined by two-step (sequential) RIAs, with FFA or FFA/albumin molar ratio; FT4 estimated by a binding-rate-based RIA or conceptually related FT4 indices [based on triiodothyronine (T3) uptake], with TBG; FT4 measured by equilibrium dialysis, with TBG and FFA/albumin molar ratio; and T4/TBG ratios, with either none or prealbumin and albumin. We could very highly (P less than 0.001) predict total T4 and T3 by considering TBG, and total T3 also by considering prealbumin and albumin, whereas reverse T3 was predictable with prealbumin only (negative relationship). We found comparatively weak associations between thyrotropin (TSH) and albumin or TBG. In clinical practice, abnormalities in key variables should call attention to possible effects of these variables on FT4 and other thyroid-test results and thus to the need for appropriate correction or alternative testing.

Carrier Proteins↗
PubMed1989

Direct and indirect techniques for free thyroxin compared in patients with nonthyroidal illness. I. Effect of free fatty acids.

We examined the effect of endogenous free fatty acids (FFA) on the measurement of free thyroxin (FT4) by five different methodologies represented in 16 different assays in a large number of patients with nonthyroidal illness (NTI). Some, but not all, one-step (analog) FT4 RIAs negatively correlated with FFA concentration. All two-step FT4 RIAs, equilibrium dialysis FT4, and the dialyzable (free) fraction of T4 positively correlated. In contrast, a binding-rate-based FT4 RIA, FT4 indices based on T3 macroaggregated albumin uptake, and T4/TBG ratios did not correlate. We also analyzed the FT4-FFA relationship with a second, more sensitive approach by correlating test results with FFA/albumin molar ratio as an estimate of the "excess" (nonalbumin bound) FFA. We found that all FT4 RIAs, equilibrium dialysis FT4, FT4 indices based on T3 uptake, the dialyzable fraction of labeled T4 in equilibrium dialysis, the fraction of labeled T4 bound to solid phase antibody in the binding-rate-based RIA, and T3 uptake correlated with the FFA/albumin molar ratio. This FFA dependency was comparable among all the various techniques and was relatively small. Thus, increases or decreases in FT4 results due to varying FFA (and albumin) concentrations are highly likely with most currently available methods (only the T4/TBG ratio did not reveal FFA-dependency), but the magnitude of changes varies with the "excess" FFA.

Dialysis↗
PubMed1989

Direct and indirect techniques for free thyroxin compared in patients with nonthyroidal illness. II. Effect of prealbumin, albumin, and thyroxin-binding globulin.

We studied the correlation of thyroxin (T4)-binding proteins with the apparent free T4 (FT4) in 101 patients with nonthyroidal illness (NTI). Most patients (95%) were seriously ill at the time of blood collection. Concentrations of T4-binding prealbumin (transthyretin), albumin, and T4-binding globulin (TBG) often were low in the sera of these patients. Albumin was the most frequently subnormal, TBG the least. FT4 in serum was determined by five methods represented in 16 different assays. With few exceptions, analog (one-step) FT4 RIAs--both the binding-rate-based RIA and the related FT4 indices (calculated from triiodothyronine-macroaggregated albumin uptake and total T4)--and T4/TBG ratios correlated positively and usually highly significantly (P less than 0.01) with concentrations of prealbumin, albumin, and TBG. Equilibrium dialysis values for FT4 did not correlate with prealbumin concentrations but showed a weakly (P less than 0.03) positive association with albumin and a highly significant (P less than 0.002) positive correlation with TBG. Of the three two-step FT4 RIAs tested, the only statistically significant but weakly (P less than 0.02) positive correlation with T4-binding proteins was between Spiria FT4 and TBG. Thus, in these NTI patients, FT4 estimates vary with methodology and, to a lesser extent, with the particular assay used. The results from two-step FT4 RIAs are least associated with binding protein concentrations.

Humans↗
PubMed1988

Factitious elevation of thyrotropin in a new ultrasensitive assay: implications for the use of monoclonal antibodies in "sandwich" immunoassay.

Three patients who had falsely elevated serum TSH concentrations (initial values, 30.5, 74, and greater than 50 mU/L) in a mouse monoclonal immunoradiometric assay are reported. Two patients were treated for hypothyroidism inappropriately, and one underwent unnecessary diagnostic testing. Immunoaffinity chromatography of serum from one patient indicated that the serum TSH level was truly low. Addition of mouse serum or immunoglobulin G (IgG) or absorption of patient serum with solid phase-bound mouse IgG-1 reduced the TSH content in the serum of the three patients to undetectable levels. Blocking studies revealed that all patients had antibodies directed at mouse IgG-1, the subclass of mouse antibody present in the assay kit. The serum of one patient who had autoimmune disease with elevated serum Igs had much broader species cross-reactivity than that of another patient who had known exposure to rats and mice. We hypothesize that such antimouse antibodies can arise either from endogenous autoimmunity or exogenous animal exposure. Serum TSH elevations also were found when the serum samples were tested in other mouse monoclonal immunoassays, underscoring the fact that antibody interference can potentially affect many assays used in endocrinology and other areas of medicine to make major diagnostic and therapeutic decisions. Clinicians must be aware of such interactions; relatively simple laboratory maneuvers can differentiate true from false results in assays of this type.

Adult↗
PubMed1988

Escape from blockade of interfering heterophile antibodies in a two-site immunoradiometric assay for thyrotropin.

Sandwich-type immunoassays in which mouse monoclonal antibodies are used are subject to positive interference by heterophile antibodies present in human serum. Manufacturers now customarily add nonspecific mouse immunoglobulins to absorb the heterophile antibodies and eliminate such interference. We describe the case of a patient who had spurious increases in thyrotropin concentration in serum despite use of the mouse immunoglobulins included in the assay kit. This resulted in a puzzling clinical picture, a workup, and treatment. We demonstrate that the observed increases in thyrotropin were markedly reduced by including additional amounts of mouse immunoglobulins of the appropriate class, subclass, and fragment type in the assay mixture.

Adolescent↗