ROC plots display test accuracy, but are still limited by the study design.
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Acid Phosphatase↗
Biomedical subjects
M H Zweig
Publications and source records attributed to M H Zweig.
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↗
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↗
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↗
Inefficiency of diagnostic efficiency.
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Acute Disease↗
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↗
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↗
High-dose hook effect in a two-site IRMA for measuring thyrotropin.
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Humans↗
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↗
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↗
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↗
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↗
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↗
The potency of immunoglobulin G fragments for inhibition of interference caused by anti-immunoglobulin antibodies in a monoclonal immunoradiometric assay for thyrotropin.
Heterophile antibodies in patients' serum may produce false increases in apparent analyte concentrations in "sandwich"-type immunoassays. Using three patients with endogenous anti-mouse IgG antibodies and a two-site mouse monoclonal assay for thyrotropin, we studied the ability of IgG fragments to block this positive interference. Mouse whole IgG and IgG Fc fragment blocked the interference virtually completely; IgG F(ab')2 and Fab fragments did not. Rat and horse immunoglobulin fragments gave variable results. We suggest that sandwich assays formulated with IgG Fab or F(ab')2 fragments may be less susceptible to positive interference by heterophile antibodies. Unlike sera from the three patients, simulated human specimens containing heterologous anti-IgG antibodies showed little or no selectivity in inhibition by IgG fragments, and therefore are not useful to study this phenomenon.
Animals↗
Evaluation of the clinical accuracy of laboratory tests.
Fundamental clinical performance of a laboratory test can be described in terms of accuracy, or the ability to correctly classify subjects into clinically relevant subgroups. Accuracy refers to the quality of the information provided by the classification device and should be distinguished from the efficacy, or practical usefulness, of the information. Receiver operating characteristic curves 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. If analytical imprecision is removed from the data, the resulting receiver operating characteristic curve represents the inherent biological variation that ultimately limits the clinical accuracy of the test.
Diagnostic Tests, Routine↗
On the albumin-dependence of measurements of free thyroxin. II. Patients with non-thyroidal illness.
We studied the relation between thyroxin-binding proteins and free thyroxin (FT4) measurements by five radioimmunoassays (RIA) and an FT4 index (FT4I) in patients with non-thyroidal illness (NTI). The one-step FT4 RIAs and the FT4I frequently failed to identify the true FT4 status (as determined by equilibrium dialysis) of NTI patients. In these patients, falsely low FT4 results with one-step RIAs and FT4I were associated with decreasing total T3 and T4 concentrations, which, furthermore, paralleled decreasing serum albumin concentrations. All NTI patients with "low T3, low T4 syndrome" had subnormal albumin concentration. The two-step RIAs and equilibrium dialysis showed normal FT4 concentrations in most patients with NTI. However, sera from a subset of NTI patients with "low T3 syndrome" gave above-normal FT4 results with these methods. From their predictably poor performance in the presence of a subnormal albumin concentration, we conclude that the one-step FT4 RIAs and FT4I are inappropriate for testing the thyrometabolic status of NTI patients.
Diagnostic Errors↗
Interference by anti-immunoglobulin G antibodies in immunoradiometric assays of thyrotropin involving mouse monoclonal antibodies.
"Sandwich"-type assays are subject to positive interference by the patient's "heterophile" antibodies. If present, these bind to the animal immunoglobulins in the assay reagents, forming artefactual sandwiches indistinguishable from those formed with the analyte itself. Immunoglobulins from non-immunized animals, added to the assay reagents, can diminish this effect by blocking the patient's antibodies. Elsewhere, we studied several patients with anti-mouse immunoglobulin activity, whose serum gave spuriously high results for thyrotropin (TSH) concentrations. Here we have studied this phenomenon by adding, to pooled zero-TSH serum, antibodies to mouse, goat, and horse immunoglobulins and then assaying TSH by several other sandwich-type assays involving mouse monoclonal antibodies. Assays not supplemented with blocking immunoglobulins from mice or other animals were more susceptible to this effect. When large amounts of antibody were added, the antibody excess diminished the interference. However, the presence of blocking immunoglobulins could reverse such antibody excess, actually enhancing, instead of diminishing, the positive interference. Users should be aware that blocking immunoglobulins may diminish but not necessarily eliminate this problem with such assays.
Animals↗
Design of protocols to evaluate the efficacy of allergenic extracts and allergy tests.
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Allergens↗