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Serial electrophysiologic testing of multiple drugs in patients with atrioventricular nodal reentrant paroxysmal tachycardia.

Serial electrophysiologic testing of multiple drugs was performed in 21 patients with recurrent atrioventricular (AV) nodal reentrant paroxysmal supraventricular tachycardia (PSVT). All patients had reproducible sustained PSVT induced before drug administration. Serial daily PSVT induction was attempted after administration of i.v. ouabain (0.01 mg/kg) (16 patients), i.v. propranolol (0.1 mg/kg (17 patients), i.v. ouabain + propranolol (same dosages) (12 patients), i.v. procainamide (600-1000 mg) (17 patients) and oral quinidine (1600-2400 mg/day) (nine patients). In two of 21 patients (10%), no tested drug prevented induction of sustained PSVT. In 19 of 21 patients (90%), one or more drugs prevented induction of sustained PSVT: ouabain--seven patients, propranolol--seven patients, ouabain + propranolol--seven patients, procainamide--11 patients, quinidine--seven patients. The site of action of ouabain and/or propranolol was either the antegrade limb or the retrograde limb (RL) of the circus movement. The site of action of procainamide or quinidine was always the RL. These 19 patients were treated with oral drugs, based on results of serial testing. Eighteen patients were successfully followed for 6-50 months. In 13 of these 18 patients PSVT did not recur. Two patients (11%) had > 95% reduction in frequency of PSVT recurrences, and three (17%) did not respond to chosen oral drugs. Serial electrophysiologic testing of multiple drugs is feasible in patients with AV nodal reentrant paroxysmal tachycardia. Drug responses are variable. In most but not all patients, serial electrophysiologic testing defines effective prophylactic drug therapy. This method of defining prophylactic drug therapy appears most suitable for patients with poorly tolerated tachycardias that occur only sporadically.

Administration, Oral↗

Persistent neurological deficit precipitated by hot bath test in multiple sclerosis.

For a half century, the hot bath test has been used as a "diagnostic test" in multiple sclerosis. The appearance of new neurological signs or aggravation of preexisting signs generally is transient, with resolution on return of body temperature to normal. We have observed four patients, however, with considerable and prolonged neurological debilitation after hot bath testing. We suggest caution in the application of such testing.

Adult↗

Assessing the effect of multiple linkage tests in complex diseases.

The significance of a lod score value of 3 is very difficult to assess in linkage studies between a genetic marker and a complex disease. One reason is that multiple tests may have been performed, voluntarily or otherwise. For the same disease, linkage may be tested by different laboratories with several markers under various genetic models and diagnostic schemes for the disease. In such a case, we show that the probability of getting a lod score value of 3 under independent transmission of the disease and the marker may be not negligible.

Female↗

Transmission/disequilibrium tests using multiple tightly linked markers.

Transmission/disequilibrium tests have attracted much attention in genetic studies of complex traits because (a) their power to detect genes having small to moderate effects may be greater than that of other linkage methods and (b) they are robust against population stratification. Highly polymorphic markers have become available throughout the human genome, and many such markers can be studied within short physical distances. Studies using multiple tightly linked markers are more informative than those using single markers. However, such information has not been fully utilized by existing statistical methods, resulting in possibly substantial loss of information in the identification of genes underlying complex traits. In this article, we propose novel statistical methods to analyze multiple tightly linked markers. Simulation studies comparing our methods versus existing methods suggest that our methods are more powerful. Finally, we apply the proposed methods to study genetic linkage between the dopamine D2 receptor locus and alcoholism.

Alcoholism↗

Maximum Shannon information content of diagnostic medical testing. Including application to multiple non-independent tests.

The increase in Shannon information available from a diagnostic test associated with grading of the test results into many outcomes, rather than simply positive or negative, was examined to determine its upper limit as the number of test outcomes is increased indefinitely. Numerical methods were employed to find the optimal locations of outcome boundaries when a single normally distributed test variable is classified into 2, 3, 4, 5, 6, 8, 14, or 20 outcome categories. In each case Shannon information was computed for values of prior probability between 0.01 and 0.99 and for distances between the means in diseased and nondiseased populations ranging from 0.5 to 5.0 standard deviations. There is an important improvement in Shannon information as the number of outcomes defined is increased, but the increment in information diminishes rapidly with each additional category. A 20%-30% increment in information may be achieved with three outcomes instead of two. A further important increase in information occurs with four to seven outcomes, but beyond this the increment in inforation is negligible. The findings were similar over a wide range of prior probabilities and distances between the means. The analysis was extended to the case of multiple nonindependent tests by demonstrating their application to a Fisher discriminant function incorporating such tests. It was concluded that for normally distributed test variables: grading of test results significantly improves the information content of both single and multiple tests; the value of information content for 8-20 outcomes represents very nearly the maximum information content of a test; there is little value in using more than five to seven test outcomes; multiple grading should not be neglected for discriminant functions.

Bayes Theorem↗

Global tests for multiple binary outcomes.

The applied statistician often encounters the need to compare two or more groups with respect to more than one outcome or response. Several options are generally available, including reducing the dimension of the problem by averaging or summarizing the outcomes, using Bonferroni or other adjustments for multiple comparisons, or applying a global test based on a suitable multivariate model. For normally distributed data, it is well established that global tests tend to be significantly more sensitive than other procedures. While global tests have also been proposed for multiple binary outcomes, their properties have not been well studied nor have they been widely discussed in the context of clustered data. In this paper, we derive a class of quasi-likelihood score tests for multiple binary outcomes, and show that special cases of this class correspond to other tests that have been proposed. We discuss extensions to allow for clustered data, and compare the results to the simple approach of collapsing the data to a single binary outcome, indicating the presence or absence of at least one response. The asymptotic relative efficiencies of the tests are shown to depend not only on the correlation between the outcomes, but also on the response probabilities. Although global tests based on a multivariate model are generally recommended, our findings suggest that a test based on the collapsed data can maintain surprisingly high efficiency, especially when the outcomes of interest are rare. Data from several developmental toxicity studies illustrate our results.

Abnormalities, Drug-Induced↗

Evaluation of diagnostic tests with multiple diagnostic categories.

The evaluation of diagnostic tests attempts to obtain one or more statistical parameters which can indicate the intrinsic diagnostic utility of a test. Sensitivity, specificity and predictive value are not appropriate for this use. The likelihood ratio has been proposed as a useful measure when using a test to diagnose one of two disease states (e.g. disease present or absent). In this paper, we generalize the likelihood ratio concept to a situation in which the goal is to diagnose one of several non-overlapping disease states. A formula is derived to determine the post-test probability of a specific disease state. The post-test odds are shown to be related to the pre-test odds of a disease and to the usual likelihood ratios derived from considering the diagnosis between the target diagnosis and each alternate in turn. Hence, likelihood ratios derived from comparing pairs of diseases can be used to determine test utility in a multiple disease diagnostic situation.

Bayes Theorem↗

Utilization review of simultaneously ordered multiple radiologic tests for the same symptom.

The purpose of this study was to analyze the utilization of multiple radiologic procedures ordered simultaneously for the same clinical problem. The method was a retrospective study of patients referred to an urban community hospital who had multiple radiologic tests ordered simultaneously before the referring physician reviewed any of the results. Utilization Findings Codes, beta versions II and III, of the American College of Radiology were applied. In- and outpatient charts were reviewed for initial indication, subsequent diagnosis, and treatment. Ninety-three patients had 214 radiologic examinations (2.3 per patient). Of the 214 total, 129 (60%) were retrospectively coded as inappropriate (beta II version). For 98 reports, the initial interpreting radiologist's coded 16% as inappropriate versus 55% when retrospectively coded by the authors (P < 0.0001). After applying the beta III version, 18% were coded as positive (and related to symptoms), 79% negative, and 3% equivocal. There were 161 (74%) examinations ordered by primary care physicians and 53 tests ordered by specialists. Using the beta III version, the negative rate for primary care physicians was 81 and 75% for specialists (P = 0.447). It was concluded that ordering multiple radiologic tests simultaneously on the same patient resulted in a high number of inappropriate procedures and negative results.

Adult↗

Evaluation of nonstress fetal heart rate testing in multiple gestations.

Routine serial nonstress fetal heart rate testing was evaluated in 94 patients with multiple gestations (193 fetuses). Reactive testing was associated with an uncomplicated perinatal outcome in 89% of the cases. Nonreactive fetuses had a significantly higher incidence of perinatal morbidity, including fetal distress in labor (77.8%), asphyxia (48%), and intrauterine growth retardation (28%). Overall perinatal mortality (21/1000) was nearly comparable to that observed in singleton pregnancies. Nonreactive fetuses had a perinatal death rate that was more than six times that of the reactive ones (80/1000 versus 12/1000). Antepartum nonstress testing was found to be a highly reliable and predictive tool in the assessment of multiple gestations.

Apgar Score↗

E-UFA test in multiple sclerosis.

Field et al. have recently suggested a blood test for multiple sclerosis based on determination of the absolute electrophoretic mobility of erythrocytes alone and in the presence of linoleic acid (LA) or arachidonic acid (AA). We attempted to reinvestigate this phenomenon in an Italian population.

Arachidonic Acids↗

Evaluating multiple diagnostic tests with partial verification.

To evaluate diagnostic tests, one would ideally like to verify, for example, with a biopsy, the disease state of all subjects in a study. Often, however, no all subjects are verified. Previous methods for evaluation assume that the decision to verify depends only on recorded variables. Sometimes, particularly if the disease process is not well understood, the decision to verify may also depend on unrecorded variables related to disease. We propose a method to estimate the true- and false-positive rates of multiple tests while adjusting for the effect, on the decision to verify, of unrecorded variables related to disease. To put the estimates into a more usable form, we develop a simple algorithm for creating a receiver-operating curve which maximizes the true-positive rate, given the false-positive rate. We apply the methodology to data on the early detection of prostate cancer using ultrasonography, digital rectal exam, and prostate specific antigen.

Biometry↗

Clinical and economic considerations associated with testing for fetal lung maturity.

Performing multiple tests of fetal lung maturity on amniotic fluid samples may not use the individual test results and laboratory personnel most effectively. To determine the best strategy for fetal lung maturity testing, we analyzed our experience with use of a variety of procedures. Clinical usefulness was assessed according to sensitivity, specificity, predictive values, and efficiency. Economic and technical aspects analyzed included time and personnel requirements, availability of tests, and expense of each procedure. Several testing sequence approaches were compared for efficiency and cost. In our laboratory the foam stability index proved to be the most useful initial test of fetal lung maturity, reserving more expensive and time-consuming tests for instances in which the foam stability index is immature. Routine multiple testing did not enhance clinical usefulness and greatly increased costs. Development of a testing strategy using a rapid, inexpensive, and widely available test such as the foam stability index would promote clinical and economic efficiency.

Amniotic Fluid↗

Menstrual phase and breast cancer surgery: influence on clinical outcome or pitfall of statistical analysis?

The influence of menstrual status at the time of surgery on the prognosis of women suffering from breast cancer is still discussed controversially. In our patient collective, including 149 patients, we obtained statistically significant results for six different time intervals, indicating that patients who underwent surgery between 11 and 22 days after the last menstrual period (LMP) have a poorer outcome. Focusing on the effect of statistical data evaluation strategy we designed a simulation study to evaluate the amount of type I error (error of a false positive test result) in a multiple testing situation involving a cyclical covariate. Accordingly, we corrected the minimum P-values for the occurring type I error rates. After that correction all six previously significant P-values failed to achieve statistical significance. The impact of different statistical data evaluation strategies in a multiple testing situation is discussed.

Adult↗

Testing for multiple species in fossil samples: an evaluation and comparison of tests for equal relative variation.

Tests for equal relative variation are valuable and frequently used tools for evaluating hypotheses about taxonomic heterogeneity in fossil hominids. In this study, Monte Carlo methods and simulated data are used to evaluate and compare 11 tests for equal relative variation. The tests evaluated include CV-based parametric bootstrap tests, modifications of Levene's test, and modified weighted scores tests. The results of these simulations show that a modified version of the weighted scores test developed by Fligner and Killeen ([1976] J. Am. Stat. Assoc. 71:210-213) is the only test that maintains an acceptable balance of type I and type II errors, even under conditions where all other tests have extraordinarily high type I error rates or little power.

Animals↗

Diagnosis of perinatal TORCH infections.

Collectively, TORCH infections create more neonatal morbidity than early-onset group B streptococcal sepsis. Fortunately, the incidence of maternal infection by CMV or toxoplasmosis is low (2-10 per 1,000 births). There have been tremendous advances in direct antigen testing and in the sensitivity and specificity of IgG and IgM testing. Consistently, research laboratories show more accurate results than in the past. Unfortunately, commercial laboratories are using older, single-kit testing. The relatively poor degree of reliability can lead to unnecessary obstetric intervention or elective termination. Any positive pathogen-specific IgM on maternal serum should have additional confirmatory testing in a reputable research laboratory before any intervention. Direct antigen testing or multiple testing would seem to be appropriate for confirmation. This may include amniocentesis of fetal blood sampling. The research on the newer tests is based of the evaluation of blood from seriously immunocompromised subjects. Extrapolations of test accuracy to similar tests on healthy, pregnant women and their fetuses are likely to be in error. The application of these accurate tests to the obstetric population is a critical research need.

Cytomegalovirus Infections↗

Response of pulmonary rapidly adapting receptors during lung inflation.

Studies were conducted to establish the factors that determine the response of canine pulmonary rapidly adapting receptors (RAR) during lung inflation. Inflations of the lung were performed at several constant rates during which the activity of individual RAR was counted. At each rate of inflation tested multiple identical tests were performed. The volume of each test inflation was controlled. Data obtained in all tests at each flow rate were averaged to give the mean response of the receptor at that rate of inflation. These studies indicate the major response characteristics of RAR during lung inflation in conditions of relatively constant lung mechanics. First, at a constant rate of inflation, the activity of RAR augments increasingly as the lung is expanded. Second, their activity is influenced markedly by the rate of inflation. However, this sensitivity is nonlinear. Specifically, at low rates of inflation increases in flow rate produce more marked augmentation of RAR firing than do identical increases in flow at higher rates of inflation. The major difference between receptors is in their threshold; however, this too is a function of flow rate. With increasing flow rate the threshold, whether measured as the inflation volume or transpulmonary pressure at which receptors begin to fire, declines. The response of receptors, however, with thresholds over the entire range show the major features discussed above. The present results provide quantitative information which are necessary to begin to eludicate the transduction properties of this receptor type.

Animals↗