The GH-2000 and GH-2004 projects have developed a method for detecting GH misuse based on measuring insulin-like growth factor-I (IGF-I) and the amino-terminal pro-peptide of type III collagen (P-III-NP). The objectives were to analyze more samples from elite athletes to improve the reliability of the decision limit estimates, to evaluate whether the existing decision limits needed revision, and to validate further non-radioisotopic assays for these markers. The study included 998 male and 931 female elite athletes. Blood samples were collected according to World Anti-Doping Agency (WADA) guidelines at various sporting events including the 2011 International Association of Athletics Federations (IAAF) World Athletics Championships in Daegu, South Korea. IGF-I was measured by the Immunotech A15729 IGF-I IRMA, the Immunodiagnostic Systems iSYS IGF-I assay and a recently developed mass spectrometry (LC-MS/MS) method. P-III-NP was measured by the Cisbio RIA-gnost P-III-P, Orion UniQ™ PIIINP RIA and Siemens ADVIA Centaur P-III-NP assays. The GH-2000 score decision limits were developed using existing statistical techniques. Decision limits were determined using a specificity of 99.99% and an allowance for uncertainty because of the finite sample size. The revised Immunotech IGF-I - Orion P-III-NP assay combination decision limit did not change significantly following the addition of the new samples. The new decision limits are applied to currently available non-radioisotopic assays to measure IGF-I and P-III-NP in elite athletes, which should allow wider flexibility to implement the GH-2000 marker test for GH misuse while providing some resilience against manufacturer withdrawal or change of assays.
The paper considers meta-analysis of diagnostic studies that use a continuous score for classification of study participants into healthy or diseased groups. Classification is often done on the basis of a threshold or cut-off value, which might vary between studies. Consequently, conventional meta-analysis methodology focusing solely on separate analysis of sensitivity and specificity might be confounded by a potentially unknown variation of the cut-off value. To cope with this phenomena it is suggested to use, instead, an overall estimate of the misclassification error previously suggested and used as Youden's index and; furthermore, it is argued that this index is less prone to between-study variation of cut-off values. A simple Mantel-Haenszel estimator as a summary measure of the overall misclassification error is suggested, which adjusts for a potential study effect. The measure of the misclassification error based on Youden's index is advantageous in that it easily allows an extension to a likelihood approach, which is then able to cope with unobserved heterogeneity via a nonparametric mixture model. All methods are illustrated at hand of an example on a diagnostic meta-analysis on duplex doppler ultrasound, with angiography as the standard for stroke prevention.
Meta-analysis of diagnostic studies experiences the common problem that different studies might not be comparable since they have been using a different cut-off value for the continuous or ordered categorical diagnostic test value defining different regions for which the diagnostic test is defined to be positive. Hence specificities and sensitivities arising from different studies might vary just because the underlying cut-off value had been different. To cope with the cut-off value problem, interest is usually directed towards the receiver operating characteristic (ROC) curve which consists of pairs of sensitivities and false positive rate (1-specificity). In the context of meta-analysis, one pair represents one study and the associated diagram is called SROC curve where the S stands for 'summary'. The paper will consider-as a novel approach-modelling SROC curves with the Lehmann family that assumes log-sensitivity is proportional to the log-false positive rate across studies. The approach allows for study-specific false positive rates which are treated as (infinitely many) nuisance parameters and eliminated by means of the profile likelihood. The adjusted profile likelihood turns out to have a simple univariate Gaussian structure which is ultimately used for building inference for the parameter of the Lehmann family. The Lehmann model is further extended by allowing the constant of proportionality to vary across studies to cope with unobserved heterogeneity. The simple Gaussian form of the adjusted profile likelihood allows this extension easily as a form of a mixed model in which unobserved heterogeneity is incorporated by means of a normal random effect. Some meta-analytic applications on diagnostic studies including brain natriuretic peptides for heart failure, alcohol use disorder identification test (AUDIT) and the consumption part of AUDIT for detection of unhealthy alcohol use as well as the mini-mental state examination for cognitive disorders are discussed to illustrate the methodology.
C.A.MAN, diagnostic testing, meta-analysis, sensitivity, specificity, summary receiver operating characteristic (SROC), summary statistics approach,
BackgroundThe GH-2000 score has been developed as a powerful and unique technique for the detection of growth hormone misuse by sportsmen and women. The score depends upon the measurement of two growth hormone (GH) sensitive markers, insulin-like growth factor-I (IGF-I) and the amino-terminal pro-peptide of type III collagen (P-III-NP). With the collection and establishment of an increasingly large database it has become apparent that the score shows a positive age effect in the male athlete population, which could potentially place older male athletes at a disadvantage.MethodsWe have used results from residual analysis of the general linear model to show that the residual of the GH-2000 score when regressed on the mean-age centred age is an appropriate way to proceed to correct this bias. As six GH-2000 scores are possible depending on the assays used for determining IGF-I and P-III-NP, methodology had to be explored for including six different age effects into a unique residual. Meta-analytic techniques have been utilized to find a summary age effect.ResultsThe age-adjusted GH-2000 score, a form of residual, has similar mean and variance as the original GH-2000 score and, hence, the developed decision limits show negligible change when compared to the decision limits based on the original score. We also show that any further scale-transformation will not change the adjusted score. Hence the suggested adjustment is optimal for the given data. The summary age effect is homogeneous across the six scores, and so the generic adjustment of the GH-2000 score formula is justified.ConclusionsA final revised GH-2000 score formula is provided which is independent of the age of the athlete under consideration.
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