Number Of False Positive Responses Research Articles

Modification of the Titmus Fly Test to Improve Accuracy

IntroductionIn spite of its well-known flaws, the Titmus test is still the most commonly available and frequently utilized stereotest worldwide. Detecting stereopsis in the patient with small-angle strabismus is an important part of the sensorimotor exam. Because these patients often have only gross stereopsis, stereoacuity may have to be evaluated with the House Fly plate alone. This study evaluates an alternative method of presentation designed to decrease the false positive rate of the Titmus Fly test.MethodsA group of orthotropic volunteers with normal binocular vision, a group of patients with small angle strabismus, and a group of patients whose angle of strabismus was large enough to preclude stereopsis were tested with the Titmus Fly using two different presentations and compared.ResultsThe sensitivity of the Titmus Fly test was 79%, but specificity was only 26% due to the large number of false positive responses detected with the modified presentation. Patients with childhood-onset strabismus who have been repeatedly exposed to this test over many visits were particularly vulnerable to overestimation of stereoacuity.ConclusionIf the Titmus fly test is the only stereoacuity measure that can be used due to the presence of manifest strabismus, modifying the presentation of the test plate with this method will improve accuracy and precision of results.

Correlation of screening and confirmatory results in tiered immunogenicity testing by solution-phase bridging assays

Biotherapeutic proteins induce undesired immune responses that can affect drug efficacy and safety. For this reason, immunogenicity assessment is an integral part of drug development and is mandated by the regulatory authorities. Immunogenicity is typically evaluated by a tiered approach consisting of a screening assay followed by a competitive inhibition with unlabeled drug serving as confirmatory assay and additional characterization of the immune response. The confirmatory assay is intended to reduce the number of false positive responses generated in the screening tier and ensure that all samples are correctly classified as positive or negative. The positive–negative sample decisions are based on screening and confirmatory assay cut points that are statistically derived through evaluation of drug-naive samples. In this paper, we describe the analysis of cut point data for the presence of statistical correlation between the screening and confirmatory results. Data were obtained from validations of solution-phase bridging assays for detection of anti-drug antibodies against monoclonal antibody therapeutics. All data sets showed moderate to strong positive correlation, indicating that the screening and confirmatory assays were not independent and were likely to generate similar information. We present theoretical evidence that correlated results may be a general feature of the tiered approach when the same test platform is used for both screening and confirmatory assays. The competitive inhibition test, therefore, may be of limited value beyond reduction of the overall false positive rate. Our results indicate that similar sample results could be obtained by using just the screening assay with the false positive rate set to 1%.

Behavioral assessment and identification of a molecular marker in a salicylate-induced tinnitus in rats

Tinnitus is a non-observable phantom sensation. As such, it is a difficult condition to investigate and, to date, no effective treatment has been developed. To approach this phantom sensation, we aimed to develop a rat behavioral model of tinnitus using salicylate, an active component of aspirin known to induce tinnitus. We also aimed to establish a molecular marker of tinnitus by assessing the expression of transient receptor potential cation channel superfamily V-1 (TRPV1) in the rat auditory pathway during salicylate-induced tinnitus. Animals were trained to perform “an active avoidance task”: animals were conditioned by electrical footshock to move to the other side of the conditioning box when hearing a sound. Animals received a single injection of saline or salicylate (400 mg/kg i.p.) and false positive responses were measured 2 h after injection as the number of movements during a silent period. The number of responses in salicylate-treated animals was highest when the conditioned stimulus was 60 dB sound pressure level (SPL) and 16 kHz. This indicates that animals could feel tinnitus 2 h after salicylate injection, equivalent to that induced by 60 dB SPL and 16 kHz. By means of real-time PCR and western blot analysis, TRPV1 expression was significantly upregulated in spiral ganglion cells 2 h after salicylate injection and this upregulation together with the increase in the number of false positive responses was significantly suppressed by capsazepine (10 mg/kg i.p.), a specific antagonist of TRPV1. This suggests that salicylate could induce tinnitus through activation of TRPV1 in the rat auditory pathway.

Salicylate Induces Tinnitus through Activation of Cochlear NMDA Receptors

Salicylate, the active component of aspirin, is known to induce tinnitus. However, the site and the mechanism of generation of tinnitus induced by salicylate remains unclear. Here, we developed a behavioral procedure to measure tinnitus in rats. The behavioral model was based on an active avoidance paradigm in which rats had to display a motor task (i.e., to jump on a climbing pole when hearing a sound). Giving salicylate led to a decrease in the percentage of correct responses (score) and a drastic increase in the number of false positive responses (i.e., animals execute the motor task during a silent period). Presentation of the sound at a constant perceptive level prevents decrease of the score, leading to the proposal that score is related to hearing performance. In contrast, the increase of false positive responses remained unchanged. In fact, animals behaved as if they hear a sound, indicating that they are experiencing tinnitus. Mefenamate in place of salicylate also increased the number of false positive responses, suggesting that salicylate-induced tinnitus is related to an inhibition of cyclooxygenase. One physiological basis of salicylate ototoxicity is likely to originate from altered arachidonic acid metabolism. Because arachidonic acid potentiates NMDA receptor currents, we tested the involvement of cochlear NMDA receptors in the occurrence of tinnitus. Application of NMDA antagonists into the perilymphatic fluids of the cochlea blocked the increase in pole-jumping behavior induced by salicylate, suggesting that salicylate induces tinnitus through activation of cochlear NMDA receptors.

Hemispheric priming by meaningful and nonmeaningful symbols in language-trained chimpanzees (Pan troglodytes): further evidence of a left hemisphere advantage.

Hemispheric priming was examined in 3 language-trained chimpanzees (Pan troglodytes) using a simple reaction time paradigm. Subjects were required to hold down a response button until the occurrence of a response cue. A warning stimulus was presented to either the left visual field (LVF) or the right visual field (RVF) before the response cue occurred. No warning stimulus was presented on control trials. The warning stimuli were geometric communicative symbols from two semantic categories: foods and tools. A third set of warning stimuli were familiar geometric symbols. Dependent measures included reaction time and the number of false-positive responses. Reaction-time data indicated an RVF advantage in priming when the warning stimuli were food or tool symbols. No significant visual half-field differences were found for familiar symbols, but a trend toward an RVF advantage was observed. These effects were enhanced when subjects responded with their left hand. False-positive data also indicated an RVF advantage for the food and tool warning stimuli. The data indicate that hemispheric asymmetries for processing communicative symbols are present in language-trained chimpanzees.

Phosphorylase Ratio and Susceptibility to Malignant Hyperthermia

The ratio of muscle phosphorylase a to total phosphorylase, expressed as a percent, was determined in vastus lateralis muscle of 26 patients to examine the efficacy of this parameter as a method for screening for susceptibility to malignant hyperthermia (MH). As standard screening, all patients also had muscle contracture responses determined to 2% halothane and 0.25-32 mM caffeine at 37 degrees C. Each drug was given separately and not combined. Nine patients were susceptible to MH, based upon caffeine threshold of 2 mM or less (seven patients) or a rapidly developing contracture tension to halothane of more than 400 mg (seven patients, including five with positive caffeine responses). Mean phosphorylase ratio in these nine patients was 14.5 +/- 2.0% (mean, SEM). In the 17 nonsusceptible patients mean phosphorylase ratio (12.4 +/- 1.9%) was not significantly different. The range of phosphorylase ratios in susceptible patients was 6.5-26% while 13 nonsusceptible patients had ratios greater than 6% and up to 29%. The unacceptably high number of false-positive responses in nonsusceptible patients precludes the use of phosphorylase ratio as a definitive diagnostic test.

The response of the blood pressure to an infusion of angiotensin in patients with essential malignant and renovascular hypertension.

SummaryThe angiotensin infusion test was performed on 251 patients.The results of the test were reproducible and not affected by hypotensive therapy in the case of patients with essential hypertension.The mean pressor dose was the same for normotensive subjects and for patients with hypertension with or without disease of the renal parenchyma.The mean pressor dose for patients with renal artery stenosis or malignant hypertension was increased. The pressor dose fell to normal when hypertension was controlled. Renal artery surgery improved hypertension in nine patients. The pressor dose was normal pre‐operatively for four patients.The angiotensin infusion test was able to detect most patients with renal artery stenosis. The large number of false positive responses and the occurrence of some false negative responses reduce its value as a screening test.