A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans.

Warfarin demonstrates a wide interindividual variability in response that is mediated partly by variants in cytochrome P450 2C9 (CYP2C9) and vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1). It is not known whether variants in calumenin (CALU) (vitamin K reductase regulator) have an influence on warfarin dose requirements. We resequenced CALU regions in a discovery cohort of dose outliers: patients with high (>90th percentile, n = 55) or low (<10th percentile, n = 53) warfarin dose requirements (after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high doses (P = 0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: (i) 496 patients of mixed ethnicity and (ii) 194 African-American patients. The G allele of rs339097 (the allele frequency was 0.14 in African Americans and 0.002 in Caucasians) was associated with the requirement for a 14.5% (SD +/- 7%) higher therapeutic dose (P = 0.03) in the first replication cohort and a higher-than-predicted dose in the second replication cohort (allele frequency 0.14, one-sided P = 0.03). CALU rs339097 A>G is associated with higher warfarin dose requirements, independent of known genetic and nongenetic predictors of warfarin dose in African Americans.

Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients.

BACKGROUND: Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common. METHODS: In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy. RESULTS: The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri-operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R(2) was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R(2) of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7-11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30-0.97). CONCLUSIONS: Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, http://www.WarfarinDosing.org.

What makes targets redundant?

Two letter-classification experiments that investigated target-redundancy effects on reaction time (RT) were conducted. Both experiments were replicated with choice reaction time (CRT) and go/no-go (GNG) procedures. In each experiment, there were two single-target conditions, one with a noise letter and one without. In one experiment, the letter classes were two letters that could be of either case. In the second experiment, each class consisted of two different capital letters. In both experiments, there were two redundant-targets conditions, one with identical targets and one with the different members of a class. In both of the GNG experiments, redundancy gains were obtained comparing the different-targets condition with the no-noise, single-target condition. Redundant stimuli are ones that lead to the same response. Visually different stimuli may be processed in parallel and jointly activate a response. GNG procedures are more sensitive than CRT in the investigation of redundancy effects.

Redundancy phenomena are affected by response requirements.

Results are reported for two go/no-go reaction time (RT) experiments, in which the redundant targets advantage was investigated. These experiments were replications of two earlier choice reaction time (CRT) experiments, in which letter stimuli were used. Important differences between the go/no-go RT experiments and the CRT experiments were obtained. Equal and significant redundancy advantages were obtained whether redundant targets were compared with a single target presented with a noise letter or without noise. In the CRT experiments, the advantage was not obtained in the comparison with a single target presented alone. Noise letters did not slow the RTs to single targets with which they were presented as was the case with CRT. Since the differing results of the two procedures depend on the response requirements, explanation of differing CRT data in terms of perceptual or attentional concepts is probably inappropriate. The presence and absence of response competition in the two situations may be the best interpretation. The results tend to support a conclusion of the parallel processing of two letter stimuli separated spatially by as much as 3 degrees.

Variable criterion analysis of brightness effects in simple reaction time.

Using light onset as the stimulus in simple reaction time (SRT), the effect of stimulus intensity was studied in both between-subjects and within-subjects experimental designs. There was a strong intensity effect in both conditions but no significant interaction between the effect of stimulus intensity and the type of design. This differs from previous results with auditory stimuli where such an interaction has been demonstrated. When the criterion parameters of variable criterion theory were evaluated directly, the only significant effect was greater criterion variability in the between-subjects condition. Theoretical functions describing the growth of sensory strength for each intensity had different starting points and were largely parallel, showing only late temporal divergence. This provides an explanation of the rarity, in the SRT literature, of interactions between visual intensity and criterion variables. Correlations illustrating the relations between reaction time (RT) measures and theoretical criterion parameters are presented. Absence of the predicted relation between intensity and RT variability is evidence against theories relating RT to impulse rate treated as a Poisson process.

Associative processes and strategies in disjunctive reaction time.

Scaling analysis based on variable criterion theory has been applied to the c-reaction form of disjunctive RT. In addition to previously identified sensory growth functions, two associative processes have been identified and functions of time describing their growth have been obtained. Associative strength to the positive stimulus begins at about 200 msec, or after, and grows with initial positive and later negative acceleration. Associative inhibition to the negative stimulus begins earlier, shortly after the sensory detection functions, and grows rapidly with negative acceleration. Subjects may adopt strategies which emphasize the use of either of these associative processes. With the pure inhibitory strategy, they respond to the positive stimulus entirely on the basis of sensory detection, but associatively inhibit response to the negative stimulus. With either strategy, the speed-accuracy tradeoff was determined by the level of criterion adjustment.

Stimulus intensity, catch trial effects, and the speed-accuracy tradeoff in reaction time: A variable criterion theory interptation.

Ss responded to a 1,000-Hz tone of 50, 80, or 100 dB. Catch trial conditions were none, blank trials, a red light, a noise, and an 1,800-Hz tone. Auditory catch signals were of the same intensities. RT distributions in the first three conditions were well described by a family of exponential growth functions dependent upon stimulus intensity and by the parameters of normal criterion distributions dependent upon catch trial conditions and between-session variability. Performance in the auditory catch trial conditions was not dependent upon the same set of sensory growth functions. Performance in these conditions was described by a two-dimensional analysis of information transmitted as a function of time and interpreted in terms of variable criterion theory. The speed-accuracy tradeoff in this situation appears to depend upon differential rates of growth of intensity and associative information and the criterion used in responding to this information.