Sources of Uncertainty and Their Association with Medical Decision Making: Exploring Mechanisms in Fanconi Anemia

Background

Effects of different sources of medical uncertainty on people’s health-related cognitions, emotions, and decision making have yet to be systematically examined.

Purpose

The aim of this study is to examine how uncertainties arising from different sources are associated with decision making regarding stem cell transplantation in Fanconi anemia, a rare, inherited bone marrow failure syndrome that typically presents during childhood.

Methods

Data were collected through a cross-sectional survey of 178 parents of 126 Fanconi anemia patients.

Results

Two distinct sources of uncertainty were associated with decision outcomes: probability was associated with a lower likelihood of choosing stem cell transplantation, and ambiguity due to conflicting expert opinions was associated with greater decision-making difficulty. Concern about transplantation may mediate these associations.

Conclusions

Different sources of uncertainty have different effects on Fanconi anemia treatment decisions, which may be mediated by parents’ emotional reactions. Further research is needed to elucidate these effects and help Fanconi anemia families cope with uncertainty.     

Analysis of CYP2D6 genotype and response to tetrabenazine

Tetrabenazine is effective in the treatment of the chorea associated with Huntington disease and other hyperkinetic movement disorders. Following oral administration, tetrabenazine is hepatically transformed into 2 active metabolites that are CYP2D6 substrates. There are 4 CYP2D6 genotypes: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. CYP2D6 genotyping was performed on sequential subjects treated with tetrabenazine, but results were not known at the time of titration. Duration of titration to a stable dose, total daily dose, response rating scores, and adverse events were retrospectively collected and subsequently analyzed. Of 127 patients, the majority (n = 100) were categorized as extensive metabolizers, 14 as intermediate metabolizers, 11 as poor metabolizers, and 2 as ultrarapid metabolizers. Ultrarapid metabolizer patients needed a longer titration (8 vs 3.3, 4.4, and 3 weeks, respectively; P < .01) to achieve optimal benefit and required a higher average daily dose than the other patients, but this difference did not reach statistical significance. The treatment response was less robust in the intermediate metabolizer group when compared with the extensive metabolizer patients (P = .013), but there were no statistically significant differences between the various groups with regard to adverse effects. Our findings demonstrate that, aside from the need for a longer titration in the ultrarapid metabolizers, there are no distinguishing features of patients with various CYP2D6 genotypes, and therefore the current recommendation to systematically genotype all patients prescribed more than 50 mg/day of tetrabenazine should be reconsidered. © 2012 Movement Disorder Society     

Which dyskinesia scale best detects treatment response?

Numerous scales assess dyskinesia in Parkinson's disease (PD), variably focusing on anatomical distribution, phenomenology, time, severity, and disability. No study has compared these scales and their relative ability to detect change related to an established treatment. We conducted a randomized placebo‐controlled trial of amantadine, assessing dyskinesia at baseline and at 4 and 8 weeks using the following scales: Unified Dyskinesia Rating Scale (UDysRS), Lang‐Fahn Activities of Daily Living Dyskinesia Rating Scale (LF), 26‐Item Parkinson's Disease Dyskinesia scale (PDD‐26), patient diaries, modified Abnormal Involuntary Movements Scale (AIMS), Rush Dyskinesia Rating Scale (RDRS), dyskinesia items from the Movement Disorder Society–sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), and Clinical Global Impression (severity and change: CGI‐S, CGI‐C). Scale order was randomized at each visit, but raters were aware of each scale as it was administered. Sensitivity to treatment was assessed using effect size. Sixty‐one randomized dyskinetic PD subjects (31 amantadine, 30 placebo) completed the study. Four of the 8 scales (CGI‐C, LF, PDD‐26, and UDysRS) detected a significant treatment. The UDysRS Total Score showed the highest effect size (η² = 0.138) for detecting treatment‐related change, with all other scales having effect sizes < 0.1. No scale was resistant to placebo effects. This study resolves 2 major issues useful for future testing of new antidyskinesia treatments: among tested scales, the UDysRS, having both subjective and objective dyskinesia ratings, is superior for detecting treatment effects; and the magnitude of the UDysRS effect size from amantadine sets a clear standard for comparison for new agents. © 2012 Movement Disorder Society