Daniel J. Roberts

A Systematic Review of Economic Evaluations of Pharmacogenetic Testing for Prevention of Adverse Drug Reactions

BackgroundPharmacogenetics offers the potential to improve health outcomes by identifying individuals who are at greater risk of harm from certain medicines. Routine adoption of pharmacogenetic tests requires evidence of their cost effectiveness.ObjectiveThe present review aims to systematically review published economic evaluations of pharmacogenetic tests that aim to prevent or reduce the incidence of ADRs.MethodsWe conducted a systematic literature review of economic evaluations of pharmacogenetic tests aimed to reduce the incidence of adverse drug reactions. Literature was searched using Embase, MEDLINE and the NHS Economic Evaluation Database with search terms relating to pharmacogenetic testing, adverse drug reactions, economic evaluations and pharmaceuticals. Titles were screened independently by two reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts reviewed.ResultsWe identified 852 articles, of which 47 met the inclusion criteria. There was evidence supporting the cost effectiveness of testing for HLA-B*57:01 (prior to abacavir), HLA-B*15:02 and HLA-A*31:01 (prior to carbamazepine), HLA-B*58:01 (prior to allopurinol) and CYP2C19 (prior to clopidogrel treatment). Economic evidence was inconclusive with respect to TPMT (prior to 6-mercaptoputine, azathioprine and cisplatin therapy), CYP2C9 and VKORC1 (to inform genotype-guided dosing of coumarin derivatives), MTHFR (prior to methotrexate treatment) and factor V Leiden testing (prior to oral contraception). Testing for A1555G is not cost effective before prescribing aminoglycosides.ConclusionsOur systematic review identified robust evidence of the cost effectiveness of genotyping prior to treatment with a number of common drugs. However, further analyses and (or) availability of robust clinical evidence is necessary to make recommendations for others.

Lexical neighborhood effects in pseudoword spelling

The general aim of this study is to contribute to a better understanding of the cognitive processes that underpin skilled adult spelling. More specifically, it investigates the influence of lexical neighbors on pseudo-word spelling with the goal of providing a more detailed account of the interaction between lexical and sublexical sources of knowledge in spelling. In prior research examining this topic, adult participants typically heard lists composed of both words and pseudo-words and had to make a lexical decision to each stimulus before writing the pseudo-words. However, these priming paradigms are susceptible to strategic influence and may therefore not give a clear picture of the processes normally engaged in spelling unfamiliar words. In our two Experiments involving 71 French-speaking literate adults, only pseudo-words were presented which participants were simply requested to write to dictation using the first spelling that came to mind. Unbeknownst to participants, pseudo-words varied according to whether they did or did not have a phonological word neighbor. Results revealed that low-probability phoneme/grapheme mappings (e.g., /o/ -> aud in French) were used significantly more often in spelling pseudo-words with a close phonological lexical neighbor with that spelling (e.g., /krepo/ derived from “crapaud,” /krapo/) than in spelling pseudo-words with no close neighbors (e.g., /frøpo/). In addition, the strength of this lexical influence increased with the lexical frequency of the word neighbors as well as with their degree of phonetic overlap with the pseudo-word targets. These results indicate that information from lexical and sublexical processes is integrated in the course of spelling, and a specific theoretical account as to how such integration may occur is introduced.

Processing deficits for familiar and novel faces in patients with left posterior fusiform lesions

Pure alexia (PA) arises from damage to the left posterior fusiform gyrus (pFG) and the striking reading disorder that defines this condition has meant that such patients are often cited as evidence for the specialisation of this region to processing of written words. There is, however, an alternative view that suggests this region is devoted to processing of high acuity foveal input, which is particularly salient for complex visual stimuli like letter strings. Previous reports have highlighted disrupted processing of non-linguistic visual stimuli after damage to the left pFG, both for familiar and unfamiliar objects and also for novel faces. This study explored the nature of face processing deficits in patients with left pFG damage. Identification of famous faces was found to be compromised in both expressive and receptive tasks. Discrimination of novel faces was also impaired, particularly for those that varied in terms of second-order spacing information, and this deficit was most apparent for the patients with the more severe reading deficits. Interestingly, discrimination of faces that varied in terms of feature identity was considerably better in these patients and it was performance in this condition that was related to the size of the length effects shown in reading. This finding complements functional imaging studies showing left pFG activation for faces varying only in spacing and frontal activation for faces varying only on features. These results suggest that the sequential part-based processing strategy that promotes the length effect in the reading of these patients also allows them to discriminate between faces on the basis of feature identity, but processing of second-order configural information is most compromised due to their left pFG lesion. This study supports a view in which the left pFG is specialised for processing of high acuity foveal visual information that supports processing of both words and faces.

Human Parahippocampal Cortex Supports Spatial Binding in Visual Working Memory.

Abstract Studies investigating the functional organization of the medial temporal lobe (MTL) suggest that parahippocampal cortex (PHC) generates representations of spatial and contextual information used by the hippocampus in the formation of episodic memories. However, evidence from animal studies also implicates PHC in spatial binding of visual information held in short term, working memory. Here we examined a 46‐year‐old man (P.J.), after he had recovered from bilateral medial occipitotemporal cortex strokes resulting in ischemic lesions of PHC and hippocampal atrophy, and a group of age‐matched healthy controls. When recalling the color of 1 of 2 objects, P.J. misidentified the target when cued by its location, but not shape. When recalling the position of 1 of 3 objects, he frequently misidentified the target, which was cued by its color. Increasing the duration of the memory delay had no impact on the proportion of binding errors, but did significantly worsen recall precision in both P.J. and controls. We conclude that PHC may play a crucial role in spatial binding during encoding of visual information in working memory.

Impaired integration of object knowledge and visual input in a case of ventral simultanagnosia with bilateral damage to area V4

This study examines how brain damage can affect the cognitive processes that support the integration of sensory input and prior knowledge during shape perception. It is based on the first detailed study of acquired ventral simultanagnosia, which was found in a patient (M.T.) with posterior occipitotemporal lesions encompassing V4 bilaterally. Despite showing normal object recognition for single items in both accuracy and response times (RTs), and intact low-level vision assessed across an extensive battery of tests, M.T. was impaired in object identification with overlapping figures displays. Task performance was modulated by familiarity: Unlike controls, M.T. was faster with overlapping displays of abstract shapes than with overlapping displays of common objects. His performance with overlapping common object displays was also influenced by both the semantic relatedness and visual similarity of the display items. These findings challenge claims that visual perception is driven solely by feedforward mechanisms and show how brain damage can selectively impair high-level perceptual processes supporting the integration of stored knowledge and visual sensory input.