Are we failing clinical trials? A case for strong aggregate outcomes.

Clinical trials in psychiatry inherit methods for design and statistical analysis from evidence-based medicine. However, trials in other clinical disciplines benefit from a more specific relationship between instruments that measure disease state (e.g. biomarkers, clinical signs), the underlying pathology and diagnosis such that primary outcomes can be readily defined. Trials in psychiatry use diagnosis (i.e. a categorical label for a syndrome) as a proxy for the underlying disorder, and outcomes are defined, for example, as a percentage change in a univariate total score on some clinical instrument. We label this approach to defining outcomes weak aggregation of disease state. Univariate measures are necessary, because statistical methodology is both tractable and well-developed for scalar outcomes, but we show that weak aggregate approaches do not capture disease state sufficiently, potentially leading to loss of information about response to intervention. We demonstrate how multivariate disease state can be captured using geometric concepts of spaces defined over routine clinical instruments, and show how clinically meaningful disease states (e.g. representing different profiles of symptoms, recovery or remission) can be defined as prototypes (geometric locations) in these spaces. Then, we show how to derive univariate (scalar) measures, which capture patient's relationships to these prototypes and argue these represent strong aggregates of disease state that may be a better basis for outcome measures. We demonstrate our proposal using a large publically available dataset. We conclude by discussing the impact of strong aggregates for analyses in traditional and novel trial designs.

Examining belief and confidence in schizophrenia.

BACKGROUND: People with psychoses often report fixed, delusional beliefs that are sustained even in the presence of unequivocal contrary evidence. Such delusional beliefs are the result of integrating new and old evidence inappropriately in forming a cognitive model. We propose and test a cognitive model of belief formation using experimental data from an interactive 'Rock Paper Scissors' (RPS) game. METHOD: Participants (33 controls and 27 people with schizophrenia) played a competitive, time-pressured interactive two-player game (RPS). Participants' behavior was modeled by a generative computational model using leaky integrator and temporal difference methods. This model describes how new and old evidence is integrated to form a playing strategy to beat the opponent and to provide a mechanism for reporting confidence in one's playing strategy to win against the opponent. RESULTS: People with schizophrenia fail to appropriately model their opponent's play despite consistent (rather than random) patterns that can be exploited in the simulated opponent's play. This is manifest as a failure to weigh existing evidence appropriately against new evidence. Furthermore, participants with schizophrenia show a 'jumping to conclusions' (JTC) bias, reporting successful discovery of a winning strategy with insufficient evidence. CONCLUSIONS: The model presented suggests two tentative mechanisms in delusional belief formation: (i) one for modeling patterns in other's behavior, where people with schizophrenia fail to use old evidence appropriately, and (ii) a metacognitive mechanism for 'confidence' in such beliefs, where people with schizophrenia overweight recent reward history in deciding on the value of beliefs about the opponent.

Sexual quality of life in women who have undergone female genital mutilation: a case-control study.

OBJECTIVE: To investigate the sexual quality of life of women who have undergone female genital mutilation (FGM) and compare them with a similar group who has not undergone FGM. DESIGN: Case-control study. SETTING: A large central London teaching hospital. POPULATION: A total of 73 women who had undergone FGM and 37 control women, who had not undergone FGM but were from a similar cultural background where FGM is practiced. METHODS: The women completed a questionnaire containing the Sexual Quality of Life-Female (SQOL-F) questionnaire. MAIN OUTCOME MEASURES: SQOL-F score. RESULTS: Women who have undergone FGM of any type have a significantly lower (P < 0.001) overall SQOL-F score than control women (mean = 62.44, SD = 27.93 versus mean = 88.84, SD = 13.73). Women who were sexually active and had undergone FGM type III differed the most from sexually active controls (P < 0.05) in their SQOL-F score. Women who were sexually inactive but who had undergone FGM reported significantly lower overall SQOL-F scores (P = 0.015) than sexually inactive controls, but were not differentiated by type of FGM. CONCLUSION: FGM significantly reduces women's sexual quality of life, based on the results of the SQOL-F questionnaire.

An evoked auditory response fMRI study of the effects of rTMS on putative AVH pathways in healthy volunteers.

BACKGROUND: Auditory verbal hallucinations (AVH) are the most prevalent symptom in schizophrenia. They are associated with increased activation within the temporoparietal cortices and are refractory to pharmacological and psychological treatment in approximately 25% of patients. Low frequency repetitive transcranial magnetic stimulation (rTMS) over the temporoparietal cortex has been demonstrated to be effective in reducing AVH in some patients, although results have varied. The cortical mechanism by which rTMS exerts its effects remain unknown, although data from the motor system is suggestive of a local cortical inhibitory effect. We explored neuroimaging differences in healthy volunteers between application of a clinically utilized rTMS protocol and a sham rTMS equivalent when undertaking a prosodic auditory task. METHOD: Single-blind placebo controlled fMRI study of 24 healthy volunteers undertaking an auditory temporoparietal activation task, who received either right temporoparietal rTMS or sham RTMS. RESULTS: The main effect of group was bilateral inferior parietal deactivation following real rTMS. An interaction of group and task type showed deactivation during real rTMS in the right superior temporal gyrus (STG), left thalamus, left postcentral gyrus and cerebellum. However, the left parietal lobe showed an increase in activation following right sided real rTMS, but this increase was specific to a non-linguistic, tone-sequence task. CONCLUSION: rTMS does cause local inhibitory effects, not only in the underlying region of application, but also in functionally connected cortical regions. However, there is also a related, task dependent, increase in activation within selected cortical areas in the contralateral hemisphere; these are likely to reflect compensatory mechanisms, and such cortical activation may in some cases contribute to, or retard, some of the therapeutic effects seen with rTMS.

Kinematic cues in perceptual weight judgement and their origins in box lifting.

When accepting a parcel from another person, we are able to use information about that person's movement to estimate in advance the weight of the parcel, that is, to judge its weight from observed action. Perceptual weight judgment provides a powerful method to study our interpretation of other people's actions, but it is not known what sources of information are used in judging weight. We have manipulated full form videos to obtain precise control of the perceived kinematics of a box lifting action, and use this technique to explore the kinematic cues that affect weight judgment. We find that observers rely most on the duration of the lifting movement to judge weight, and make less use of the durations of the grasp phase, when the box is first gripped, or the place phase, when the box is put down. These findings can be compared to the kinematics of natural box lifting behaviour, where we find that the duration of the grasp component is the best predictor of true box weight. The lack of accord between the optimal cues predicted by the natural behaviour and the cues actually used in the perceptual task has implications for our understanding of action observation in terms of a motor simulation. The differences between perceptual and motor behaviour are evidence against a strong version of the motor simulation hypothesis.