Performance Evaluation of Interim Analysis in Bioequivalence Studies.

Under current bioequivalence guidelines in Japan, it is mandatory to establish bioequivalence using a single pivotal study. Clinical trials with limited resources usually have a pre-defined maximum permissible number of participants. In this manuscript, we considered a trial design that would allow for bioequivalence evaluation at an interim analysis in which the total number of participants takes into account the resource constraints. Then, available options at the interim analysis are group sequential designs and adaptive designs, A comparison of the performance of the two methods under same maximum participant number has not been conducted thus far. So we examined which method should be used by conducting a simulation study. Since bioequivalence is expected to be achieved at the interim analysis, a study design using a Pocock-type alpha spending function is preferrable. Simulation results using a Pocock-type alpha spending function showed similar performance between group sequential and adaptive designs. Consequently, due to statistical and operational complexity, it is preferable to choose group sequential designs for bioequivalence study in Japan.

Advancing clinical trial design in pulmonary hypertension.

In pulmonary hypertension, as in many other diseases, there is a need for a smarter approach to evaluating new treatments. The traditional randomized controlled trial has served medical science well, but constrains the development of treatments for rare diseases. A workshop was established to consider alternative clinical trial designs in pulmonary hypertension and here discusses their merits, limitations and challenges to implementation of novel approaches.

Fracture risk with use of liver enzyme inducing antiepileptic drugs in people with active epilepsy: cohort study using the general practice research database.

PURPOSE: Liver enzyme inducing antiepileptic drugs (LEI AEDs) have adverse effects on bone metabolism but it is unclear whether this translates into increased fracture risk. This population based cohort study aimed to evaluate whether treatment with LEI AEDs is associated with increased risk of fracture in people with active epilepsy. METHODS: The cohort included patients diagnosed with epilepsy and prescribed AEDs while registered at a GPRD general practice during 1993-2008. The hazard ratio with current use of LEI AEDs for fracture at any site and hip fracture was estimated using Cox proportional hazards models. RESULTS: There were 7356 fractures (788 hip fractures) in 63259 participants. In women, the adjusted hazard ratio with use of LEI AEDs was 1.22 for fracture (95% CI 1.12-1.34; p<0.001) and 1.49 for hip fracture (1.15-1.94; p=0.002). In men, the hazard ratio for fracture was 1.09 (0.98-1.20; p=0.123) and for hip fracture 1.53 (1.10-2.12; p=0.011). For every 10000 women treated with LEI AEDs for one year, there could be 48 additional fractures, including 10 additional hip fractures. For every 10000 men treated with LEI AEDs for one year, there could be 4 additional hip fractures. CONCLUSIONS: LEI AEDs may increase the risk of fracture in people with epilepsy. In patients at high risk of osteoporotic fracture alternative AED therapy may be appropriate. Further information is urgently needed on the safety of valproate and newer AEDs and on strategies to maintain bone health in people who need to be treated with LEI.

Potential application of item-response theory to interpretation of medical codes in electronic patient records.

BACKGROUND: Electronic patient records are generally coded using extensive sets of codes but the significance of the utilisation of individual codes may be unclear. Item response theory (IRT) models are used to characterise the psychometric properties of items included in tests and questionnaires. This study asked whether the properties of medical codes in electronic patient records may be characterised through the application of item response theory models. METHODS: Data were provided by a cohort of 47,845 participants from 414 family practices in the UK General Practice Research Database (GPRD) with a first stroke between 1997 and 2006. Each eligible stroke code, out of a set of 202 OXMIS and Read codes, was coded as either recorded or not recorded for each participant. A two parameter IRT model was fitted using marginal maximum likelihood estimation. Estimated parameters from the model were considered to characterise each code with respect to the latent trait of stroke diagnosis. The location parameter is referred to as a calibration parameter, while the slope parameter is referred to as a discrimination parameter. RESULTS: There were 79,874 stroke code occurrences available for analysis. Utilisation of codes varied between family practices with intraclass correlation coefficients of up to 0.25 for the most frequently used codes. IRT analyses were restricted to 110 Read codes. Calibration and discrimination parameters were estimated for 77 (70%) codes that were endorsed for 1,942 stroke patients. Parameters were not estimated for the remaining more frequently used codes. Discrimination parameter values ranged from 0.67 to 2.78, while calibration parameters values ranged from 4.47 to 11.58. The two parameter model gave a better fit to the data than either the one- or three-parameter models. However, high chi-square values for about a fifth of the stroke codes were suggestive of poor item fit. CONCLUSION: The application of item response theory models to coded electronic patient records might potentially contribute to identifying medical codes that offer poor discrimination or low calibration. This might indicate the need for improved coding sets or a requirement for improved clinical coding practice. However, in this study estimates were only obtained for a small proportion of participants and there was some evidence of poor model fit. There was also evidence of variation in the utilisation of codes between family practices raising the possibility that, in practice, properties of codes may vary for different coders.

Estimates of outcomes up to ten years after stroke: analysis from the prospective South London Stroke Register.

BACKGROUND: Although stroke is acknowledged as a long-term condition, population estimates of outcomes longer term are lacking. Such estimates would be useful for planning health services and developing research that might ultimately improve outcomes. This burden of disease study provides population-based estimates of outcomes with a focus on disability, cognition, and psychological outcomes up to 10 y after initial stroke event in a multi-ethnic European population. METHODS AND FINDINGS: Data were collected from the population-based South London Stroke Register, a prospective population-based register documenting all first in a lifetime strokes since 1 January 1995 in a multi-ethnic inner city population. The outcomes assessed are reported as estimates of need and included disability (Barthel Index <15), inactivity (Frenchay Activities Index <15), cognitive impairment (Abbreviated Mental Test < 8 or Mini-Mental State Exam <24), anxiety and depression (Hospital Anxiety and Depression Scale >10), and mental and physical domain scores of the Medical Outcomes Study 12-item short form (SF-12) health survey. Estimates were stratified by age, gender, and ethnicity, and age-adjusted using the standard European population. Plots of outcome estimates over time were constructed to examine temporal trends and sociodemographic differences. Between 1995 and 2006, 3,373 first-ever strokes were registered: 20%-30% of survivors had a poor outcome over 10 y of follow-up. The highest rate of disability was observed 7 d after stroke and remained at around 110 per 1,000 stroke survivors from 3 mo to 10 y. Rates of inactivity and cognitive impairment both declined up to 1 y (280/1,000 and 180/1,000 survivors, respectively); thereafter rates of inactivity remained stable till year eight, then increased, whereas rates of cognitive impairment fluctuated till year eight, then increased. Anxiety and depression showed some fluctuation over time, with a rate of 350 and 310 per 1,000 stroke survivors, respectively. SF-12 scores showed little variation from 3 mo to 10 y after stroke. Inactivity was higher in males at all time points, and in white compared to black stroke survivors, although black survivors reported better outcomes in the SF-12 physical domain. No other major differences were observed by gender or ethnicity. Increased age was associated with higher rates of disability, inactivity, and cognitive impairment. CONCLUSIONS: Between 20% and 30% of stroke survivors have a poor range of outcomes up to 10 y after stroke. Such epidemiological data demonstrate the sociodemographic groups that are most affected longer term and should be used to develop longer term management strategies that reduce the significant poor outcomes of this group, for whom effective interventions are currently elusive. Please see later in the article for the Editors' Summary.

Parental assessment of adolescent quality of life: can it replace self-assessment?

PURPOSE: (a) To compare the agreement between adolescent assessments of their quality of life (QoL) and that of their mothers; (b) to explore how the comparison is influenced by the method of analysis. METHODS: Forty-nine adolescents aged 12-18 years who received liver transplants, and their mothers completed the Child Health Questionnaire self (CF87) and parent (PF50) report. RESULTS: There was wide variation in agreement between adolescent and parent responses depending on the method of analysis used. Analysis with t test showed no differences in physical function (t = 1.42, P = 0.16), role/social-physical (t = 0.07, P = 0.94), mental health (t = 0.55, P = 0.59) and family activities (t = -0.40, P = 0.69). Using Pearson correlation coefficients, there were significant correlations in every domain; however, there were no intraclass correlation or concordance correlation coefficients ≥0.80 suggesting less than strong agreement. Finally, the Bland-Altman comparison indicated wide variation in the 95% limits of agreement ranging from -46 to 58.5. CONCLUSIONS: There was considerable inconsistency in agreement according to the methods of analysis. The wide variation in scores between adolescent and parent assessment of QoL suggests self rather than proxy report should be used as the primary outcome where possible.

Ethnic group disparities in 10-year trends in stroke incidence and vascular risk factors: the South London Stroke Register (SLSR).

BACKGROUND AND PURPOSE: Data monitoring trends in stroke risk among different ethnic groups are lacking. Thus, we investigated trends in stroke incidence and modifiable stroke risk factors over a 10-year time period between different ethnic groups. METHODS: Changes in stroke incidence were investigated with the South London Stroke Register (SLSR). The SLSR is a population-based stroke register, covering a multiethnic population of 271 817 inhabitants in South London with 63% white, 28% black, and 9% of other ethnic group (2001 Census). RESULTS: Between 1995 and 2004, 2874 patients with first-ever stroke of all age groups were included. Total stroke incidence decreased over the 10-year study period in men (incidence rate ratio 1995 to 1996 versus 2003 to 2004 [IRR] 0.82, 95% CI 0.69 to 0.97) and in women (IRR 0.76, 95% CI 0.64 to 0.90). A similar decline in total stroke incidence could be observed in whites for men and women (IRR 0.76, 95% CI 0.62 to 0.93 versus IRR 0.73, 95% CI 0.59 to 0.89, respectively); in blacks, total stroke incidence was reducing only in women (IRR 0.48, 95% CI 0.31 to 0.75). In whites, the prevalence of prior-to-stroke hypertension (P=0.0017), atrial fibrillation (P=0.0113), and smoking (P=0.0177) decreased; no statistically significant changes in prior-to-stroke risk factors were observed in blacks. Total stroke incidence was higher in blacks compared to whites (IRR 1.27, 95% CI 1.10 to 1.46 in men; IRR 1.29, 95% CI 1.11 to 1.50 in women), but the black-white gap reduced during the 10-year time period (IRR 1.43, 95% CI 1.13 to 1.82 in 1995 to 1996 to 1.18, 95% CI 0.93 to 1.49 in 2003 to 2004). CONCLUSIONS: Stroke incidence decreased over a 10-year time period. The greatest decline in incidence was observed in black women, but ethnic group disparities still exist, indicating a higher stroke risk in black people compared to white people. Advances in risk factor reduction observed in the white population were failed transferring to the black population.