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Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially(More)
OBJECTIVE Several groups have reported apparent association between month of birth and multiple sclerosis. We sought to test the extent to which such studies might be confounded by extraneous variables such as year and place of birth. METHODS Using national birth statistics from 2 continents, we assessed the evidence for seasonal variations in birth rate(More)
For most of us, the foundations of our understanding of genetics were laid by considering Mendelian diseases in which familial recurrence risks are high, and mutant alleles are both necessary and sufficient. One consequence of this deterministic teaching is that our conceptualization of genetics tends to be dominated by the notion that the genetic aspects(More)
Multi-arm multi-stage designs can improve the efficiency of the drug-development process by evaluating multiple experimental arms against a common control within one trial. This reduces the number of patients required compared to a series of trials testing each experimental arm separately against control. By allowing for multiple stages experimental(More)
Multistage designs allow considerable reductions in the expected sample size of a trial. When stopping for futility or efficacy is allowed at each stage, the expected sample size under different possible true treatment effects (δ) is of interest. The δ-minimax design is the one for which the maximum expected sample size is minimised amongst all designs that(More)
Two-stage designs are commonly used for Phase II trials. Optimal two-stage designs have the lowest expected sample size for a specific treatment effect, for example, the null value, but can perform poorly if the true treatment effect differs. Here we introduce a design for continuous treatment responses that minimizes the maximum expected sample size across(More)
Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as(More)
BACKGROUND Genome-wide association studies (GWAS) are a widely used study design for detecting genetic causes of complex diseases. Current studies provide good coverage of common causal SNPs, but not rare ones. A popular method to detect rare causal variants is haplotype testing. A disadvantage of this approach is that many parameters are estimated(More)
Traditionally, phase II cancer trials test a binary endpoint formed from a dichotomisation of the continuous change in tumour size. Directly testing the continuous endpoint provides considerable gains in power, although also results in several statistical issues. One such issue is when complete responses, i.e. complete tumour removal, are observed in(More)
Although genome-wide association studies (GWAS) have proven remarkably effective at identifying reliably associated genetic variants, the biology underlying these discoveries is rarely immediately apparent and in most cases seems bound to require extensive fine mapping and functional analysis before it is revealed. In this context, it is logical and(More)