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1.  Sample size requirements to estimate key design parameters from external pilot randomised controlled trials: a simulation study 
Trials  2014;15:264.
External pilot or feasibility studies can be used to estimate key unknown parameters to inform the design of the definitive randomised controlled trial (RCT). However, there is little consensus on how large pilot studies need to be, and some suggest inflating estimates to adjust for the lack of precision when planning the definitive RCT.
We use a simulation approach to illustrate the sampling distribution of the standard deviation for continuous outcomes and the event rate for binary outcomes. We present the impact of increasing the pilot sample size on the precision and bias of these estimates, and predicted power under three realistic scenarios. We also illustrate the consequences of using a confidence interval argument to inflate estimates so the required power is achieved with a pre-specified level of confidence. We limit our attention to external pilot and feasibility studies prior to a two-parallel-balanced-group superiority RCT.
For normally distributed outcomes, the relative gain in precision of the pooled standard deviation (SDp) is less than 10% (for each five subjects added per group) once the total sample size is 70. For true proportions between 0.1 and 0.5, we find the gain in precision for each five subjects added to the pilot sample is less than 5% once the sample size is 60. Adjusting the required sample sizes for the imprecision in the pilot study estimates can result in excessively large definitive RCTs and also requires a pilot sample size of 60 to 90 for the true effect sizes considered here.
We recommend that an external pilot study has at least 70 measured subjects (35 per group) when estimating the SDp for a continuous outcome. If the event rate in an intervention group needs to be estimated by the pilot then a total of 60 to 100 subjects is required. Hence if the primary outcome is binary a total of at least 120 subjects (60 in each group) may be required in the pilot trial. It is very much more efficient to use a larger pilot study, than to guard against the lack of precision by using inflated estimates.
PMCID: PMC4227298  PMID: 24993581
sample size; feasibility studies; pilot studies; binary outcomes; continuous outcomes, RCTs
4.  The HubBLe trial: haemorrhoidal artery ligation (HAL) versus rubber band ligation (RBL) for haemorrhoids 
BMC Gastroenterology  2012;12:153.
Haemorrhoids (piles) are a very common condition seen in surgical clinics. After exclusion of more sinister causes of haemorrhoidal symptoms (rectal bleeding, perianal irritation and prolapse), the best option for treatment depends upon persistence and severity of the symptoms. Minor symptoms often respond to conservative treatment such as dietary fibre and reassurance. For more severe symptoms treatment such as rubber band ligation may be therapeutic and is a very commonly performed procedure in the surgical outpatient setting. Surgery is usually reserved for those who have more severe symptoms, as well as those who do not respond to non-operative therapy; surgical techniques include haemorrhoidectomy and haemorrhoidopexy. More recently, haemorrhoidal artery ligation has been introduced as a minimally invasive, non destructive surgical option.
There are substantial data in the literature concerning efficacy and safety of 'rubber band ligation including multiple comparisons with other interventions, though there are no studies comparing it to haemorrhoidal artery ligation. A recent overview has been carried out by the National Institute for Health and Clinical Excellence which concludes that current evidence shows haemorrhoidal artery ligation to be a safe alternative to haemorrhoidectomy and haemorrhoidopexy though it also highlights the lack of good quality data as evidence for the advantages of the technique.
The aim of this study is to establish the clinical effectiveness and cost effectiveness of haemorrhoidal artery ligation compared with conventional rubber band ligation in the treatment of people with symptomatic second or third degree (Grade II or Grade III) haemorrhoids.
Design: A multi-centre, parallel group randomised controlled trial.
Outcomes: The primary outcome is patient-reported symptom recurrence twelve months following the intervention. Secondary outcome measures relate to symptoms, complications, health resource use, health related quality of life and cost effectiveness following the intervention.
Participants: 350 patients with grade II or grade III haemorrhoids will be recruited in surgical departments in up to 14 NHS hospitals.
Randomisation: A multi-centre, parallel group randomised controlled trial. Block randomisation by centre will be used, with 175 participants randomised to each group.
The results of the research will help inform future practice for the treatment of grade II and III haemorrhoids.
Trial Registration
PMCID: PMC3503770  PMID: 23098097
Haemorrhoids; Rubber band ligation; Haemorrhoidal artery ligation; Surgical randomised controlled trial
Behavioral neuroscience  2012;126(2):314-324.
Despite the fact that acute cases of MS-related pure-tone hearing loss have been reported in the literature, consensus is lacking as to the chronic influences of MS on pure-tone thresholds. Most studies examining such influences have been limited by small sample sizes, lack of statistical comparisons between patients and controls, and confounding of the hearing measure with influences from sex and age. To date, associations between pure-tone thresholds and central MS-related brain lesions have not been assessed. In this study, pure-tone thresholds ranging from 0.5 kHz to 8 kHz were measured in 73 MS patients and 73 individually age- and gender-matched normal controls. In 63 MS patients, correlations were computed between the threshold values and MRI-determined lesion activity in 26 central brain regions. Although thresholds were strongly influenced by sex, age, and tonal frequency, no meaningful influences of MS were discerned. Moreover, no significant association between the threshold values and central MS-related lesion activity was evident in any brain region evaluated. This study, the largest on this topic to employ carefully matched control subjects and the sole study to assess relationships between auditory thresholds and central MS-related lesions, strongly suggests that (a) MS is not chronically associated with pure-tone hearing loss and (b) pure-tone thresholds are unrelated to MS lesion activity in higher brain regions. These findings, along with general reports from the literature, support the concept that when MS-related hearing threshold deficits are found, they are episodic and primarily dependent upon lesions within the eighth nerve or brainstem.
PMCID: PMC3478152  PMID: 22309444
multiple sclerosis; hearing; audition; pure-tone thresholds; psychophysics; magnetic resonance imaging
6.  A breast cancer risk haplotype in the caspase-8 gene 
Cancer research  2009;69(7):2724-2728.
Recent large-scale studies have been successful in identifying common, low penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional impact of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNPs) chosen to tag all common variation in the gene (tSNPs). We used a staged study design based on 3200 breast cancer and 3324 control subjects from the UK, Utah and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a 4-SNP haplotype that was significantly associated with breast cancer and superior to any other single or multi-locus combination (P=8.0×10−5), with a per allele odds ratio and 95% confidence interval [OR (95% CI)] of 1.30 (1.12, 1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate (FDR), q=0.044). As expected, this haplotype includes the D302H locus. Multi-center analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for re-sequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.
PMCID: PMC2730164  PMID: 19318553
Polymorphism; breast cancer; apoptosis; haplotype; association
7.  Data for Genetic Analysis Workshop (GAW) 15 Problem 2, genetic causes of rheumatoid arthritis and associated traits 
BMC Proceedings  2007;1(Suppl 1):S3.
For Genetic Analysis Workshop 15 Problem 2, we organized data from several ongoing studies designed to identify genetic and environmental risk factors for rheumatoid arthritis. Data were derived from the North American Rheumatoid Arthritis Consortium (NARAC), collaboration among Canadian researchers, the European Consortium on Rheumatoid Arthritis Families (ECRAF), and investigators from Manchester, England. All groups used a common standard for defining rheumatoid arthritis, but NARAC also further selected for a more severe phenotype in the probands. Genotyping and family structures for microsatellite-based linkage analysis were provided from all centers. In addition, all centers but ECRAF have genotyped families for linkage analysis using SNPs and these data were additionally provided. NARAC also had additional data from a dense genotyping analysis of a region of chromosome 18 and results from candidate gene studies, which were provided. Finally, smoking influences risk for rheumatoid arthritis, and data were provided from the NARAC study on this behavior as well as some additional phenotypes measuring severity. Several questions could be evaluated using the data that were provided. These include comparing linkage analysis using single-nucleotide polymorphisms versus microsatellites and identifying credible regions of linkage outside the HLA region on chromosome 6p13, which has been extensively documented; evaluating the joint effects of smoking with genetic factors; and identifying more homogenous subsets of families for whom genetic susceptibility might be stronger, so that linkage and association studies may be more efficiently conducted.
PMCID: PMC2367518  PMID: 18466527
8.  Fine mapping of genes within the IDDM8 region in rheumatoid arthritis 
The IDDM8 region on chromosome 6q27, first identified as a susceptibility locus for type 1 diabetes, has previously been linked and associated with rheumatoid arthritis (RA). The region contains a number of potential candidate genes, including programmed cell death 2 (PDCD2), the proteosome subunit beta type 1 (PSMB1), delta-like ligand 1 (DLL-1) and TATA box-binding protein (TBP) amongst others. The aim of this study was to fine map the IDDM8 region on chromosome 6q27, focusing on the genes in the region, to identify polymorphisms that may contribute to susceptibility to RA and potentially to other autoimmune diseases. Validated single nucleotide polymorphisms (SNPs; n = 65) were selected from public databases from the 330 kb region of IDDM8. These were genotyped using Sequenom MassArray genotyping technology in two datasets; the test dataset comprised 180 RA cases and 180 controls. We tested 50 SNPs for association with RA and any significant associations were genotyped in a second dataset of 174 RA cases and 192 controls, and the datasets were combined before analysis. Association analysis was performed by chi-square test implemented in Stata software and linkage disequilibrium and haplotype analysis was performed using Helix tree version 4.1. There was initial weak evidence of association, with RA, of a number of SNPs around the loc154449 putative gene and within the KIAA1838 gene; however, these associations were not significant in the combined dataset. Our study has failed to detect evidence of association with any of the known genes mapping to the IDDM8 locus with RA.
PMCID: PMC1779440  PMID: 16945141
9.  Will the real disease gene please stand up? 
BMC Genetics  2005;6(Suppl 1):S66.
A common dilemma arising in linkage studies of complex genetic diseases is the selection of positive signals, their follow-up with association studies and discrimination between true and false positive results. Several strategies for overcoming these issues have been devised. Using the Genetic Analysis Workshop 14 simulated dataset, we aimed to apply different analytical approaches and evaluate their performance in discerning real associations. We considered a) haplotype analyses, b) different methods adjusting for multiple testing, c) replication in a second dataset, and d) exhaustive genotyping of all markers in a sufficiently powered, large sample group. We found that haplotype-based analyses did not substantially improve over single-point analysis, although this may reflect the low levels of linkage disequilibrium simulated in the datasets provided. Multiple testing correction methods were in general found to be over-conservative. Replication of nominally positive results in a second dataset appears to be less stringent, resulting in the follow-up of false positives. Performing a comprehensive assay of all markers in a large, well-powered dataset appears to be the most effective strategy for complex disease gene identification.
PMCID: PMC1866716  PMID: 16451679
10.  In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype 
The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1–0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.
PMCID: PMC1526560  PMID: 16507114
11.  Linkage analysis of cross-sectional and longitudinally derived phenotypic measures to identify loci influencing blood pressure 
BMC Genetics  2003;4(Suppl 1):S26.
The design of appropriate strategies to analyze and interpret linkage results for complex human diseases constitutes a challenge. Parameters such as power, definition of phenotype, and replicability have to be taken into account in order to reach meaningful conclusions. Incorporating data on repeated phenotypic measures may increase the power to detect linkage but requires sophisticated analysis methods. Using the simulated Genetic Analysis Workshop 13 data set, we have estimated a variety of systolic blood pressure (SBP) phenotypic measures and examined their performance with respect to consistency among replicates and to true and false positive linkage signals.
The whole-genome scan conducted on a dichotomous hypertension phenotype indicated the involvement of few true loci with nominal significance and gave rise to a high rate of false positives. Analysis of a cross-sectional quantitative SBP measure performed better, although genome-wide significance was again not reached. Additional phenotypic measures were derived from the longitudinal data using random effects modelling for censored data with varying levels of covariate adjustment. These models provided evidence for significant linkage to most genes influencing SBP and produced few false positive results. Overall, replicability of results was poor for loci, representing weak effects.
Longitudinally derived phenotypes performed better than cross-sectional measures in linkage analyses. Bearing in mind the sample design and size of these data, linkage results that fail to replicate should not be dismissed; instead, different lines of evidence derived from complementary analysis methods should be combined to prioritize follow up.
PMCID: PMC1866461  PMID: 14975094
12.  Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis 
Arthritis and Rheumatism  2009;60(1):258-263.
Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease of childhood. Two well-established genetic factors known to contribute to JIA susceptibility, HLA and PTPN22, account for less than half of the genetic susceptibility to disease; therefore, additional genetic factors have yet to be identified. The purpose of this study was to perform a systematic search of the genome to identify novel susceptibility loci for JIA.
A genome-wide association study using Affymetrix GeneChip 100K arrays was performed in a discovery cohort (279 cases and 184 controls). Single-nucleotide polymorphisms (SNPs) showing the most significant differences between cases and controls were then genotyped in a validation sample of cases (n = 321) and controls, combined with control data from the 1958 UK birth cohort (n = 2,024). In one region in which association was confirmed, fine-mapping was performed (654 cases and 1,847 controls).
Of the 112 SNPs that were significantly associated with JIA in the discovery cohort, 6 SNPs were associated with JIA in the independent validation cohort. The most strongly associated SNP mapped to the HLA region, while the second strongest association was with a SNP within the VTCN1 gene. Fine-mapping of that gene was performed, and 10 SNPs were found to be associated with JIA.
This study is the first to successfully apply a SNP-based genome-wide association approach to the investigation of JIA. The replicated association with markers in the VTCN1 gene defined an additional susceptibility locus for JIA and implicates a novel pathway in the pathogenesis of this chronic disease of childhood.
PMCID: PMC3001111  PMID: 19116933
13.  Derivation and validation of a risk adjustment model for predicting seven day mortality in emergency medical admissions: mixed prospective and retrospective cohort study 
Objectives To derive and validate a risk adjustment model for predicting seven day mortality in emergency medical admissions, to test the value of including physiology and blood parameters, and to explore the constancy of the risk associated with each model variable across a range of settings.
Design Mixed prospective and retrospective cohort study.
Setting Nine acute hospitals (n=3 derivation, n=9 validation) and associated ambulance services in England, Australia, and Hong Kong.
Participants Adults with medical emergencies (n=5644 derivation, n=13 762 validation) who were alive and not in cardiac arrest when attended by an ambulance and either were admitted to hospital or died in the ambulance or emergency department.
Interventions Data were either collected prospectively or retrospectively from routine sources and extraction from ambulance and emergency department records.
Main outcome measure Mortality up to seven days after hospital admission.
Results In the derivation phase, age, ICD-10 code, active malignancy, Glasgow coma score, respiratory rate, peripheral oxygen saturation, temperature, white cell count, and potassium and urea concentrations were independent predictors of seven day mortality. A model based on age and ICD-10 code alone had a C statistic of 0.80 (95% confidence interval 0.78 to 0.83), which increased to 0.81 (0.79 to 0.84) with the addition of active malignancy. This was markedly improved only when physiological variables (C statistic 0.87, 0.85 to 0.89), blood variables (0.87, 0.84 to 0.89), or both (0.90, 0.88 to 0.92) were added. In the validation phase, the models with physiology variables (physiology model) and all variables (full model) were tested in nine hospitals. Overall, the C statistics ranged across centres from 0.80 to 0.91 for the physiology model and from 0.83 to 0.93 for the full model. The rank order of hospitals based on adjusted mortality differed markedly from the rank order based on crude mortality. ICD-10 code, Glasgow coma score, respiratory rate, systolic blood pressure, oxygen saturation, haemoglobin concentration, white cell count, and potassium, urea, creatinine, and glucose concentrations all had statistically significant interactions with hospital.
Conclusion A risk adjustment model for emergency medical admissions based on age, ICD-10 code, active malignancy, and routinely recorded physiological and blood variables can provide excellent discriminant value for seven day mortality across a range of settings. Using risk adjustment markedly changed hospitals’ rankings. However, evidence was found that the association between key model variables and mortality were not constant.
Supplementary data appendix
PMCID: PMC3341268  PMID: 22550349

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