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OBJECTIVE: To investigate whether there are differential effects of disease activity and damage on physical functioning as measured by the Health Assessment Questionnaire (HAQ) over the course of psoriatic arthritis (PsA). METHODS: Between June 1993 and March 2005, 382 patients attending the University of Toronto PsA clinic had completed >/=2 HAQs on an annual basis. At the time of each HAQ assessment, clinical and laboratory measures of disease activity and damage were recorded. Generalized linear mixed-effects models were used to investigate the longitudinal relationship between disease activity, damage, and the HAQ score. To avoid floor effects that would arise in a single mixed-effects model, we adopted a 2-part model. RESULTS: The number of actively inflamed joints (measure of disease activity) and the number of clinically deformed joints (measure of damage) were positively and significantly related to the HAQ score. Furthermore, interaction terms for illness duration with the number of actively inflamed joints were statistically significant, with or without inclusion of the erythrocyte sedimentation rate and morning stiffness in the model (P = 0.029 and P < 0.001, respectively). The positive effects of actively inflamed joints on the level of the HAQ score decreased over increasing duration of PsA. There was less evidence to suggest that the positive effect of joint damage on the HAQ score increased over time. CONCLUSION: Our results support the view that the influence of disease activity on HAQ scores declines with increased disease duration. We could not demonstrate strong evidence that the effect of clinical damage increases over the course of illness. [ABSTRACT FROM AUTHOR]

The identification of sets of co-regulated genes that share a common function is a key question of modern genomics. Bayesian profile regression is a semi-supervised mixture modelling approach that makes use of a response to guide inference toward relevant clusterings. Previous applications of profile regression have considered univariate continuous, categorical, and count outcomes. In this work, we extend Bayesian profile regression to cases where the outcome is longitudinal (or multivariate continuous) and provide PReMiuMlongi, an updated version of PReMiuM, the R package for profile regression. We consider multivariate normal and Gaussian process regression response models and provide proof of principle applications to four simulation studies. The model is applied on budding yeast data to identify groups of genes co-regulated during the Saccharomyces cerevisiae cell cycle. We identify 4 distinct groups of genes associated with specific patterns of gene expression trajectories, along with the bound transcriptional factors, likely involved in their co-regulation process.

Background: Recruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings., Methods: We monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status., Results: A total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95-0.99]), high education (OR = 1.64 [1.23-2.17]), male sex (OR = 1.56 [1.19-2.04]), and positive family history of dementia (OR = 1.66 [1.19-2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02-1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81-4.94]). These results were similar across prescreen settings., Conclusions: Numbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD.

Background: Most reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome. The aims of this review were to assess the range of missing data rates in primary composite outcomes and to document the current practice for handling and reporting missing data in published RA trials compared to the Consolidated Standards of Reporting Trials (CONSORT) recommendations., Methods: A systematic search for randomised controlled trials was conducted for RA trials published between 2008 and 2013 in four rheumatology and four high impact general medical journals., Results: A total of 51 trials with a composite primary outcome were identified, of which 38 (75 %) used the binary American College of Rheumatology responder index and 13 (25 %) used the Disease Activity Score for 28 joints (DAS28). Forty-four trials (86 %) reported on an intention-to-treat analysis population, while 7 trials (14 %) analysed according to a modified intention-to-treat population. Missing data rates for the primary composite outcome ranged from 2-53 % and were above 30 % in 9 trials, 20-30 % in 11 trials, 10-20 % in 18 trials and below 10 % in 13 trials. Thirty-eight trials (75 %) used non-responder imputation and 10 (20 %) used last observation carried forward to impute missing composite outcome data at the primary time point. The rate of dropout was on average 61 % times higher in the placebo group compared to the treatment group in the 34 placebo controlled trials (relative rate 1.61, 95 % CI: 1.29, 2.02). Thirty-seven trials (73 %) did not report the use of sensitivity analyses to assess the handling of missing data in the primary analysis as recommended by CONSORT guidelines., Conclusions: This review highlights an improvement in rheumatology trial practice since the revision of CONSORT guidelines, in terms of power calculation and participant's flow diagram. However, there is a need to improve the handling and reporting of missing composite outcome data and their components in RA trials. In particular, sensitivity analyses need to be more widely used in RA trials because imputation is widespread and generally uses single imputation methods, and in this area the missing data rates are commonly differentially higher in the placebo group.

Objective: MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA., Methods: A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores)., Results: Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events., Conclusions: This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA. Trial registration. Current Controlled Trials, www.controlled-trials.com, ISRCTN:54376151.

Objective: To test the bidirectional hypothesis that depressive symptoms influence changes in pain over time, and pain influences changes in depressive symptoms., Methods: A total of 394 patients attending the University of Toronto Psoriatic Arthritis clinic were followed over a mean period of 7.5 years with annual assessments, including number of swollen joints (SJC), Health Assessment Questionnaire (HAQ), and the Medical Outcomes Survey Short Form 36 (SF-36). Linear mixed-effects models were used to examine the cross- and lagged associations between the changes in HAQ pain and in the SF-36 mental component summary (MCS) score, adjusting for SJC and other covariates., Results: The strongest predictors of changes in pain, SJC, and depressive symptoms between visits were scores of the corresponding variables at the previous visit, with standardized regression coefficients exceeding 0.75 in absolute value. There was, however, evidence of a small, but consequential, bidirectional relationship (i.e., standardized regression coefficients <0.3) between depressive symptoms and pain. Both previous MCS scores and change in MCS scores were associated with change in pain between visits; conversely, previous pain scores and change in pain scores were associated with change in depressive symptoms between visits., Conclusion: Even though cross-variable associations between pain and depressive symptoms exist, changes in pain and depressive symptoms appear to be strongly driven by their measurements at the previous visit. To optimize patient outcomes, a clinical approach that assesses and treats clinically significant depressive symptoms, as well as pain, is required., (Copyright © 2012 by the American College of Rheumatology.)

In psoriatic arthritis, permanent joint damage characterizes disease progression and represents a major debilitating aspect of the disease. Understanding the process of joint damage will assist in the treatment and disease management of patients. Multistate models provide a means to examine patterns of disease, such as symmetric joint damage. Additionally, the link between damage and the dynamic course of disease activity (represented by joint swelling and stress pain) at both the individual joint level and otherwise can be represented within a correlated multistate model framework. Correlation is reflected through the use of random effects for progressive models and robust variance estimation for non-progressive models. Such analyses, undertaken with data from a large psoriatic arthritis cohort, are discussed and the extent to which they permit causal reasoning is considered. For this, emphasis is given to the use of the Bradford Hill criteria for causation in observational studies and the concept of local (in)dependence to capture the dynamic nature of the relationships.

Objective: To assess the impact of the 2009 A/H1N1 influenza pandemic in England during the two waves of activity up to end of February 2010 by estimating the probabilities of cases leading to severe events and the proportion of the population infected., Design: A Bayesian evidence synthesis of all available relevant surveillance data in England to estimate severity of the pandemic., Data Sources: All available surveillance systems relevant to the pandemic 2009 A/H1N1 influenza outbreak in England from June 2009 to February 2010. Pre-existing influenza surveillance systems, including estimated numbers of symptomatic cases based on consultations to the health service for influenza-like illness and cross sectional population serological surveys, as well as systems set up in response to the pandemic, including follow-up of laboratory confirmed cases up to end of June 2009 (FF100 and Fluzone databases), retrospective and prospective follow-up of confirmed hospitalised cases, and reported deaths associated with pandemic 2009 A/H1N1 influenza. Main outcome measures Age specific and wave specific probabilities of infection and symptomatic infection resulting in hospitalisation, intensive care admission, and death, as well as infection attack rates (both symptomatic and total). The probabilities of intensive care admission and death given hospitalisation over time are also estimated to evaluate potential changes in severity across waves., Results: In the summer wave of A/H1N1 influenza, 0.54% (95% credible interval 0.33% to 0.82%) of the estimated 606,100 (419,300 to 886,300) symptomatic cases were hospitalised, 0.05% (0.03% to 0.08%) entered intensive care, and 0.015% (0.010% to 0.022%) died. These correspond to 3200 (2300 to 4700) hospital admissions, 310 (200 to 480) intensive care admissions, and 90 (80 to 110) deaths in the summer wave. In the second wave, 0.55% (0.28% to 0.89%) of the 1,352,000 (829,900 to 2,806,000) estimated symptomatic cases were hospitalised, 0.10% (0.05% to 0.16%) were admitted to intensive care, and 0.025% (0.013% to 0.040%) died. These correspond to 7500 (5900 to 9700) hospitalisations, 1340 (1030 to 1790) admissions to intensive care, and 240 (310 to 380) deaths. Just over a third (35% (26% to 45%)) of infections were estimated to be symptomatic. The estimated probabilities of infections resulting in severe events were therefore 0.19% (0.12% to 0.29%), 0.02% (0.01% to 0.03%), and 0.005% (0.004% to 0.008%) in the summer wave for hospitalisation, intensive care admission, and death respectively. The corresponding second wave probabilities are 0.19% (0.10% to 0.32%), 0.03% (0.02% to 0.06%), and 0.009% (0.004% to 0.014%). An estimated 30% (20% to 43%) of hospitalisations were detected in surveillance systems in the summer, compared with 20% (15% to 25%) in the second wave. Across the two waves, a mid-estimate of 11.2% (7.4% to 18.9%) of the population of England were infected, rising to 29.5% (16.9% to 64.1%) in 5-14 year olds. Sensitivity analyses to the evidence included suggest this infection attack rate could be as low as 5.9% (4.2% to 8.7%) or as high as 28.4% (26.0% to 30.8%). In terms of the probability that an infection leads to death in the second wave, these correspond, respectively, to a high estimate of 0.017% (0.011% to 0.024%) and a low estimate of 0.0027% (0.0024% to 0.0031%)., Conclusions: This study suggests a mild pandemic, characterised by case and infection severity ratios increasing between waves. Results suggest low ascertainment rates, highlighting the importance of systems enabling early robust estimation of severity, to inform optimal public health responses, particularly in light of the apparent resurgence of the 2009 A/H1N1 strain in the 2010-11 influenza season.

Characterization of the incubation time from infection to onset is important for understanding the natural history of infectious diseases. Attempts to estimate the incubation time distribution for novel A(H1N1v) have been, up to now, based on limited data or peculiar samples. We characterized this distribution for a generic group of symptomatic cases using laboratory-confirmed swine influenza case-information. Estimates of the incubation distribution for the pandemic influenza were derived through parametric time-to-event analyses of data on onset of symptoms and exposure dates, accounting for interval censoring. We estimated a mean of about 1·6-1·7 days with a standard deviation of 2 days for the incubation time distribution in those who became symptomatic after infection with the A(H1N1v) virus strain. Separate analyses for the <15 years and ≥ 15 years age groups showed a significant (P<0·02) difference with a longer mean incubation time in the older age group.

Semicontinuous data in the form of a mixture of zeros and continuously distributed positive values frequently arise in biomedical research. Two-part mixed models with correlated random effects are an attractive approach to characterize the complex structure of longitudinal semicontinuous data. In practice, however, an independence assumption about random effects in these models may often be made for convenience and computational feasibility. In this article, we show that bias can be induced for regression coefficients when random effects are truly correlated but misspecified as independent in a 2-part mixed model. Paralleling work on bias under nonignorable missingness within a shared parameter model, we derive and investigate the asymptotic bias in selected settings for misspecified 2-part mixed models. The performance of these models in practice is further evaluated using Monte Carlo simulations. Additionally, the potential bias is investigated when artificial zeros, due to left censoring from some detection or measuring limit, are incorporated. To illustrate, we fit different 2-part mixed models to the data from the University of Toronto Psoriatic Arthritis Clinic, the aim being to examine whether there are differential effects of disease activity and damage on physical functioning as measured by the health assessment questionnaire scores over the course of psoriatic arthritis. Some practical issues on variance component estimation revealed through this data analysis are considered.

Objective: To determine the prevalence and types of malignancy in a large cohort of patients with psoriatic arthritis (PsA), and to compare this rate with that in the general population., Methods: A cohort analysis of patients who were followed up prospectively from 1978 to 2004 at the University of Toronto Psoriatic Arthritis Clinic was performed. Patients were followed up at 6-12-month intervals according to a standard protocol, which included recording of malignancy, and tracked on a computer database. The cohort was linked with a provincial database to find malignancies that may have been missed by the protocol or developed after patients were lost to followup. Data were presented and analyzed using descriptive statistics and the Cox regression model with robust estimate of variance. Rates of first malignancy in the cohort were compared with rates in the population to derive standardized incidence ratios (SIRs)., Results: Of the 665 patients included, 68 (10.2%) developed a malignancy at an average age of 62.4 years. The most frequently seen malignancies were breast (20.6%), lung (13.2%), and prostate (8.8%) cancer. The SIR for all cancers was 0.98 (95% confidence interval 0.77-1.24). Overall cancer type-specific SIRs were 0.69 (95% CI 0.26-1.83) for hematologic and 0.88 (95% CI 0.46-1.69) for lung cancer. In females, the SIR for breast cancer was 1.55 (95% CI 0.92-2.62), and in males, the SIR for prostate cancer was 0.65 (95% CI 0.29-1.44)., Conclusion: Overall, 10.2% of patients in the Toronto PsA cohort developed cancer. The most frequent cancers were breast, lung, and prostate cancer. The incidence of malignancy in the large PsA cohort did not differ from that in the general population.

Objective: To determine whether there has been a change in mortality rates over the last 3 decades in patients with psoriatic arthritis (PsA) whose cases were followed prospectively., Methods: Patients receiving followup care according to a standard protocol at the University of Toronto PsA Clinic between 1978 and 2004 were included. Information on patient deaths was collected prospectively. Mortality data for the general population of Ontario, Canada, stratified by 5-year age bands, sex, and calendar year from 1978 to 2004, were used to calculate the reference rates. Standardized mortality ratios (SMRs) were calculated through use of Poisson regression models for the number of observed deaths. Time trend analyses were performed through the use of 10-year "rolling-average" SMRs and followup period-specific SMRs stratified by the period of entry into clinic., Results: Of 680 patients with PsA, 106 (15.6%) (55 women and 51 men) have died. Major causes of death were disease of the circulatory system, neoplasms, diseases of the respiratory system, diseases of the gastrointestinal system, injuries/poisoning, and unknown. The overall SMR for the period 1978-2004 was 1.36 (95% confidence interval 1.12, 1.64). The estimated number of life-years lost by the PsA patient cohort overall was 2.99 years (95% confidence interval 1.14, 4.77). For patients who entered the cohort during the years 1978-1986, the SMRs were 1.89, 1.83, and 1.21 for followup periods 1978-1986, 1987-1995, and 1996-2004, respectively. For patients who entered the cohort during the years 1987-1995, the SMRs were 0.55 and 0.82, while the SMR for those who entered during 1996-2004 was 0.56., Conclusion: The drop in SMRs in this PsA clinic population suggests that the mortality risk has improved over time. This improved survival may reflect disease severity at presentation in the earlier cohort as well as earlier diagnosis and more aggressive treatment in the more recent followup period.

Background: Evidence suggests the wide variation in platelet response within the population is genetically controlled. Unraveling the complex relationship between sequence variation and platelet phenotype requires accurate and reproducible measurement of platelet response., Objective: To develop a methodology suitable for measuring signaling pathway-specific platelet phenotype, to use this to measure platelet response in a large cohort, and to demonstrate the effect size of sequence variation in a relevant model gene., Methods: Three established platelet assays were evaluated: mobilization of [Ca(2+)](i), aggregometry and flow cytometry, each in response to adenosine 5'-diphosphate (ADP) or the glycoprotein (GP) VI-specific crosslinked collagen-related peptide (CRP). Flow cytometric measurement of fibrinogen binding and P-selectin expression in response to a single, intermediate dose of each agonist gave the best combination of reproducibility and inter-individual variability and was used to measure the platelet response in 506 healthy volunteers. Pathway specificity was ensured by blocking the main subsidiary signaling pathways., Results: Individuals were identified who were hypo- or hyper-responders for both pathways, or who had differential responses to the two agonists, or between outcomes. 89 individuals, retested three months later using the same methodology, showed high concordance between the two visits in all four assays (r(2) = 0.872, 0.868, 0.766 and 0.549); all subjects retaining their phenotype at recall. The effect of sequence variation at the GP6 locus accounted for approximately 35% of the variation in the CRP-XL response., Conclusion: Genotyping-phenotype association studies in a well-characterized, large cohort provides a powerful strategy to measure the effect of sequence variation in genes regulating the platelet response.

Background: A common feature of microarray experiments is the occurrence of missing gene expression data. These missing values occur for a variety of reasons, in particular, because of the filtering of poor quality spots and the removal of undefined values when a logarithmic transformation is applied to negative background-corrected intensities. The efficiency and power of an analysis performed can be substantially reduced by having an incomplete matrix of gene intensities. Additionally, most statistical methods require a complete intensity matrix. Furthermore, biases may be introduced into analyses through missing information on some genes. Thus methods for appropriately replacing (imputing) missing data and/or weighting poor quality spots are required., Results: We present a likelihood-based method for imputing missing data or weighting poor quality spots that requires a number of biological or technical replicates. This likelihood-based approach assumes that the data for a given spot arising from each channel of a two-dye (two-channel) cDNA microarray comparison experiment independently come from a three-component mixture distribution--the parameters of which are estimated through use of a constrained E-M algorithm. Posterior probabilities of belonging to each component of the mixture distributions are calculated and used to decide whether imputation is required. These posterior probabilities may also be used to construct quality weights that can down-weight poor quality spots in any analysis performed afterwards. The approach is illustrated using data obtained from an experiment to observe gene expression changes with 24 hr paclitaxel (Taxol) treatment on a human cervical cancer derived cell line (HeLa)., Conclusion: As the quality of microarray experiments affect downstream processes, it is important to have a reliable and automatic method of identifying poor quality spots and arrays. We propose a method of identifying poor quality spots, and suggest a method of repairing the arrays by either imputation or assigning quality weights to the spots. This repaired data set would be less biased and can be analysed using any of the appropriate statistical methods found in the microarray literature.

Motivation: It is widely acknowledged that microarray data are subject to high noise levels and results are often platform dependent. Therefore, microarray experiments should be replicated several times and in several laboratories before the results can be relied upon. To make the best use of such extensive datasets, methods for microarray data fusion are required. Ideally, the fused data should distil important aspects of the data while suppressing unwanted sources of variation and be amenable to further informal and formal methods of analysis. Also, the variability in the quality of experimentation should be taken into account., Results: We present such an approach to data fusion, based on multivariate regression. We apply our methodology to data from a previous study on cell-cycle control in Schizosaccharomyces pombe., Availability: The algorithm implemented in R is freely available from the authors on request.

Cluster of differentiation (CD) antigens are expressed on cells of myeloid and lymphoid lineages. As most disease processes involve immune system activation or suppression, these antigens offer unique opportunities for monitoring host responses. Immunophenotyping using limited numbers of CD antigens enables differentiation states of immune system cells to be determined. Extended phenotyping involving parallel measurement of multiple CD antigens may help identify expression pattern signatures associated with specific disease states. To explore this possibility we have made a CD monoclonal antibody array and scanner, enabling the parallel immunophenotyping of leukocyte cell suspensions in a single and rapid analysis. To demonstrate this approach, we used the specific example of patients infected with human immunodeficiency virus type-1 (HIV-1). An invariant HIV-induced CD antigen signature has been defined that is both robust and independent of clinical outcome, composed of a unique profile of CD antigen expression levels that are both increased and decreased relative to internal controls. The results indicate that HIV-induced changes in CD antigen expression are disease specific and independent of outcome. Their invariant nature indicates an irreversible component to retroviral infection and suggests the utility of CD antigen expression patterns in other disease settings.

Objective: To describe the longitudinal course of physical functioning in patients with psoriatic arthritis., Methods: Between June 1993 and June 2003, 341 patients attending the University of Toronto Psoriatic Arthritis Clinic completed 2 or more Health Assessment Questionnaires (HAQs). At the time of administration of each HAQ, patients were assigned to 1 of 3 physical functional disability states, based on their HAQ score. A Markov model that allowed for transitions to and from these 3 disability states was used to characterize the longitudinal course of physical functioning, as well as to identify factors for both progression and regression of disability., Results: Despite patient variability in the course of physical functioning, the following 3 longitudinal patterns were observed: 1) a stable state of disability throughout the entire study period, with 28%, 12%, and 6% of patients experiencing no, moderate, or severe disability, respectively; 2) a steady improvement or deterioration in disability over time (this pattern was observed in 27% of patients); and 3) a fluctuating state of disability, occurring in 27% of the patients. Sex, age, disease duration, number of actively inflamed joints, and number of deformed joints predicted transitions between disability states., Conclusion: Although 28% of patients appeared resistant to becoming disabled over the duration of this study, the remaining patients were observed either to experience enduring disability or to move between disability states.

Objective: To evaluate the impact of an ultrasound finding of a pseudo-sac (PS), a uterine sac without a double decidual ring or a yolk sac, on the management of cases with possible ectopic pregnancy., Design: A retrospective review of a series of cases., Setting: A general hospital., Patient(s): Seventy-seven patients who had a diagnostic laparoscopy over a period of 3 years for suspected ectopic pregnancy., Main Outcome Measure(s): A logistic regression analysis was conducted to evaluate the effect of the ultrasound finding of a PS on predicting a negative finding at laparoscopy., Result(s): The report of a PS is significantly associated with a false-positive diagnosis of ectopic pregnancy., Conclusion(s): A diagnosis of PS should not be interpreted as indicative of an ectopic pregnancy because radiological differentiation between an early intrauterine pregnancy failure and an ectopic pregnancy is not possible.

The response of the human endometrium to the ovarian hormones, estrogen and progesterone, has been the focus of decades of research. In order to understand this critical aspect of endometrial physiology, we undertook a genome-wide analysis of transcript abundance and changes in transcript level between normal endometrium in the proliferative and secretory phases of the menstrual cycle. A high-density, oligonucleotide gene array, comprising 60 000 gene targets, was used to define the gene expression profile of proliferative and secretory phase endometrium. Results from the arrays were verified using real-time PCR. The expression levels of 149 transcripts differed significantly between the two phases of the cycle determined by stringent range limits (99.99%), calculated using local variance values. These transcripts include previously documented steroidally responsive genes (such as placental protein 14 and stromelysin-3) and novel transcripts not previously linked to either endometrial physiology or steroid regulation (such as intestinal trefoil factor and a number of expressed sequence tags). Examination of the 5' promoter regions of these genes identified many putative estrogen and progesterone receptor DNA binding domains, suggesting a direct response of these genes to the ovarian hormones.

This three-part study investigated the reproducibility of natural head posture (NHP) using radiographs and photographs. In part 1, reproducibility of cephalograms 1 year after the introduction of NHP was investigated and found to be less favourable (Dahlberg coefficient of 2.99 degrees) than most other previous investigations. In order to minimize radiation exposure of patients, reproducibility of photographs and method agreement between photographs and cephalograms were investigated in part 2. Reproducibility of the two photographs was poor (2.71 degrees). However, method agreement between cephalograms and the photographs taken at the same time was good (1.39 degrees). Replacement of the radiographic method with the photographic method for assessing NHP reproducibility appeared justified. Changing the protocol for achieving NHP in part 3 of the study improved reproducibility substantially (1.41 degrees). Various statistical methods were used to assess reproducibility and method agreement. Bland and Altman's graphical representation was found to be the most appropriate for method agreement. The Dahlberg coefficient, commonly used to assess NHP repeatability/reproducibility, does not provide an extreme enough interval to allow a sufficient clinical assessment of a method to be undertaken, compared with the reproducibility coefficient. That is, the latter provides a 95 per cent range, compared with 52 per cent with Dahlberg.

Aim: A case of severe normal tension glaucoma is reported in a trumpet player, along with a study investigating the association between glaucoma and raised intrathoracic pressure, using measurements of pulsatile ocular blood flow (POBF)., Methods: Three patient groups were studied; normals (n = 34), untreated primary open angle glaucoma (POAG) (n = 20), and untreated normal tension glaucoma (NTG) (n = 22), with a total of 76 patients who underwent measurements of POBF using the OBF pneumotonometer at rest and while forcibly exhaling through a mouthpiece connected to a mercury manometer (30 mm Hg) (Valsalva manoeuvre)., Results: POBF fell during Valsalva in all groups with the greatest predictor being the resting value of POBF. There was no evidence of significant differences in the mean change in POBF occurring during the Valsalva manoeuvre for the three groups studied before or after adjusting for the sex, the resting POBF, and the resting IOP of the patients (p = 0.294 and p = 0.542, respectively). However, statistically significant associations were found between the change in POBF and sex (p = 0.049), resting POBF (p<0.0001) and resting IOP (p = 0.032). Males had a greater drop, on average, in POBF during Valsalva manoeuvre than females after adjusting for the other factors. Additionally, there was a significant difference in the mean change in IOP during Valsalva for the three groups (p = 0.002), with the difference occurring between the normal and POAG groups (p<0.005). The POAG group had, on average, a drop in IOP during Valsalva, while the other two groups had an increase in IOP. Also noted was a significant difference in the distributions of the risk factors among the three groups (p = 0.002)., Conclusions: This study demonstrates no difference between groups with respect to resting or Valsalva POBF, but does demonstrate a possible trend with respect to IOP, with a drop in IOP occurring during Valsalva in the POAG group. There is, however, much variability in the data left unexplained by our models. Thus, unfortunately, we cannot advise our trumpet player whether his NTG is directly related to his trumpet playing.

Background: Complementary DNA array analysis of gene expression has a potential application for clinical diagnosis of disease processes. However, accessibility, affordability, reproducibility of results, and management of the data generated remain issues of concern. Use of cDNA arrays tailored for studies of specific pathways, tissues, or disease states may render a cost- and time-effective method to define potential hallmark genotype alterations., Materials and Methods: We produced a 332-membered human cDNA array on nylon membranes tailored for studies of angiogenesis and tumorigenesis in reproductive disease. We tested the system for reproducibility using a novel statistical approach for analysis of array data and employed the arrays to investigate gene expression alterations in ovarian cancer., Results: Intra-assay analysis and removal of agreement outliers was shown to be a critical step prior to interpretation of cDNA array data. The system revealed highly reproducible results, with intermembrane coefficient of reproducibility of +/- 0.98. Comparison of placental and ovarian sample data confirmed expected differences in angiogenic profiles and tissue-specific markers, such as human placental lactogen (hPL). Analysis of expression profiles of five normal ovary and four poorly differentiated serous papillary ovarian adenocarcinoma samples revealed an overall increase in angiogenesis-related markers, including vascular endothelial growth factor (VEGF) and angiopoietin-1 in the diseased tissue. These were accompanied by increases in immune response mediators (e.g. HLA-DR, Ron), apoptotic and neoplastic markers (e.g. BAD protein, b-myb), and novel potential markers of ovarian cancer, such as cofilin, moesin, and neuron-restrictive silencer factor (REST) protein., Conclusions: In-house production of tailored cDNA arrays, coupled to comprehensive analysis of resulting hybridization profiles, provides an accessible, reliable, and highly effective method of applying array technology to study disease processes. In the ovary, abundance of specific tumor markers, increased macrophage recruitment mediators, a late-stage angiogenesis profile, and the presence of chemoresistance-related markers distinguished normal and advanced ovarian cancer tissue samples. Detection of such parallel changes in pathway- and tissue-specific markers may prove a hallmark ready for application in reproductive disease diagnostic and therapeutic developments.

Purpose: To determine whether the outcome of primary retinal reattachment surgery in a subregion is improved by surgery being performed in a specialist vitreoretinal unit (VRU)., Methods: A subregional, population-based, retrospective audit cycle of primary retinal reattachment surgery was conducted by independent investigators. The subregion was defined as the catchment area of a teaching hospital (TH) with a specialist VRU and three neighbouring district general hospitals (DGHs). During the initial audit period (January 1989 to December 1990), 142 cases were treated at all four hospitals: TH/VRU (83), DGH-A (15), DGH-B (13), and DGH-C (31). Policy changes after the initial audit led to primary retinal reattachment surgery being predominantly performed by the VRU. During the re-audit period (September 1995 to August 1997), 160 cases were treated at two hospitals: VRU (148) and DGH-C (12). The outcome measure employed was complete retinal reattachment after a single procedure with a minimum follow-up of 12 months., Results: The success rate for primary retinal reattachment surgery in the subregion improved from 76.1% to 88.8% (p = 0.006) following the policy changes. The success rate of the vitreoretinal specialists in the VRU (90%) was greater than the general ophthalmologists in the DGHs (ranging from 47% to 77%), despite case selection by the general ophthalmologists. The number of cases treated by the VRU increased by 156% in the 6.5 year interval between the two audits due to a widespread change in the model of care for primary retinal detachments (both within and outside the subregion). During the re-audit period, the VRU treated 348 primary retinal detachments (including referrals from outside the subregion), achieving a success rate of 86.8% with a single procedure and 97.4% with further surgery. This primary success rate included 35 cases (10%) treated by vitrectomy with silicone oil tamponade who did not undergo silicone oil removal., Conclusions: The outcome of primary retinal reattachment surgery can be improved if surgery is performed by a specialist VRU. It is suggested that the current standard for retinal reattachment with a single procedure should be set in the region of 85% to 90%. Changing the model of care so that primary retinal reattachment surgery is predominantly performed by a specialist VRU has important resource implications.