Interim recruitment prediction for multi-center clinical trials.

We introduce a general framework for monitoring, modeling, and predicting the recruitment to multi-center clinical trials. The work is motivated by overly optimistic and narrow prediction intervals produced by existing time-homogeneous recruitment models for multi-center recruitment. We first present two tests for detection of decay in recruitment rates, together with a power study. We then introduce a model based on the inhomogeneous Poisson process with monotonically decaying intensity, motivated by recruitment trends observed in oncology trials. The general form of the model permits adaptation to any parametric curve-shape. A general method for constructing sensible parameter priors is provided and Bayesian model averaging is used for making predictions which account for the uncertainty in both the parameters and the model. The validity of the method and its robustness to misspecification are tested using simulated datasets. The new methodology is then applied to oncology trial data, where we make interim accrual predictions, comparing them to those obtained by existing methods, and indicate where unexpected changes in the accrual pattern occur.

Recruitment prediction for multicenter clinical trials based on a hierarchical Poisson-gamma model: Asymptotic analysis and improved intervals.

We analyze predictions of future recruitment to a multicenter clinical trial based on a maximum-likelihood fitting of a commonly used hierarchical Poisson-gamma model for recruitments at individual centers. We consider the asymptotic accuracy of quantile predictions in the limit as the number of recruitment centers grows large and find that, in an important sense, the accuracy of the quantiles does not improve as the number of centers increases. When predicting the number of further recruits in an additional time period, the accuracy degrades as the ratio of the additional time to the census time increases, whereas when predicting the amount of additional time to recruit a further n•+$n^+_\bullet$ patients, the accuracy degrades as the ratio of n•+$n^+_\bullet$ to the number recruited up to the census period increases. Our analysis suggests an improved quantile predictor. Simulation studies verify that the predicted pattern holds for typical recruitment scenarios in clinical trials and verify the much improved coverage properties of prediction intervals obtained from our quantile predictor. In the process of extending the applicability of our methodology, we show that in terms of the accuracy of all integer moments it is always better to approximate the sum of independent gamma random variables by a single gamma random variable matched on the first two moments than by the moment-matched Gaussian available from the central limit theorem.

Direct statistical inference for finite Markov jump processes via the matrix exponential.

Given noisy, partial observations of a time-homogeneous, finite-statespace Markov chain, conceptually simple, direct statistical inference is available, in theory, via its rate matrix, or infinitesimal generator, Q , since exp ( Q t ) is the transition matrix over time t. However, perhaps because of inadequate tools for matrix exponentiation in programming languages commonly used amongst statisticians or a belief that the necessary calculations are prohibitively expensive, statistical inference for continuous-time Markov chains with a large but finite state space is typically conducted via particle MCMC or other relatively complex inference schemes. When, as in many applications Q arises from a reaction network, it is usually sparse. We describe variations on known algorithms which allow fast, robust and accurate evaluation of the product of a non-negative vector with the exponential of a large, sparse rate matrix. Our implementation uses relatively recently developed, efficient, linear algebra tools that take advantage of such sparsity. We demonstrate the straightforward statistical application of the key algorithm on a model for the mixing of two alleles in a population and on the Susceptible-Infectious-Removed epidemic model.

Prevalence of HIV infection and acceptability of point-of-care testing in a Canadian inner-city emergency department.

OBJECTIVES: The objective of this study was to estimate the seroprevalence of HIV infection and the acceptability of point-of-care HIV testing in an innercity Canadian emergency department. METHODS: We conducted a prospective cohort study in an urban tertiary care emergency department between August 2009 and January 2011. Randomly selected patients were enrolled using probabilistic sampling based on patient volumes. Inclusion criteria were age 19-75 years and ability to provide informed consent. Patients who were intoxicated or in extremis were excluded. After informed consent and brief pre-test counselling, participants' HIV status was obtained using the INSTI HIV-1/HIV-2 Antibody Test. Participants completed a questionnaire on HIV risk behaviours and satisfaction with emergency department HIV testing. Participants with a positive result or those having other blood tests received confirmatory Western blot testing. HIV-positive participants were offered immediate referral to an HIV specialty clinic. RESULTS: A total of 2,077 patients were approached, and 1,402 (67.5%) agreed to participate. Participants' mean age was 43.3 years, and 58.4% of participants were male. The HIV antibody seroprevalence based on the point-of-care test was 65/1,402 (4.6%; 95% confidence interval: 3.5%-5.8%). No new diagnoses of HIV were identified in our cohort. Patient satisfaction with point-of-care HIV testing was high (mean satisfaction score 9.6/10). CONCLUSION: On the basis of a rapid, point-of-care HIV antibody test, the seroprevalence rate of HIV in an inner city emergency department was 4.6%. Point-of-care testing in the emergency department is acceptable, and patients' satisfaction with the testing procedure was high.

Idiopathic focal eosinophilic enteritis (IFEE), an emerging cause of abdominal pain in horses: the effect of age, time and geographical location on risk.

BACKGROUND: Idiopathic focal eosinophilic enteritis (IFEE) is an emerging cause of abdominal pain (colic) in horses that frequently requires surgical intervention to prevent death. The epidemiology of IFEE is poorly understood and it is difficult to diagnose pre-operatively. The aetiology of this condition and methods of possible prevention are currently unknown. The aims of this study were to investigate temporal and spatial heterogeneity in IFEE risk and to ascertain the effect of horse age on risk. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective, nested case-control study was undertaken using data from 85 IFEE cases and 848 randomly selected controls admitted to a UK equine hospital for exploratory laparotomy to investigate the cause of colic over a 10-year period. Generalised additive models (GAMs) were used to quantify temporal and age effects on the odds of IFEE and to provide mapped estimates of 'residual' risk over the study region. The relative risk of IFEE increased over the study period (p = 0.001) and a seasonal pattern was evident (p<0.01) with greatest risk of IFEE being identified between the months of July and November. IFEE risk decreased with increasing age (p<0.001) with younger (0-5 years old) horses being at greatest risk. The mapped surface estimate exhibited significantly atypical sub-regions (p<0.001) with increased IFEE risk in horses residing in the North-West of the study region. CONCLUSIONS/SIGNIFICANCE: IFEE was found to exhibit both spatial and temporal variation in risk and is more likely to occur in younger horses. This information may help to identify horses at increased risk of IFEE, provide clues about the aetiology of this condition and to identify areas that require further research.

Inference for reaction networks using the linear noise approximation.

We consider inference for the reaction rates in discretely observed networks such as those found in models for systems biology, population ecology, and epidemics. Most such networks are neither slow enough nor small enough for inference via the true state-dependent Markov jump process to be feasible. Typically, inference is conducted by approximating the dynamics through an ordinary differential equation (ODE) or a stochastic differential equation (SDE). The former ignores the stochasticity in the true model and can lead to inaccurate inferences. The latter is more accurate but is harder to implement as the transition density of the SDE model is generally unknown. The linear noise approximation (LNA) arises from a first-order Taylor expansion of the approximating SDE about a deterministic solution and can be viewed as a compromise between the ODE and SDE models. It is a stochastic model, but discrete time transition probabilities for the LNA are available through the solution of a series of ordinary differential equations. We describe how a restarting LNA can be efficiently used to perform inference for a general class of reaction networks; evaluate the accuracy of such an approach; and show how and when this approach is either statistically or computationally more efficient than ODE or SDE methods. We apply the LNA to analyze Google Flu Trends data from the North and South Islands of New Zealand, and are able to obtain more accurate short-term forecasts of new flu cases than another recently proposed method, although at a greater computational cost.

A coupled hidden Markov model for disease interactions.

To investigate interactions between parasite species in a host, a population of field voles was studied longitudinally, with presence or absence of six different parasites measured repeatedly. Although trapping sessions were regular, a different set of voles was caught at each session, leading to incomplete profiles for all subjects. We use a discrete time hidden Markov model for each disease with transition probabilities dependent on covariates via a set of logistic regressions. For each disease the hidden states for each of the other diseases at a given time point form part of the covariate set for the Markov transition probabilities from that time point. This allows us to gauge the influence of each parasite species on the transition probabilities for each of the other parasite species. Inference is performed via a Gibbs sampler, which cycles through each of the diseases, first using an adaptive Metropolis-Hastings step to sample from the conditional posterior of the covariate parameters for that particular disease given the hidden states for all other diseases and then sampling from the hidden states for that disease given the parameters. We find evidence for interactions between several pairs of parasites and of an acquired immune response for two of the parasites.

Hormonal regulation of the humoral innate immune response in Drosophila melanogaster.

Juvenile hormone (JH) and 20-hydroxy-ecdysone (20E) are highly versatile hormones, coordinating development, growth, reproduction and aging in insects. Pulses of 20E provide key signals for initiating developmental and physiological transitions, while JH promotes or inhibits these signals in a stage-specific manner. Previous evidence suggests that JH and 20E might modulate innate immunity, but whether and how these hormones interact to regulate the immune response remains unclear. Here we show that JH and 20E have antagonistic effects on the induction of antimicrobial peptide (AMP) genes in Drosophila melanogaster. 20E pretreatment of Schneider S2 cells promoted the robust induction of AMP genes, following immune stimulation. On the other hand, JH III, and its synthetic analogs (JHa) methoprene and pyriproxyfen, strongly interfered with this 20E-dependent immune potentiation, although these hormones did not inhibit other 20E-induced cellular changes. Similarly, in vivo analyses in adult flies confirmed that JH is a hormonal immuno-suppressor. RNA silencing of either partner of the ecdysone receptor heterodimer (EcR or Usp) in S2 cells prevented the 20E-induced immune potentiation. In contrast, silencing methoprene-tolerant (Met), a candidate JH receptor, did not impair immuno-suppression by JH III and JHa, indicating that in this context MET is not a necessary JH receptor. Our results suggest that 20E and JH play major roles in the regulation of gene expression in response to immune challenge.

Feasibility of self-collection of specimens for human papillomavirus testing in hard-to-reach women.

To study the feasibility of self-collected specimens for testing human papillomavirus (HPV) status among hard-to-reach women, outreach nurses recruited women in women's centres, shelters and alleys in Vancouver's Downtown Eastside. Of the 151 participants for whom samples were available, 43 (28.5%) tested positive for high-risk HPV. Outreach nurses were able to recontact 81.4% of the participants who tested positive and referred them for further testing. About 14% (21/151) of participants had never received a Papanicolaou smear in British Columbia, as compared with 8.3% (608/7336) of women in the BC general population (p < 0.05). This difference suggests that self-collection of specimens for HPV testing is a feasible method to reach women who have not previously participated in cervical cancer screening programs.

The role of the cytomegalovirus antigenemia assay in the detection and prevention of cytomegalovirus syndrome and disease in solid organ transplant recipients: A review of the British Columbia experience.

BACKGROUND: The pp65 cytomegalovirus (CMV) antigenemia assay has been used as a means of guiding the pre-emptive therapy of CMV disease in solid organ transplant (SOT) recipients. Recently, concerns have been raised regarding the utility of the test to accurately and precisely detect viral activity early enough to reduce the morbidity and mortality associated with CMV OBJECTIVE: To determine the performance characteristics of the method of antigenemia testing of SOT recipients used at Vancouver General Hospital, Vancouver, British Columbia. METHODS: All SOT recipients between January 1, 1999, and June 30, 2000, were retrospectively reviewed for six months following transplantation. Physical examination results, laboratory parameters, antigenemia results and treatment information were reviewed. RESULTS: A total of 134 kidney, liver, lung and kidney-pancreas transplant recipients were included in the analysis. The overall performance characteristics of the antigenemia assay in predicting CMV disease included a sensitivity of 64%, a specificity of 81%, a positive predictive value of 76% and a negative predictive value of 71%. A mean of 18 days passed between the onset of signs and symptoms of CMV disease/syndrome and the first recorded positive antigenemia result, and only 26% of patients had a positive test result before the onset of symptoms. It was found that an antigenemia test breakpoint of at least one positive cell for defining a positive test provided the most sensitive and specific prediction, with increased odds of developing CMV disease. CONCLUSIONS: Based on performance characteristics, the Vancouver General Hospital's current method of antigenemia testing to guide pre-emptive ganciclovir therapy in SOT patients is not optimal for the early detection of disease. Further study is needed on new molecular testing methods to determine if our ability to predict CMV disease can be improved.

Successful HCV genotyping of previously failed and low viral load specimens using an HCV RNA qualitative assay based on transcription-mediated amplification in conjunction with the line probe assay.

BACKGROUND: Hepatitis C virus (HCV) genotyping is a critical part of the diagnostic work-up for chronic hepatitis C. The VERSANT HCV line probe assay (LiPA) marketed by Bayer Corporation requires PCR-derived amplicons for genotyping usually obtained from commercial assays, including Amplicor HCV 2.0 (Amplicor 2.0), Amplicor HCV Monitor 2.0, or SuperQuant. Occasionally, PCR-based methods in conjunction with LiPA fail to give a genotyping result. Although most genotyping failures occur among low viral load specimens, some occur in specimens with relatively high viral loads. The Bayer HCV RNA Qualitative assay (HCV TMA), with a limit of detection of approximately 5-10 IU/ml, is more sensitive than other commercial assays. OBJECTIVES: An HCV genotyping protocol using HCV TMA linked with LiPA (TMA-LiPA) was developed and tested for ability to genotype samples that had previously failed genotyping by PCR-based methods in conjunction with LiPA. STUDY DESIGN: Clinical specimens were obtained from eight independent laboratories in Canada and the US and tested with TMA-LiPA at the Bayer Reference Testing Laboratory. Specimens included those that failed to produce a genotype result when a PCR-based assay was used in conjunction with LiPA and specimens for which genotyping was not attempted because the viral load was below the validated cut-off determined in the laboratory of origin. RESULTS AND CONCLUSIONS: TMA-LiPA successfully genotyped 68 of 75 (90.7%) specimens that had failed genotyping by PCR-based methods used in conjunction with LiPA and 36 of 40 (90.0%) specimens that were rejected for genotyping due to low viral load. Moreover, TMA-LiPA assigned subtype for 79 of 107 (73.8%) specimens. Our TMA-LiPA results reflected the distribution of HCV genotypes found in North America, and were 100% concordant with those of Amplicor 2.0 in conjunction with LiPA for control specimens genotyped by both assays. TMA-LiPA may prove useful both in optimizing LiPA performance and genotyping patient specimens.

Genital tract and plasma human immunodeficiency virus viral load throughout the menstrual cycle in women who are infected with ovulatory human immunodeficiency virus.

OBJECTIVE: The purpose of this study was to determine the vaginal, cervical, and plasma viral load through the menstrual cycle in women who are positive for human immunodeficiency virus. STUDY DESIGN: A prospective cohort study was performed on 14 women with ovulatory menstrual cycles who have human immunodeficiency virus. Duplicate cervical and vaginal viral load samples (n = 301) were taken at four stages (menstrual, follicular, periovulatory, and luteal) of two consecutive cycles. RESULTS: Participant characteristics were mean age of 32.7 years, median human immunodeficiency virus helper cell count value of 355, and median plasma viral load of 24,000 copies/mL. Through the menstrual cycle, there was no statistically significant difference in plasma viral load, but there was a significant decrease in genital tract viral load at the periovulatory phase (vagina, P =.018; cervix, P =.007). Vaginal and cervical viral load were correlated (r = 0.582, P <.001). CONCLUSION: Although the plasma viral load remained constant throughout the menstrual cycle, the genital viral load decreased at the periovulatory phase. These results suggest that local factors may affect the genital viral load compartment independent of plasma viral load.

New variant of varicella-zoster virus.

In 1998, a varicella-zoster virus glycoprotein E (gE) mutant virus (VZV-MSP) was isolated from a child with chickenpox. VZV-MSP, representing a second VZV serotype, was considered a rarity. We isolated another VZV-MSP-like virus from an elderly man with herpes zoster. These gE mutant viruses may have arisen through independent mutation or may represent a distinct VZV subpopulation that emerged more than 50 years ago.