Spatial variation and hot-spots of district level diarrhea incidences in Ghana: 2010–2014

Background: Diarrhea is a public health menace, especially in developing countries. Knowledge of the biological and anthropogenic characteristics is abundant. However, little is known about its spatial patterns especially in developing countries like Ghana. This study aims to map and explore the spatial variation and hot-spots of district level diarrhea incidences in Ghana. Methods: Data on district level incidences of diarrhea from 2010 to 2014 were compiled together with population data. We mapped the relative risks using empirical Bayesian smoothing. The spatial scan statistics was used to detect and map spatial and space-Time clusters. Logistic regression was used to explore the relationship between space-Time clustering and urbanization strata, i.e. rural, peri-urban, and urban districts. Results: We observed substantial variation in the spatial distribution of the relative risk. There was evidence of significant spatial clusters with most of the excess incidences being long-Term with only a few being emerging clusters. Space-Time clustering was found to be more likely to occur in peri-urban districts than in rural and urban districts. Conclusion: This study has revealed that the excess incidences of diarrhea is spatially clustered with peri-urban districts showing the greatest risk of space-Time clustering. More attention should therefore be paid to diarrhea in peri-urban districts. These findings also prompt public health officials to integrate disease mapping and cluster analyses in developing location specific interventions for reducing diarrhea

Estimation of colorectal adenoma recurrence with dependent censoring

<p>Abstract</p> <p>Background</p> <p>Due to early colonoscopy for some participants, interval-censored observations can be introduced into the data of a colorectal polyp prevention trial. The censoring could be dependent of risk of recurrence if the reasons of having early colonoscopy are associated with recurrence. This can complicate estimation of the recurrence rate.</p> <p>Methods</p> <p>We propose to use midpoint imputation to convert interval-censored data problems to right censored data problems. To adjust for potential dependent censoring, we use information from auxiliary variables to define risk groups to perform the weighted Kaplan-Meier estimation to the midpoint imputed data. The risk groups are defined using two risk scores derived from two working proportional hazards models with the auxiliary variables as the covariates. One is for the recurrence time and the other is for the censoring time. The method described here is explored by simulation and illustrated with an example from a colorectal polyp prevention trial.</p> <p>Results</p> <p>We first show that midpoint imputation under an assumption of independent censoring will produce an unbiased estimate of recurrence rate at the end of the trial, which is often the main interest of a colorectal polyp prevention trial, and then show in simulations that the weighted Kaplan-Meier method using the information from auxiliary variables based on the midpoint imputed data can improve efficiency in a situation with independent censoring and reduce bias in a situation with dependent censoring compared to the conventional methods, while estimating the recurrence rate at the end of the trial.</p> <p>Conclusion</p> <p>The research in this paper uses midpoint imputation to handle interval-censored observations and then uses the information from auxiliary variables to adjust for dependent censoring by incorporating them into the weighted Kaplan-Meier estimation. This approach can handle a situation with multiple auxiliary variables by deriving two risk scores from two working PH models. Although the idea of this approach might appear simple, the results do show that the weighted Kaplan-Meier approach can gain efficiency and reduce bias due to dependent censoring.</p

Estimation of Recurrence of Colorectal Adenomas with Dependent Censoring Using Weighted Logistic Regression

In colorectal polyp prevention trials, estimation of the rate of recurrence of adenomas at the end of the trial may be complicated by dependent censoring, that is, time to follow-up colonoscopy and dropout may be dependent on time to recurrence. Assuming that the auxiliary variables capture the dependence between recurrence and censoring times, we propose to fit two working models with the auxiliary variables as covariates to define risk groups and then extend an existing weighted logistic regression method for independent censoring to each risk group to accommodate potential dependent censoring. In a simulation study, we show that the proposed method results in both a gain in efficiency and reduction in bias for estimating the recurrence rate. We illustrate the methodology by analyzing a recurrent adenoma dataset from a colorectal polyp prevention trial

A new approach of nonparametric estimation of incidence and lifetime risk based on birth rates and incident events

<p>Abstract</p> <p>Background</p> <p>Incidence and lifetime risk of diabetes are important public health measures. Traditionally, nonparametric estimates are obtained from survey data by means of a Nelson-Aalen estimator which requires data information on both incident events and risk sets from the entire cohort. Such data information is rarely available in real studies.</p> <p>Methods</p> <p>We compare two different approaches for obtaining nonparametric estimates of age-specific incidence and lifetime risk with emphasis on required assumptions. The first and novel approach only considers incident cases occurring within a fixed time window–we have termed this <it>cohort-of-cases </it>data–which is linked explicitly to the birth process in the past. The second approach is the usual Nelson-Aalen estimate which requires knowledge on observed time at risk for the entire cohort and their incident events. Both approaches are used on data on anti-diabetic medications obtained from Odense Pharmacoepidemiological Database, which covers a population of approximately 470,000 over the period 1993–2003. For both methods we investigate if and how incidence rates can be projected.</p> <p>Results</p> <p>Both the new and standard method yield similar sigmoidal shaped estimates of the cumulative distribution function of age-specific incidence. The Nelson-Aalen estimator gives somewhat higher estimates of lifetime risk (15.65% (15.14%; 16.16%) for females, and 17.91% (17.38%; 18.44%) for males) than the estimate based on cohort-of-cases data (13.77% (13.74%; 13.81%) for females, 15.61% (15.58%; 15.65%) for males). Accordingly the projected incidence rates are higher based on the Nelson-Aalen estimate–also too high when compared to observed rates. In contrast, the cohort-of-cases approach gives projections that fit observed rates better.</p> <p>Conclusion</p> <p>The developed methodology for analysis of cohort-of-cases data has potential to become a cost-effective alternative to a traditional survey based study of incidence. To allow more general use of the methodology, more research is needed on how to relax stationarity assumptions.</p

Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies

<p>Abstract</p> <p>Background</p> <p>The relatively short durations of the initial pivotal randomized placebo-controlled trials involving atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder (ADHD) provided limited insight into the time courses of ADHD core symptom responses to this nonstimulant, selective norepinephrine reuptake inhibitor. The aim of this analysis was to evaluate time courses of treatment responses or remission, as assessed by attainment of prespecified scores on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scales, during up to 1 year of atomoxetine treatment in children with ADHD.</p> <p>Methods</p> <p>Using pooled data from three Canadian open-label studies involving 338 children ages 6-11 years with ADHD who were treated with atomoxetine for 3, 6 and 12 months, and survival analysis methods for interval-censored data, we estimated the time to: 1) improvement and robust improvement defined by ≥25% and ≥40% reductions from baseline ADHDRS-IV-PI total scores, respectively; and 2) remission using two definitions: a final score of ADHDRS-IV-PI ≤18 or a final score of CGI-ADHD-S ≤2.</p> <p>Results</p> <p>The median time to improvement was 3.7 weeks (~1 month), but remission of symptoms did not occur until a median of 14.3 weeks (~3.5 months) using the most stringent CGI-ADHD-S threshold. Probabilities of robust improvement were 47% at or before 4 weeks of treatment; 76% at 12 weeks; 85% at 26 weeks; and 96% at 52 weeks. Probabilities of remission at these corresponding time points were 30%, 59%, 77%, and 85% (using the ADHDRS-IV scale) and 8%, 47%, 67%, and 75% (using the CGI-ADHD-S scale). The change from atomoxetine treatment month 5 to month 12 of -1.01 (1.03) was not statistically significant (<it>p </it>= .33).</p> <p>Conclusions</p> <p>Reductions in core ADHD symptoms during atomoxetine treatment are gradual. Although approximately one-half of study participants showed improvement at 1 month of atomoxetine treatment, remission criteria were not met until about 3 months. Understanding the time course of children's responses to atomoxetine treatment may inform clinical decision making and also influence the durations of trials comparing the effects of this medication with other ADHD treatments.</p> <p>Trial Registrations</p> <p>clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00191633">NCT00191633</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00216918">NCT00216918</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00191880">NCT00191880</a>.</p

Estimation in a Competing Risks Proportional Hazards Model Under Length-biased Sampling With Censoring

International audienceWhat population does the sample represent? The answer to this question is of crucial importance when estimating a survivor function in duration studies. As is well-known, in a stationary population, survival data obtained from a cross-sectional sample taken from the population at time $t_0$ represents not the target density $f(t)$ but its length-biased version proportional to $tf(t)$, for $t>0$. The problem of estimating survivor function from such length-biased samples becomes more complex, and interesting, in presence of competing risks and censoring. This paper lays out a sampling scheme related to a mixed Poisson process and develops nonparametric estimators of the survivor function of the target population assuming that the two independent competing risks have proportional hazards. Two cases are considered: with and without independent consoring before length biased sampling. In each case, the weak convergence of the process generated by the proposed estimator is proved. A well-known study of the duration in power for political leaders is used to illustrate our results. Finally, a simulation study is carried out in order to assess the finite sample behaviour of our estimators

HIV Incidence and Risk Factors for Acquisition in HIV Discordant Couples in Masaka, Uganda: An HIV Vaccine Preparedness Study

To determine the incidence of and risk factors for HIV acquisition in a cohort of HIV-uninfected partners from HIV discordant couples in Masaka, Uganda, and to establish its suitability for HIV vaccine trials.HIV-uninfected adults living in HIV discordant couple relationships were enrolled and followed for 2 years. Interviews, medical investigations, HIV counseling and testing, syphilis and urine pregnancy (women) tests were performed at quarterly visits. Sexual risk behaviour data were collected every 6 months.495 participants were enrolled, of whom 34 seroconverted during 786.6 person-years of observation (PYO). The overall HIV incidence rate [95% confidence interval (CI)] was 4.3 [3.1-6]; and 4.3 [2.8-6.4] and 4.4 [2.5-8] per 100 PYO in men and women respectively. Independent baseline predictors for HIV acquisition were young age [18-24 (aRR = 4.1, 95% CI 1.6-10.8) and 25-34 (aRR = 2.7, 95% CI 1.2-5.8) years]; alcohol use (aRR = 2.6, 95% CI 1.1-6); and reported genital discharge (aRR = 3.4, 95% CI 1.6-7.2) in the past year. Condom use frequency in the year preceding enrolment was predictive of a reduced risk of HIV acquisition [sometimes (aRR = 0.4, 95% CI 0.2-0.8); always (aRR = 0.1, 95% CI 0.02-0.9)]. In the follow-up risk analysis, young age [18-24 (aRR = 6.2, 95% CI 2.2-17.3) and 25-34 (aRR = 2.3, 95% CI 1.1-5.0) years], reported genital discharge (aRR = 2.5, 95% CI 1.1-5.5), serological syphilis (aRR 3.2, 95% CI 1.3-7.7) and the partner being ART naïve (aRR = 4.8, 95% CI 1.4-16.0) were independently associated with HIV acquisition. There were no seroconversions among participants who reported consistent condom use during the study.The study has identified important risk factors for HIV acquisition among HIV discordant couples. HIV-uninfected partners in discordant couples may be a suitable population for HIV vaccine efficacy trials. However, recent confirmation that ART reduces heterosexual HIV transmission may make it unfeasible to conduct HIV prevention trials in this population

Anthrax Lethal Toxin Disrupts Intestinal Barrier Function and Causes Systemic Infections with Enteric Bacteria

A variety of intestinal pathogens have virulence factors that target mitogen activated protein kinase (MAPK) signaling pathways, including Bacillus anthracis. Anthrax lethal toxin (LT) has specific proteolytic activity against the upstream regulators of MAPKs, the MAPK kinases (MKKs). Using a murine model of intoxication, we show that LT causes the dose-dependent disruption of intestinal epithelial integrity, characterized by mucosal erosion, ulceration, and bleeding. This pathology correlates with an LT-dependent blockade of intestinal crypt cell proliferation, accompanied by marked apoptosis in the villus tips. C57BL/6J mice treated with intravenous LT nearly uniformly develop systemic infections with commensal enteric organisms within 72 hours of administration. LT-dependent intestinal pathology depends upon its proteolytic activity and is partially attenuated by co-administration of broad spectrum antibiotics, indicating that it is both a cause and an effect of infection. These findings indicate that targeting of MAPK signaling pathways by anthrax LT compromises the structural integrity of the mucosal layer, serving to undermine the effectiveness of the intestinal barrier. Combined with the well-described immunosuppressive effects of LT, this disruption of the intestinal barrier provides a potential mechanism for host invasion via the enteric route, a common portal of entry during the natural infection cycle of Bacillus anthracis

Leukaemia incidence among workers in the shoe and boot manufacturing industry: a case-control study

BACKGROUND: Previous reports have indicated an excess of leukaemia in Broome County, New York, particularly in the Town of Union. Surveillance of cancer incidence data indicates that a large proportion of these cases occurred among males ages 65 and older. Shoe and boot manufacturing has been the largest single industry in this area throughout much of the past century. Occupational studies from Europe suggest a link between leukaemia and employment in the shoe and boot manufacturing industry. However, researchers have not found a positive association between leukaemia and employment in the shoe industry among workers in the United States. METHODS: A matched case-control study was conducted to investigate the association between leukaemia incidence among males 65 and older and employment in the shoe and boot manufacturing industry. Thirty-six cases of leukaemia occurring between 1981–1990; among males age 65 and older; residing in the town of Union met the study case criteria. Death certificates were obtained for each of the cases. These were matched to death certificates of 144 controls on date of death and date of birth +/- 1 year. Death certificates were then examined to determine the employer and occupation of each study subject. Conditional logistic regression was used to determine the risk of leukaemia among those working in the industry. RESULTS: The risk of both leukaemia (OR = 1.47; 95% CI 0.70, 3.09) and acute myeloid leukaemia (OR = 1.19; 95% CI 0.33, 4.28) were elevated among those employed in the shoe and boot manufacturing industry, however neither was statistically significant. CONCLUSION: The results, though suggestive of an association between leukaemia and employment in the shoe and boot manufacturing industry, were not statistically conclusive due mainly to limited study power. Several additional limitations may also have prevented the observance of more conclusive findings. Better exposure assessment, information on length of exposure and types of job held, control of confounding factors and information on chemicals used by this company would strengthen any future investigation

High Degree of Heterogeneity in Alzheimer's Disease Progression Patterns

There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline