Multivariate muti-level non-linear mixed-effect models and their application to the modeling of drug-concentration time curves

This thesis discusses the techniques involved in the fitting of nonlinear mixed effect (NLME) models. In particular, it looks at the application of these techniques to the analysis of concentration-time data for the aforementioned antimalarial compounds, and details the necessary extensions to the basic modeling process that were required in order to accommodate multiple responses and multiple observation phases (pregnant and postpartum)

Joint Models with Multiple Longitudinal Outcomes and a Time-to-Event Outcome: a Corrected Two-Stage Approach

Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a novel approach that enables the fitting of such models with more realistic computational times. The idea behind the approach is to split the estimation of the joint model in two steps; estimating a multivariate mixed model for the longitudinal outcomes, and then using the output from this model to fit the survival submodel. So called two-stage approaches have previously been proposed, and shown to be biased. Our approach differs from the standard version, in that we additionally propose the application of a correction factor, adjusting the estimates obtained such that they more closely resemble those we would expect to find with the multivariate joint model. This correction is based on importance sampling ideas. Simulation studies show that this corrected-two-stage approach works satisfactorily, eliminating the bias while maintaining substantial improvement in computational time, even in more difficult settings.Comment: 33 pages, 7 figures and 7 tables including appendices. Accepted in Statistics and Computin

Joint models with multiple longitudinal outcomes and a time-to-event outcome: a corrected two-stage approach

Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a novel approach that enables the fitting of such models with more realistic computational times. The idea behind the approach is to split the estimation of the joint model in two steps: estimating a multivariate mixed model for the longitudinal outcomes and then using the output from this model to fit the survival submodel. So-called two-stage approaches have previously been proposed and shown to be biased. Our approach differs from the standard version, in that we additionally propose the application of a correction factor, adjusting the estimates obtained such that they more closely resemble those we would expect to find with the multivariate joint model. This correction is based on importance sampling ideas. Simulation studies show that this corrected two-stage approach works satisfactorily, eliminating the bias while maintaining substantial improvement in computational time, even in more difficult settings

Five Years of Antimalarial Resistance Marker Surveillance in Gaza Province, Mozambique, Following Artemisinin-Based Combination Therapy Roll Out

Antimalarial drug resistance is a major obstacle to malaria control and eventual elimination. The routine surveillance for molecular marker of resistance is an efficient way to assess drug efficacy, which remains feasible in areas where malaria control interventions have succeeded in substantially reducing malaria transmission. Community based asexual parasite prevalence surveys were conducted annually in sentinel sites in Gaza Province, Mozambique from 2006 until 2010, before, during and after antimalarial policy changes to artesunate plus sulfadoxine-pyrimethamine in 2006 and to artemether-lumefantrine in 2008. Genetic analysis of dhfr, dhps, crt, and mdr1 resistant genes was conducted on 3 331 (14.4%) Plasmodium falciparum PCR positive samples collected over the study period from 23 229 children aged 2 to 15 years. The quintuple dhfr/dhps mutation associated with sulfadoxine-pyrimethamine resistance increased from 56.2% at baseline to 75.8% by 2010. At baseline the crt76T and mdr186Y mutants were approaching fixation, 96.1% and 74.7%, respectively. Following the deployment of artemisinin-based combination therapy, prevalence of both these chloroquine-resistance markers began declining, reaching 32.4% and 30.9%, respectively, by 2010. All samples analysed over the 5-year period possessed a single copy of the mdr1 gene. The high and increasing prevalence of the quintuple mutation supports the change in drug policy from artesunate plus sulfadoxine-pyrimethamine to artemether-lumefantrine in Mozambique. As chloroquine related drug pressure decreased in the region, so did the molecular markers associated with chloroquine resistance (crt76T and mdr186Y). However, this reversion to the wild-type mdr186N predisposes parasites towards developing lumefantrine resistance. Close monitoring of artemether-lumefantrine efficacy is therefore essential, particularly given the high drug pressure within the region where most countries now use artemether-lumefantrine as first line treatment

Spare the rod and save the child: Assessing the impact of parenting on child behaviour and mental health

Parenting has a considerable impact on children’s behaviour and mental health. Improving child health and behaviour requires an understanding of the relationship between parenting practices; contexual factors such asparental mental health, intimate partner violence, substance abuse and poverty; and children’s behaviour. In this article the authors report the findings of a survey of parenting and child behaviour in a small rural South Africancommunity. The findings show that corporal punishment, the stress of parenting and parental mental health are significantly associated with both children’s internalising (depression and anxiety) and externalising (rulebreakingand aggression) symptoms. Intimate partner violence in the home was also associated with children’s externalising symptoms. These findings imply that parent support and training, and an increase in services to address intimate partner violence and mental health problems, should be prioritised as part of a nationalviolence reduction strategy

Residency, habitat use and sexual segregation of white sharks, Carcharodon carcharias in False Bay, South Africa

White sharks ( Carcharodon carcharias ) are threatened apex predators and identification of their critical habitats and how these are used are essential to ensuring improved local and ultimately global white shark protection. In this study we investigated habitat use by white sharks in False Bay, South Africa, using acoustic telemetry. 56 sharks (39 female, 17 male), ranging in size from 1.7-5 m TL, were tagged with acoustic transmitters and monitored on an array of 30 receivers for 975 days. To investigate the effects of season, sex and size on habitat use we used a generalized linear mixed effects model. Tagged sharks were detected in the Bay in all months and across all years, but their use of the Bay varied significantly with the season and the sex of the shark. In autumn and winter males and females aggregated around the Cape fur seal colony at Seal Island, where they fed predominantly on young of the year seals. In spring and summer there was marked sexual segregation, with females frequenting the Inshore areas and males seldom being detected. The shift from the Island in autumn and winter to the Inshore region in spring and summer by females mirrors the seasonal peak in abundance of juvenile seals and of migratory teleost and elasmobranch species respectively. This study provides the first evidence of sexual segregation at a fine spatial scale and demonstrates that sexual segregation in white sharks is not restricted to adults, but is apparent for juveniles and sub-adults too. Overall, the results confirm False Bay as a critical area for white shark conservation as both sexes, across a range of sizes, frequent the Bay on an annual basis. The finding that female sharks aggregate in the Inshore regions when recreational use peaks highlights the need for ongoing shark-human conflict mitigation strategies

Inferential reproduction analysis demonstrated that “paracetamol for acute low back pain” trial conclusions were reproducible

Objectives: The aim of this study was to reanalyze and reinterpret data obtained in Paracetamol in Acute Low Back Pain (PACE), the first large randomized controlled trial evaluating the efficacy of paracetamol in acute low back pain, to assess the inferential reproducibility of the original conclusions. Study Design and Setting: Mixed effects models were used to reanalyze pain intensity (primary outcome; 11-point Numeric Rating Scale) and physical functioning, health-related quality of life, sleep quality, and time until recovery (as secondary outcomes), according to the intention-to-treat principle. The original authors of the PACE study were not involved in the development of the methods for this reanalysis. Results: The reproduction analyses indicated no effect of treatment on pain intensity and confidence intervals excluded clinically worthwhile effects (adjusted main effect for regular paracetamol vs. placebo 0.00 [−0.02, 0.01; P = 0.85]; adjusted main effect for paracetamol as-needed vs. placebo 0.00 [−0.02, 0.01; P = 0.92]). Similar results were obtained for all secondary outcomes. Conclusion: This study indicates that the conclusions of the PACE trial are inferentially reproducible, even when using a different analytical approach. This reinforces the notion that the management of acute low back pain should focus on providing patients advice and reassurance without the addition of paracetamol

Interobserver variability in the classification of appendicitis during laparoscopy

Background: The intraoperative classification of appendicitis dictates the patient's postoperative management. Prolonged antibiotic prophylaxis is recommended for complex appendicitis (gangrenous, perforated, abscess), whereas preoperative prophylaxis suffices for simple appendicitis. Distinguishing these two conditions can be challenging. The aim of this study was to assess interobserver variability in the classification of appendicitis during laparoscopy. Methods: Short video recordings taken during laparoscopy for suspected appendicitis were shown to surgeons and surgical residents. They were asked to: classify the appendix as indicative of no, simple or complex appendicitis; categorize the appendix as normal, phlegmonous, gangrenous, perforated and/or abscess; and decide whether they would prescribe postoperative antibiotics. Inter-rater reliability was evaluated using Fleiss' κ score and the S* statistic. Results: Some 80 assessors participated in the study. Video recordings of 20 patients were used. Interobserver agreement was minimal for both the classification of appendicitis (κ score 0·398, 95 per cent c.i. 0·385 to 0·410) and the decision to prescribe postoperative antibiotic treatment (κ score 0·378, 0·362 to 0·393). Agreement was slightly higher when published criteria were applied (κ score 0·552, 0·537 to 0·568). Conclusion: There is considerable variability in the intraoperative classification of appendicitis and the decision to prescribe postoperative antibiotic treatment

Summer at the beach: spatio-temporal patterns of white shark occurrence along the inshore areas of False Bay, South Africa

Background Understanding white shark (Carcharodon carcharias) habitat use in coastal areas adjacent to large cities, is an important step when formulating potential solutions to the conservation conflict that exists between humans and large predatory sharks. In this study, we present the findings of a 2.5-year study of white shark occurrence and movement patterns adjacent to the City of Cape Town in False Bay, South Africa, with a focus on spring and summer months. Fifty-one white sharks were monitored annually at three offshore and twelve inshore sites by VR2 acoustic receivers, over 975 days from 1 May 2005 to 31 December 2007. Results Occurrence patterns at inshore sites during spring and summer were analysed using a generalized additive mixed model (GAMM) with a spatial term (longitude, latitude), time of day and year included as explanatory variables for site use. We found that sharks occurred more frequently at inshore sites along the northern and northwestern shores, compared to the rest of the bay, and they transitioned most frequently between four adjacent beach sites that encompass the most popular recreational water use areas in Cape Town. There was significant diel variation, with higher shark occurrence around midday, and a peak in shark occurrence in 2005, when human-shark interactions also peaked. However, we found no effect of shark size on occurrence patterns at inshore sites. Conclusions White sharks showed the highest levels of occurrence at specific inshore sites between Muizenberg and Strandfontein beach, and thus inclusion of these sites within False Bay’s marine protected area (MPA) network or recognition as Ecological or Biological Significant Areas (EBSAs) should be a future consideration. These insights into white shark habitat use at inshore sites in False Bay are important for successfully applying the principles of marine spatial planning (MSP) and for making science-based policy decisions. Furthermore, this information can be used to reduce potential shark-human conflict by incorporating it into future shark safety education campaigns

RAIN study: A protocol for a randomised controlled trial evaluating efficacy, safety and cost-effectiveness of intravenous-to-oral antibiotic switch therapy in neonates with a probable bacterial infection

__Introduction__ High morbidity and mortality rates of proven bacterial infection are the main reason for substantial use of intravenous antibiotics in neonates during the first week of life. In older children, intravenous-to-oral switch after 48 hours of intravenous therapy has been shown to have many advantages and is nowadays commonly practised. We, therefore, aim to evaluate the effectiveness, safety and cost-effectiveness of an early intravenous-to-oral switch in neonates with a probable bacterial infection. __Methods and analysis__ We present a protocol for a multicentre randomised controlled trial assessing the non-inferiority of an early intravenous-to-oral antibiotic switch compared with a full course of intravenous antibiotics in neonates (0-28 days of age) with a probable bacterial infection. Five hundred and fifty patients will be recruited in 17 hospitals in the Netherlands. After 48 hours of intravenous treatment, they will be assigned to either continue with intravenous therapy for another 5 days (control) or switch to amoxicillin/clavulanic acid suspension (intervention). Both groups will be treated for a total of 7 days. The primary outcome will be bacterial (re)infection within 28 days after treatment completion. Secondary outcomes are the pharmacokinetic profile of oral amoxicillin/clavulanic acid, the impact on quality of life, cost-effectiveness, impact on microbiome development and additional yield of molecular techniques in diagnosis of probable bacterial infection. __Ethics and dissemination__ This study has been approved by the Medical Ethics Committee of the Erasmus Medical Centre. Results will be presented in peer-reviewed journals and at international conferences