Diagnostics for joint models for longitudinal and survival data

Joint models for longitudinal and survival data are a class of models that jointly analyse an outcome repeatedly observed over time such as a bio-marker and associated event times. These models are useful in two practical applications; firstly focusing on survival outcome whilst accounting for time varying covariates measured with error and secondly focusing on the longitudinal outcome while controlling for informative censoring. Interest on the estimation of these joint models has grown in the past two and half decades. However, minimal effort has been directed towards developing diagnostic assessment tools for these models. The available diagnostic tools have mainly been based on separate analysis of residuals for the longitudinal and survival sub-models which could be sub-optimal. In this thesis we make four contributions towards the body of knowledge. We first developed influence diagnostics for the shared parameter joint model for longitudinal and survival data based on Cook's statistics. We evaluated the performance of the diagnostics using simulation studies under different scenarios. We then illustrated these diagnostics using real data set from a multi-center clinical trial on TB pericarditis (IMPI). The second contribution was to implement a variance shift outlier model (VSOM) in the two-stage joint survival model. This was achieved by identifying outlying subjects in the longitudinal sub-model and down-weighting before the second stage of the joint model. The third contribution was to develop influence diagnostics for the multivariate joint model for longitudinal and survival data. In this setting we considered two longitudinal outcomes, square root CD4 cell count which was Gaussian in nature and antiretroviral therapy (ART) uptake which was binary. We achieved this by extending the univariate case i based on Cook's statistics for all parameters. The fourth contribution was to implement influence diagnostics in joint models for longitudinal and survival data with multiple failure types (competing risk). Using IMPI data set we considered two competing events in the joint model; death and constrictive pericarditis. Using simulation studies and IMPI dataset the developed diagnostics identified influential subjects as well as observations. The performance of the diagnostics was over 98% in simulation studies. We further conducted sensitivity analyses to check the impact of influential subjects and/or observations on parameter estimates by excluding them and re-fitting the joint model. We observed subtle differences, overall in the parameter estimates, which gives confidence that the initial inferences are credible and can be relied on. We illustrated case deletion diagnostics using the IMPI trial setting, these diagnostics can also be applied to clinical trials with similar settings. We therefore make a strong recommendation to analysts to conduct influence diagnostics in the joint model for longitudinal and survival data to ascertain the reliability of parameter estimates. We also recommend the implementation of VSOM in the longitudinal part of the two-stage joint model before the second stage

The Treatment of Possible Severe Infection in Infants: An Open Randomized Safety Trial of Parenteral Benzylpenicillin and Gentamicin Versus Ceftriaxone in Infants <60 days of Age in Malawi

Background - The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment of infants with sepsis in low income settings (LICs), and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 LICs, Staphylococcus aureus, Klebsiella spp. and E.coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was >50% of all isolates, and 44% of Gram-negative isolates were gentamicin resistant. However, ceftriaxone may cause neonatal jaundice and gentamicin may cause deafness. Therefore, we compared parenteral benzylpenicillin plus gentamicin to ceftriaxone as first line treatment, assessing outcome and adverse events. Methods - This was an open randomized trial carried out in the Queen Elizabeth Central Hospital, Blantyre, Malawi from 2010 to 2013. Infants < 60 days of age with possible severe sepsis received either benzylpenicillin and gentamicin or ceftriaxone. Adverse events and outcomes were recorded until 6 months post discharge. Results - 348 infants were included in analyses. Outcome in the benzylpenicillin and gentamicin or ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae 14.5% and 11.2% respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% v 5%, p=0.03. Thirteen (6%) survivors had bilateral hearing loss. There was no difference between the treatment groups. By 6 months post discharge 11 more infants had died and 17 more children were found to have sequelae. Conclusions - Ceftriaxone and gentamicin are safe for infants in our setting. Infants should receive long term follow up as many poor outcomes occurred after hospital discharge

Copyright © 2014 SciRes. OPEN ACCESS Scaling up of trachoma mapping in Salima District, Central Malawi

Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-dance of the Creative Commons Attribution License all Copyrights © 2014 are reserved for SCIRP and the owner of the intellectual property Khumbo Kalua et al. All Copyright © 2014 are guarded by law and by SCIRP as a guardian. Background: A number of suspected endemic districts with Trachoma have not been mapped in Malawi, and this contributes to delays for scaling up trachoma control activities. Objec-tives: To determine the prevalence of trachoma and associated risk factors in one of the sus-pected endemic districts (Salima District) in cen-tral Malawi and to generate information to guide policy decisions. Methods: A population-based survey conducted in randomly selected cluster

Virologic outcomes with tenofovir-lamivudine-dolutegravir in adults failing PI-based second-line ART

Background: In South African antiretroviral guidelines, selected patients failing second-line protease inhibitor (PI)-based therapy qualify for genotypic resistance testing – those with PI resistance receive darunavir-based third-line regimens; those without PI resistance continue current regimen with adherence support. The Western Cape province, from September 2020, implemented a strategy of tenofovir-lamivudine-dolutegravir (TLD) for patients, provided there was no tenofovir resistance, irrespective of PI resistance. Objectives: To evaluate virologic outcomes with TLD among adults failing second-line PI regimens with no tenofovir resistance. Method: An observational cohort study comparing outcomes in patients switched to TLD with those continuing the same PI or switched to darunavir-based regimens. Follow-up was until virologic suppression (HIV-1 RNA 400 copies/mL), or at the point of censoring. Results: One hundred and thirty-three patients switched to TLD, 101 to darunavir-based regimens, and 121 continued with the same PI. By 12 months, among patients with PI resistance, 42/47 (89%) in the TLD group had HIV-1 RNA 400 copies/mL compared to 91/99 (92%) in the darunavir group (hazard ratio, 1.11; 95% confidence interval, 0.77–1.60). In patients without PI resistance, 66/86 (77%) in the TLD group had HIV-1 RNA 400 copies/mL compared to 42/120 (35%) in those continuing with the same PI (hazard ratio, 4.03; 95% confidence interval, 2.71–5.98). Two patients receiving TLD developed virologic failure with high-level dolutegravir resistance. Conclusion: Amongst patients failing second-line PI with no PI resistance, switching to TLD was associated with higher virologic suppression, likely due to improved adherence. Virologic outcomes were similar in patients with PI resistance switched to darunavir-based regimens or TLD

Predictors of late virologic failure after initial successful suppression of HIV replication on efavirenz-based antiretroviral therapy

Background: Practical issues, including cost, hinder implementing virologic monitoring of patients on antiretroviral therapy (ART) in resource-limited settings. We evaluated factors that might guide monitoring frequency and efforts to prevent treatment failure after initial virologic suppression. Methods: Participants were the 911 HIV-infected antiretroviral-naïve adults with CD4 count <300 cells/μL who started efavirenz-based ART in the international A5175/PEARLS trial and achieved HIV-1 RNA <1000 copies/mL at 24 weeks. Participant report of ART adherence was evaluated using a structured questionnaire in monthly interviews. Adherence and readily available clinical and laboratory measures were evaluated as predictors of late virologic failure (late VF: confirmed HIV-1 RNA ≥1000 copies/mL after 24 weeks). Results: During median follow-up of 3.5 years, 82/911 participants (9%) experienced late VF. Of 516 participants reporting missed doses during the first 24 weeks of ART, 55 (11%) experienced late VF, compared with 27 (7%) of 395 participants reporting no missed doses (hazard ratio: 1.73; 95% CI: 1.08, 2.73). This difference persisted in multivariable analysis, in which lower pre-ART hemoglobin and absence of Grade ≥3 laboratory results prior to week 24 were also associated with higher risk of late VF. Discussion: In this clinical trial, the late VF rate after successful suppression was very low. If achievable in routine clinical practice, virologic monitoring involving infrequent (e.g. annual) measurements might be considered; the implications of this for development of resistance need evaluating. Patients reporting missed doses early after ART initiation, despite achieving initial suppression, might require more frequent measurement and/or strategies for promoting adherence

The Association between Multiple Sources of Information and Risk Perceptions of Tuberculosis, Ntcheu District, Malawi

<div><p>Background</p><p>Tuberculosis (TB) is one of the main causes of death in developing countries. Awareness and perception of risk of TB could influence early detection, diagnosis and care seeking at treatment centers. However, perceptions about TB are influenced by sources of information.</p><p>Aim</p><p>This study aimed to determine the association between multiple sources of information, and perceptions of risk of TB among adults aged 18–49 years.</p><p>Methods</p><p>A cross-sectional study was conducted in Ntcheu district in Malawi. A total of 121 adults were sampled in a three-stage simple random sampling technique. Data were collected using a structured questionnaire. Perceptions of risk were measured using specific statements that reflected common myths and misconceptions. Low risk perception implied a person having strong belief in myths and misconceptions about TB and high risk perception meant a person having no belief in myths or misconceptions and demonstrated understanding of the disease.</p><p>Results</p><p>Females were more likely to have low risk perceptions about TB compared to males (67.7% vs. 32.5%, p = 0.01). The higher the household asset index the more likely an individual had higher risk perceptions about TB (p = 0.006). The perception of risk of TB was associated with sources of information (p = 0.03). Use of both interpersonal communication and mass media was 2.8 times more likely to be associated with increased perception of risk of TB (Odds Ratio [OR] = 2.8; 95% Confidence interva1[CI]: 3.1–15. 6; p = 0.01). After adjusting for sex and asset ownership, use of interpersonal communication and mass media were more likely to be associated with higher perception of risk of TB (OR, 2.0; 95% CI: 1.65–10.72; p = 0.003) compared with interpersonal communication only (OR 1.6, 95%; CI: 1.13–8.98, p = 0.027).</p><p>Conclusion</p><p>The study found that there was association between multiple sources of information, and higher perceptions of risk of TB among adults aged 18–49 years.</p></div

Comparison of socio-demographic characteristic of participants by risk perception of TB.

<p>Note: *p< 0.05 is significant;</p><p>**Inter-Personal Communication</p><p>Comparison of socio-demographic characteristic of participants by risk perception of TB.</p

A Randomized Comparison of Anthropomorphic Changes With Preferred and Alternative Efavirenz-Based Antiretroviral Regimens in Diverse Multinational Settings

Background. Existing data on anthropomorphic changes in resource-limited settings primarily come from observational or cross-sectional studies. Data from randomized clinical trials are needed to inform treatment decisions in these areas of the world. Methods. The AIDS Clinical Trials Group Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) study was a prospective, randomized evaluation of the efficacy of emtricitabine/tenofovir + efavirenz (FTC/TDF + EFV) vs lamivudine/zidovudine + efavirenz (3TC/ZDV + EFV) for the initial treatment of human immunodeficiency virus (HIV)-1-infected individuals from resource-diverse settings. Changes in anthropomorphic measures were analyzed using mixed-effect models for repeated measurements, using all available measurements at weeks 48, 96, and 144. Intent-to-treat results are presented; as-treated results were similar. Results. Five hundred twenty-six participants were randomized to FTC/TDF + EFV, and 519 participants were randomized to 3TC/ZDV + EFV. Significantly greater increases from baseline to week 144 were seen among those randomized to FTC/TDF + EFV vs 3TC/ZDV + EFV in all measures except waist-to-hip ratio, with the following mean changes: weight, 4.8 vs 3.0 kg; body mass index, 1.8 vs 1.1 kg/m2; mid-arm, 1.7 vs 0.7 cm; waist, 5.2 vs 4.3 cm; hip, 3.8 vs 1.4 cm; and mid-thigh circumference, 3.1 vs 0.9 cm. There were 7 clinical diagnoses of lipoatrophy in the 3TC/ZDV + EFV arm compared with none in the FTC/TDF + EFV arm. The proportion of overweight or obese participants increased from 25% (week 0) to 42% (week 144) for FTC/TDF + EFV and from 26% to 38% for 3TC/ZDV + EFV. Conclusions. Our findings support first-line use of FTC/TDF + EFV in resource-limited settings and emphasize the need for interventions to limit weight gain among overweight or obese HIV-infected participants in all settings

Distribution of socio-demographic characteristics of the participants.

<p>Distribution of socio-demographic characteristics of the participants.</p

Factors associated with risk perceptions of tuberculosis: Sources of information while adjusting for sex, ownership of assets and ever been diagnosed with TB.

<p>Note: *p< 0.05 is significant</p><p>Note: **Inter-personal Communication</p><p>Factors associated with risk perceptions of tuberculosis: Sources of information while adjusting for sex, ownership of assets and ever been diagnosed with TB.</p