Markov chain Monte Carlo and expectation maximization approaches for estimation of haplotype frequencies for multiply infected human blood samples

Background Haplotypes are important in anti-malarial drug resistance because genes encoding drug resistance may accumulate mutations at several codons in the same gene, each mutation increasing the level of drug resistance and, possibly, reducing the metabolic costs of previous mutation. Patients often have two or more haplotypes in their blood sample which may make it impossible to identify exactly which haplotypes they carry, and hence to measure the type and frequency of resistant haplotypes in the malaria population. Results This study presents two novel statistical methods expectation–maximization (EM) and Markov chain Monte Carlo (MCMC) algorithms to investigate this issue. The performance of the algorithms is evaluated on simulated datasets consisting of patient blood characterized by their multiplicity of infection (MOI) and malaria genotype. The datasets are generated using different resistance allele frequencies (RAF) at each single nucleotide polymorphisms (SNPs) and different limit of detection (LoD) of the SNPs and the MOI. The EM and the MCMC algorithm are validated and appear more accurate, faster and slightly less affected by LoD of the SNPs and the MOI compared to previous related statistical approaches. Conclusions The EM and the MCMC algorithms perform well when analysing malaria genetic data obtained from infected human blood samples. The results are robust to genotyping errors caused by LoDs and function well even in the absence of MOI data on individual patients

Reconceptualizing Open Access to Theses and Dissertations

The global COVID-19 crisis has turned public attention to the special need for accessing those cutting-edge studies that are needed for further scientific innovation. Theses and dissertations (TDs) are prominent examples of such studies. TDs are academic research projects conducted by graduate students to acquire a high academic degree, such as a PhD. They encompass not only knowledge about basic science but also knowledge that generates social and economic value for society. Therefore, access to TDs is imperative for promoting science and innovation. Open access to scientific publications has been in the focus of public policy discourse for two decades, but progress toward this end has been limited. As part of this discourse, there has been no systematic discussion of the special case of TDs and of the justification for adopting an open access publication policy toward them. The present study aims to fill this gap. We argue that the essence of TDs as unique outputs of academic research merits a special policy mandating the publication of these studies in open access format, subject to certain exceptions. This policy is underpinned by several arguments, which we develop in our study, based on historic and normative analysis. These considerations support reconceiving access to TDs using an open access approach designated particularly for them. To better understand current open access policies toward TDs, we conducted a limited semi-empirical investigation to collect information. Our findings confirm that–despite the growing awareness of the importance of an open access TDs policy–no standard policy exists. Therefore, we propose to establish a mandatory global policy and standardization regarding the publication of TDs in designated repositories, open to the public, that would generate together an “open world wide web of TDs.” Such a global framework would facilitate the progress of science and promote the public good worldwide. In the aftermath of the global COVID-19 crisis, it seems that the time is ripe for such a move at both international and national levels

Reconceptualizing Open Access to Theses and Dissertations

Theses and dissertations (TD) are academic research projects that are conducted by graduate students to acquire a high academic degree, such as a PhD. The perception of the written TD has evolved over the years, following changes concerning the purpose of advanced academic studies. Today, these academic fruits should meet a high standard of academic innovation, which is understood broadly as encompassing not only knowledge concerning basic science but also the knowledge that generates social and economic value for society. The modern perception of TD has generated a call for their greater accessibility, as part of the Open Science movement. Nevertheless, in many countries around the world TD are not published in an open access format. While the normative basis for open access approach to publicly funded academic research is extensively discussed in the literature, there is a lack of legal and normative discussion concerning the special case of TD. The present study aims at filling this gap. We argue that the essence of TD as unique outputs of academic research merits a special stance compelling the publication of these studies in open access format, subject to certain exceptions. This stance is underpinned by several arguments, which we develop in our study, based on historic and normative analysis. Moreover, we propose to establish a mandatory global policy and standardization regarding the publication of TD in designated repositories, open to the public, that would generate together an open world wide web of TD. Such a global framework will facilitate the progress of science and promote the public good worldwide

Comparing the Efficacy of Drug Regimens for Pulmonary Tuberculosis: Meta-analysis of Endpoints in Early-Phase Clinical Trials

Background A systematic review of early clinical outcomes in tuberculosis was undertaken to determine ranking of efficacy of drugs and combinations, define variability of these measures on different endpoints, and to establish the relationships between them. Methods Studies were identified by searching PubMed, Medline, Embase, LILACS (Latin American and Caribbean Health Sciences Literature), and reference lists of included studies. Outcomes were early bactericidal activity results over 2, 7, and 14 days, and the proportion of patients with negative culture at 8 weeks. Results One hundred thirty-three trials reporting phase 2A (early bactericidal activity) and phase 2B (culture conversion at 2 months) outcomes were identified. Only 9 drug combinations were assessed on >1 phase 2A endpoint and only 3 were assessed in both phase 2A and 2B trials. Conclusions The existing evidence base supporting phase 2 methodology in tuberculosis is highly incomplete. In future, a broader range of drugs and combinations should be more consistently studied across a greater range of phase 2 endpoints

Quality of reporting of outcomes in phase III studies of pulmonary tuberculosis: a systematic review

Abstract Background Despite more than 60 years of clinical trials, tuberculosis (TB) still causes a high global burden of mortality and morbidity. Treatment currently requires multiple drugs in combination, taken over a prolonged period. New drugs are needed to shorten treatment duration, prevent resistance and reduce adverse events. However, to improve on current methodology in drug development, a more complete understanding of the existing clinical evidence base is required. Methods A systematic review was undertaken to summarise outcomes reported in phase III trials of patients with newly diagnosed pulmonary TB. A systematic search of databases (PubMed, MEDLINE, EMBASE, CENTRAL and LILACs) was conducted on 30 November 2017 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes. Results Of 248 included studies, 229 considered “on-treatment” outcomes whilst 148 reported “off-treatment” outcomes. There was wide variation and ambiguity in the definition of reported outcomes, including their relationship to treatment and in the time points evaluated. Additional challenges were observed regarding the analysis approach taken (per protocol versus intention to treat) and the varying durations of “intensive” and “continuation” phases of treatment. Bacteriological outcomes were most frequently reported but radiological and clinical data were often included as an implicit or explicit component of the overall definition of outcome. Conclusions Terminology used to define long-term outcomes in phase III trials is inconsistent, reflecting evolving differences in protocols and practices. For successful future cumulative meta-analysis, the findings of this review suggest that greater availability of individual patient data and the development of a core outcome set would be desirable. In the meantime, we propose a simple and logical approach which should facilitate combination of key evidence and inform improvements in the methodology of TB drug development and clinical trials

Meta-analysis of changes in the levels of catecholamines and blood pressure with continuous positive airway pressure therapy in obstructive sleep apnea

Stress from obstructive sleep apnea (OSA) stimulates catecholamine release consequently exacerbating hypertension. However, different studies have shown a conflicting impact of continuous positive airway pressure (CPAP) treatment in patients with OSA on catecholamine levels and blood pressure. We aimed to examine changes to catecholamine levels and blood pressure in response to CPAP treatment. We conducted a meta‐analysis of data published up to May 2020. The quality of the studies was evaluated using standard tools for assessing the risk of bias. Meta‐analysis was conducted using RevMan (v5.3) and expressed in standardized mean difference (SMD) for catecholamines and mean difference (MD) for systolic (SBP) and diastolic blood pressure (DBP). A total of 38 studies met our search criteria; they consisted of 14 randomized control trials (RCT) totaling 576 participants and 24 prospective cohort studies (PCS) of 547 participants. Mean age ranged between 41 and 62 year and body mass index between 27.2 and 35.1 kg/m(2). CPAP treatment reduced 24‐hour urinary noradrenaline levels both in RCT (SMD = −1.1; 95% confidence interval (CI): −1.63 to − 0.56) and in PCS (SMD = 0.38 (CI: 0.24 to 0.53). SBP was also reduced by CPAP treatment in RCT (4.8 mmHg; CI: 2.0‐7.7) and in PCS (7.5 mmHg; CI: 3.3‐11.7). DBP was similarly reduced (3.0 mmHg; CI: 1.4‐4.6) and in PCS (5.1 mmHg; CI: 2.3‐8.0). In conclusion, CPAP treatment in patients with OSA reduces catecholamine levels and blood pressure. This suggests that sympathetic activity plays an intermediary role in hypertension associated with OSA‐related stress

The Use of Haplotypes in the Identification of Interaction between SNPs

Although haplotypes can provide great insight into the complex relationships between functional polymorphisms at a locus, their use in modern association studies has been limited. This is due to our inability to directly observe haplotypes in studies of unrelated individuals, but also to the extra complexity involved in their analysis and the difficulty in identifying which is the truly informative haplotype. Using a series of simulations, we tested a number of different models of a haplotype carrying two functional single nucleotide polymorphisms (SNPs) to assess the ability of haplotypic analysis to identify functional interactions between SNPs at the same locus. We found that, when phase is known, analysis of the haplotype is more powerful than analysis of the individual SNPs. The difference between the two approaches becomes less either as an increasing number of non-informative SNPs are included, or when the haplotypic phase is unknown, while in both cases the SNP association becomes progressively better at identifying the association. Our results suggest that when novel genotyping and bioinformatics methods are available to reconstruct haplotypic phase, this will permit the emergence of a new wave of haplotypic analysis able to consider interactions between SNPs with increased statistical power.</p