Kevin Marsh

BackgroundSymptoms of systemic lupus erythematosus (SLE) vary between patients, but those of increased disease activity typically include musculoskeletal and mucocutaneous manifestations such as joint pain, swelling, and rashes. Several treatment options are available to patients with SLE with variable efficacy. Many treatments, especially corticosteroids, cause unwanted side effects, although little is currently known about patients’ preferences for treatments of SLE.ObjectiveWe aimed to identify which attributes of SLE treatment are valued by patients and to quantify their relative importance.MethodsAdult participants with moderate-to-severe SLE were asked to make a series of choices between two hypothetical treatments in an online discrete choice experiment (DCE). A latent class model (LCL) was estimated to analyze choice data. Relative attribute importance (RAI) was calculated to determine the …

The WHO recommends that all affected countries work toward the elimination of malaria, even those still experiencing a high burden of disease. However, malaria programs in the final phase of elimination or those working to prevent re-establishment of transmission after elimination could benefit from specific evidence-based recommendations for these settings as part of comprehensive and quality-controlled malaria guidelines. The WHO convened an external guideline development group to formulate recommendations for interventions to reduce or prevent malaria transmission in areas with very low–to low-transmission levels and those that have eliminated malaria. In addition, several interventions that could be deployed in higher burden areas to accelerate elimination, such as mass drug administration, were reviewed. Systematic reviews were conducted that synthesized and evaluated evidence for the benefits …

Interest in using patient preference (PP) data alongside traditional economic models in health technology assessment (HTA) is growing, including using PP data to quantify non-health benefits. However, this is limited by a lack of standardised methods. In this article, we describe a method for using discrete choice experiment (DCE) data to estimate the value of non-health benefits in terms of quality-adjusted survival equivalence (QASE), which is consistent with the concept of value prevalent among HTA agencies. We describe how PP data can be used to estimate QASE, assess the ability to test the face-validity of QASE estimates of changes in mode of administration calculated from five published DCE oncology studies and review the methodological and normative considerations associated with using QASE to support HTA. We conclude that QASE may have some methodological advantages over alternative …

IntroductionInformation about patient preferences for the treatment of anaemia associated with chronic kidney disease (CKD) is scarce. Hence, our aim was to examine how patients with non-dialysis-dependent CKD valued attributes of alternative hypothetical anaemia treatments.MethodsA discrete choice experiment (DCE) was conducted in adult patients who reported a clinical diagnosis of CKD-related anaemia. Treatment attributes included mode and frequency of administration, need for iron supplementation, risk of gastrointestinal side effects, risk of major cardiovascular events and impact on energy levels (as defined by the vitality section of the SF-6D health index). Logit models were used to analyse patients’ preferences.ResultsThe DCE was completed by 200 patients in four countries. Patients preferred an oral mode of administration. Patients were willing to tolerate a 5.1% (95% CI 2.0–8.3%) increase in …

ObjectivesEngagement with decision-makers is crucial to the development of decision tools in health technology assessment. This study applied a continual stakeholder engagement approach to develop an open-source multi-criteria decision analysis (MCDA) to support decision-making in major depressive disorder (MDD) by diverse stakeholders in the US.MethodsThe MCDA was developed based on the 8-step process in ISPOR Good Practices Reports. We convened a twenty-member advisory group (AG) consisting of representatives from patient, clinician, employer, payer, manufacturer, and researcher perspectives throughout the process to ensure the module can effectively address real-world decision needs. Facilitated discussions were conducted to define decision problems, prioritize criteria, and identify performance metrics for different criteria. Three MCDA experts provided guidance to identify the best …

Background The Coronavirus disease 2019 (COVID-19) pandemic caused significantly lower reported mortalities on the African continent as compared to other regions. Yet, many countries on the continent are still contending with the devastating economic, social and indirect health impacts. African researchers and policy makers have identified research priority areas which take cognisance of the unique research needs of African countries. A baseline assessment of the alignment of funded research in Africa to these priorities and World Health Organization’s COVID-19 research priorities was undertaken in July, 2020. We present a two-year update to this analysis of funded COVID-19 research in Africa. Methods Data captured in the UK Collaborative on Development Research and Global Research Collaboration for Infectious Disease Preparedness COVID-19 Research Project Tracker as of 15th July, 2022 was analysed. An additional analysis of institutions receiving funding for COVID-19 research is presented. We also analysed the change in funding for COVID-19 research in Africa since July, 2020. Results The limited COVID-19 research identified in Africa early in the pandemic has persisted over the subsequent two-year period assessed. When number of projects are considered, governmental funders based in Europe and United States supported the most research. Only nine research funders based in Africa were identified. A number of partnerships between African institutions and institutions based on other continents were identified, however, most research projects were undertaken in research institutions based in Africa only. Our …

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS, S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short …

Objective: Blood pressure control is a challenge for patients for reasons including adherence, medication side effects, poor access to healthcare, and inconvenience of long-term treatment. Renal denervation is a treatment option that lowers blood pressure in combination with lifestyle modifications and medications, but it requires a minimally invasive procedure. This study assessed how patients make choices between treatments, and quantified their willingness to undergo renal denervation. Methods: An online discrete choice experiment (DCE) was completed by US adults with uncontrolled hypertension despite being prescribed ≥1 medication. In 10 DCE tasks, participants chose between two hypothetical treatments defined by the 10-year cardiovascular (CV) risk, current treatments (procedure/number of pills per day), durability/need for future treatments (additional procedure or pills), and risks of mild-to …

Benefit-risk assessment is commonly conducted by drug and medical device developers and regulators, to evaluate and communicate issues around benefit-risk balance of medical products. Quantitative benefit-risk assessment (qBRA) is a set of techniques that incorporate explicit outcome weighting within a formal analysis to evaluate the benefit-risk balance. This report describes emerging good practices for the 5 main steps of developing qBRAs based on the multicriteria decision analysis process. First, research question formulation needs to identify the needs of decision makers and requirements for preference data and specify the role of external experts. Second, the formal analysis model should be developed by selecting benefit and safety endpoints while eliminating double counting and considering attribute value dependence. Third, preference elicitation method needs to be chosen, attributes framed …

Natural killer (NK) cells are potent immune effectors that can be activated via antibody-mediated Fc receptor engagement. Using multiparameter flow cytometry, we found that NK cells degranulate and release IFN-γ upon stimulation with antibody-opsonized Plasmodium falciparum merozoites. Antibody-dependent NK (Ab-NK) activity was largely strain transcending and enhanced invasion inhibition into erythrocytes. Ab-NK was associated with the successful control of parasitemia after experimental malaria challenge in African adults. In an independent cohort study in children, Ab-NK increased with age, was boosted by concurrent P. falciparum infections, and was associated with a lower risk of clinical episodes of malaria. Nine of the 14 vaccine candidates tested induced Ab-NK, including some less well-characterized antigens: P41, P113, MSP11, RHOPH3, and Pf_11363200. These data highlight an important …

Host genetic factors can confer resistance against malaria, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member, –PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the …

Introduction Patient preferences (PPs) are an important source of evidence in health technology assessment (HTA). However, a methodological framework to achieve their integration in decision-making is lacking. We aim to investigate the potential role of evaluative frameworks to integrate PP evidence into HTA and decision-making. Methods We undertook a scoping review to identify potential methodological frameworks to consider PP evidence in HTA and evidence of the acceptability of these frameworks for decision-makers. We searched PubMed, Cochrane, and the grey literature to identify relevant studies, reports, or guidance documents. We restricted our search to the use of PP rather than patient experience data and excluded articles solely relating to deliberative approaches. Results Frameworks identified as having the potential to integrate PP evidence included cost-utility analysis, cost …

Background The increased use of patient preference data in healthcare decision making has raised concerns about the reliability and consistency of the estimates generated by patient preference studies. However, literature reviews to assess the consistency of preferences are confounded by heterogeneity in study designs. Methods This paper adopted a novel approach to evaluating preference consistency: comparing estimates of a single trade-off—the marginal rate of substitution (MRS) between survival improvements and risks of adverse events—across multiple patient groups and using meta-regression to assess whether MRS varied systematically between patients. A log-linear, random effects regression was run, weighted for the sample sizes of studies from which estimates were extracted. Results Using studies identified in …

Aim We examined the preferences of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for benefits and risks of tyrosine kinase inhibitors combined with chemotherapy for first-line treatment. Methods In a discrete choice experiment, 201 patients chose between hypothetical treatment alternatives with varied levels of remission duration and overall survival (OS), and risks of major cardiovascular (CV) events and myelosuppression. Results Although OS was the most important attribute to patients with Ph+ ALL, they were willing to tolerate a 2.9% increase in CV risk for 1 additional month of OS. Older patients (>59 years) and patients not in remission were less likely to tolerate increased CV risk. Conclusion Preferences and risk tolerance varied between patients, highlighting the importance of shared decision making when selecting treatments for Ph+ ALL.

Background Plasmodium falciparum variant surface antigens (VSAs) contribute to malaria pathogenesis by mediating cytoadhesion of infected red blood cells to the microvasculature endothelium. In this study, we investigated the association between anti-VSA antibodies and clinical outcome in a controlled human malaria infection (CHMI) study. Method We used flow cytometry and ELISA to measure levels of IgG antibodies to VSAs of five heterologous and one homologous P. falciparum parasite isolates, and to two PfEMP1 DBLβ domains in blood samples collected a day before the challenge and 14 days after infection. We also measured the ability of an individual’s plasma to inhibit the interaction between PfEMP1 and ICAM1 using competition ELISA. We then assessed the association between the antibody levels, function, and CHMI defined clinical outcome during a 21-day follow-up period post infection using Cox proportional hazards regression. Results Antibody levels to the individual isolate VSAs, or to two ICAM1-binding DBLβ domains of PfEMP1, were not associated with a significantly reduced risk of developing parasitemia or of meeting treatment criteria after the challenge after adjusting for exposure. However, anti-VSA antibody breadth (i.e., cumulative response to all the isolates) was a significant predictor of reduced risk of requiring treatment [HR 0.23 (0.10-0.50) p= 0.0002]. Conclusion The breadth of IgG antibodies to VSAs, but not to individual isolate VSAs, is associated with protection in CHMI.

Objective The objective of this study was to ascertain to what extent adults with migraine value an early onset of efficacy for preventive migraine treatments. Background In placebo‐controlled clinical trials, treatment with eptinezumab resulted in a lower proportion of adults with migraine on the first day following infusion (day 1; 14% point‐reduction for chronic migraine [CM] in PROMISE‐2 and 8% point‐reduction for episodic migraine [EM] in PROMISE‐1). Methods Adults with migraine completed an online preference‐elicitation thresholding exercise to ascertain to what extent they value not having a migraine on day 1 postdosing relative to a clinically relevant reduction in number of migraine days during the first month postdosing (≥2 migraine‐free days for CM and ≥1 migraine‐free days for EM). Results One hundred and one participants (mean age, 50.6 ± 12.4 years; 81 [80%] women) were included. In …

Background and ObjectiveNodding syndrome (NS) is a unique childhood-onset epileptic disorder that occurs predominantly in several regions of sub-Saharan Africa. The disease has been associated with Onchocerca volvulus (Ov)–induced immune responses and possible cross-reactivity with host proteins. The aim of this study was to compare structural changes in the brain on MRI between NS and other forms of onchocerciasis-associated epilepsies (OAEs) and to relate structural changes to the Ov-induced immune responses and level of disability.MethodsThirty-nine children with NS and 14 age-matched participants with other forms of OAE from an endemic region in Uganda underwent detailed clinical examination, serologic evaluation (including Ov-associated antibodies to Ov-16 and Hu-leiomodin-1) and quantitative volumetric analysis of brain MRIs (1.5 T scanner) using Neuroreader, a cloud-based …

BackgroundThe increase in artemisinin resistance threatens malaria elimination in Asia by the target date of 2030 and could derail control efforts in other endemic regions. This study aimed to develop up-to-date spatial distribution visualisations of the kelch13 (K13) gene markers of artemisinin resistance in Plasmodium falciparum for policy makers.MethodsIn this systematic review and spatiotemporal analysis we used the WorldWide Antimalarial Resistance Network (WWARN) surveyor molecular markers of artemisinin resistance database. We updated the database by searching PubMed and SCOPUS for studies published between Jan 1, 1990, and March 31, 2021. Articles were included if they contained data on K13 markers of artemisinin resistance from patients' samples in Asia and articles already included in the WWARN database were excluded. Data were extracted from the published articles and authors …

BackgroundResearch about the decision to participate in a clinical study has tended to be limited to single indications and has focused on narrow sets of study and participant characteristics. This study applied stated preference methods to understand the clinical trial design attributes that most influence willingness to participate and how this varied with participant characteristics.MethodsAdults residing in the US, China, or Poland with a self-reported diagnosis of cancer, heart disease, migraine, rheumatoid arthritis, or multiple sclerosis completed an online survey. Participants were asked whether they would participate in clinical studies defined by seventeen attributes within five categories (payment/support, administration/procedures, treatment-related, study location/time commitment, and data collection/feedback). Participants saw six different hypothetical clinical study profiles. Depending on their participation …

Background: Studies of long-term malaria cohorts have provided essential insights into how Plasmodium falciparum interacts with humans, and influences the development of antimalarial immunity. Immunity to malaria is acquired gradually after multiple infections, some of which present with clinical symptoms. However, there is considerable variation in the number of clinical episodes experienced by children of the same age within the same cohort. Understanding this variation in clinical symptoms and how it relates to the development of naturally acquired immunity is crucial in identifying how and when some children stop experiencing further malaria episodes. Where variability in clinical episodes may result from different rates of acquisition of immunity, or from variable exposure to the parasite.Methods: Using data from a longitudinal cohort of children residing in an area of moderate P. falciparum transmission in …

Background Malaria caused by Plasmodium falciparum remains a serious global public health challenge especially in Africa. Interventions that aim to reduce malaria transmission by targeting the gametocyte reservoir are key to malaria elimination and/or eradication. However, factors that are associated with gametocyte carriage have not been fully explored. Consequently, identifying predictors of the infectious reservoir is fundamental in the elimination campaign. Methods We cultured P. falciparum NF54 gametocytes (to stage V) and prepared crude gametocyte extract. Samples from a total of 687 participants (aged 6 months to 67 years) representing two cross-sectional study cohorts in Kilifi, Kenya were used to assess IgG antibody responses by ELISA. We also analyzed IgG antibody responses to the blood-stage antigen AMA1 as a marker of asexual parasite exposure. Gametocytemia and asexual parasitemia data quantified by microscopy and molecular detection (QT-NASBA) were used to determine the relationship with antibody responses, season, age, and transmission setting. Multivariable logistic regression models were used to study the association between antibody responses and gametocyte carriage. The predictive power of the models was tested using the receiver operating characteristic (ROC) curve. Results Multivariable logistic regression analysis showed that IgG antibody response to crude gametocyte extract predicted both microscopic (OR=1.81 95% CI: 1.06–3.07, p=0.028) and molecular (OR=1.91, 95% CI: 1.11–3.29, p=0.019) P. falciparum gametocyte carriage. Antibody responses to AMA1 were also associated with …

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant loss of life and developed into a historic threat to numerous healthcare systems around the world [1–5]. In response, many governments have imposed public health interventions with the aim of slowing down the spread of the SARS-Cov-2 virus causing COVID-19 [6–8]. While varying between countries, these interventions often included self-isolation, social distancing, closure of public places, restricted internal movement, and stay-at-home requirements [9]. Despite being effective in slowing the spread of the disease, the policies have detrimental effects on the economy, elective health care provision, mental health, and societal freedom [10, 11]. To pave a way for an exit strategy from imposed public health interventions, the development of medical treatments and vaccines has become a priority for governments worldwide [12]. However …

After decades of research, our understanding of when and why individuals infected with Plasmodium falciparum develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these interindividual variations, we analysed the long-term malaria epidemiology of children≤ 12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort’s limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria

A major obstacle to malaria elimination is the great capacity of the parasite and vector populations to evolve in response to malaria control interventions. The widespread use of chloroquine and DDT in the 1950’s led to high levels of drug and insecticide resistance, and the same pattern has been repeated for other first-line antimalarial drugs and insecticides. Over the past 15 years, mass distribution of pyrethroid-treated bednets in Africa and worldwide use of artemisinin combination therapy (ACT) has led to substantial reductions in malaria prevalence and mortality, but there are rapidly increasing levels of resistance to ACT in Southeast Asian parasites and of pyrethroid resistance in African mosquitoes. A deep understanding of local patterns of resistance and the continually changing nature of the local parasite and vector populations is necessary to manage the use of drugs and insecticides and to deploy public …

Higher academic institutions in the UK need to drive improvements in equity, diversity, and inclusion (EDI) through sustainable practical interventions. A broad view of inclusivity is based on an intersectional approach that considers race, geographical location, caring responsibilities, disability, neurodiversity, religion, and LGBTQIA+ identities. We describe the establishment of a diverse stakeholder group to develop practical grass-roots recommendations through which improvements can be advanced. We have developed a manifesto for change, comprising six domains through which academic institutions can drive progress through setting short, medium, and long-term priorities. Interventions will yield rewards in recruitment and retention of a diverse talent pool, leading to enhanced impact and output.

Objective: To determine the extent that patients with migraine value the early onset of efficacy of preventive migraine treatments. Background: Eptinezumab (anti-calcitonin gene-related peptide monoclonal antibody) was associated with an absolute therapeutic benefit of reducing migraine-likelihood on Day-1 post-infusion by 14% and 8% compared with placebo in patients with chronic migraine (CM; PROMISE-2 study) and episodic migraine (EM; PROMISE-1 study), respectively. Design/Methods: Adults (≥ 18yr) with CM or EM self-reporting≥ 4 monthly migraine days (MMDs) for≥ 3 months, with migraine history for≥ 12 months, completed a thresholding exercise (comparing 2 hypothetical treatments by varying 2 key attributes) to ascertain the relative value of migraine prevention on Day-1 post-dosing compared with meaningful reductions in MMDs in the first month post-dosing. Two frames were presented:(1) fixed first-month MMD reduction and varied migraine likelihood on Day-1 post-dosing;(2 …

Background Patients taking low-dose aspirin to prevent cardiovascular disease (CVD) may also benefit from a reduced risk of colorectal cancer (CRC). Objective The aim was to examine the preferences of people eligible for preventive treatment with low-dose aspirin and the trade-offs they are willing to make between CVD prevention, CRC prevention, and treatment risks. Methods A cross-sectional study using a discrete choice experiment (DCE) survey was conducted in Italy in 2019 to elicit preferences for three benefit attributes (prevention of ischemic stroke, myocardial infarction, and CRC) and four risk attributes (intracranial and gastrointestinal bleeding, peptic ulcer, and severe allergic reaction) associated with use of low-dose aspirin. Latent class logit models were used to evaluate variation in treatment preferences …

BackgroundEpilepsy remains a leading chronic neurological disorder in Low- and Middle-Income Countries. In Uganda, the highest burden is among young rural people. We aimed to; (i) describe socio-economic status (including schooling), and household poverty in adolescents living with epilepsy (ALE) compared to unaffected counterparts in the same communities and (ii) determine the factors associated with the overall quality of life (QoL).MethodsThis was a cross-sectional survey nested within a larger study of ALE compared to age-matched healthy community children in Uganda. Between Sept 2016 to Sept 2017, 154 ALE and 154 healthy community controls were consecutively recruited. Adolescents recruited were frequency and age-matched based on age categories 10–14 and 15–19 years. Clinical history and standardized assessments were conducted. One control participant had incomplete …

Background: The Kilifi Health and Demographic Surveillance System (KHDSS) was established in 2000 to define the incidence and prevalence of local diseases and evaluate the impact of community-based interventions. KHDSS morbidity data have been reported comprehensively but mortality has not been described. This analysis describes mortality in the KHDSS over 16 years.Methods: We calculated mortality rates from 2003–2018 in four intervals of equal duration and assessed differences in mortality across these intervals by age and sex. We calculated the period survival function and median survival using the Kaplan–Meier method and mean life expectancies using abridged life tables. We estimated trend and seasonality by decomposing a time series of monthly mortality rates. We used choropleth maps and random-effects Poisson regression to investigate geographical heterogeneity.Results: Mortality …

Host genetic factors can confer resistance against malaria, raising the question of whether this has led to evolutionary adaptation of parasite populations. In this study we investigated the correlation between host and parasite genetic variation in 4,171 Gambian and Kenya children ascertained with severe malaria due to Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and variation in three regions of the parasite genome, including nonsynonymous variants in the acyl-CoA synthetase family member PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The HbS-associated parasite alleles are in strong linkage disequilibrium and have frequencies which covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome, and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.

BackgroundSevere metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings.MethodsA retrospective analysis of the ‘Artesunate versus quinine in the treatment of severe falciparum malaria in African children’ (AQUAMAT) trial was conducted to identify clinical features of severe metabolic acidosis and uraemia in 5425 children from nine African countries. Separate models were fitted for uraemia and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis and uraemia. Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model …

Introduction Naturally acquired immune responses against antigens expressed on the surface of mature gametocytes develop in individuals living in malaria-endemic areas. Evidence suggests that such anti-gametocyte immunity can block the development of the parasite in the mosquito, thus playing a role in interrupting transmission. A better comprehension of naturally acquired immunity to these gametocyte antigens can aid the development of transmission-blocking vaccines and improve our understanding of the human infectious reservoir. Methods Antigens expressed on the surface of mature gametocytes that had not previously been widely studied for evidence of naturally acquired immunity were identified for protein expression alongside Pfs230-C using either the mammalian HEK293E or the wheat germ cell-free expression systems. Where there was sequence variation in the candidate antigens (3D7 vs a clinical isolate PfKE04), both variants were expressed. ELISA was used to assess antibody responses against these antigens, as well as against crude stage V gametocyte extract (GE) and AMA1 using archived plasma samples from individuals recruited to participate in malaria cohort studies. We analyzed antibody levels (estimated from optical density units using a standardized ELISA) and seroprevalence (defined as antibody levels greater than three standard deviations above the mean levels of a pool of malaria naïve sera). We described the dynamics of antibody responses to these antigens by identifying factors predictive of antibody levels using linear regression models. Results Of the 25 antigens selected, seven antigens were …

Health technology assessment (HTA) agencies vary in their use of quantitative patient preference data (PP) and the extent to which they have formalized this use in their guidelines. Based on the authors' knowledge of the literature, we identified six different PP “use cases” that integrate PP into HTA in five different ways: through endpoint selection, clinical benefit rating, predicting uptake, input into economic evaluation, and a means to weight all HTA criteria. Five types of insight are distinguished across the use cases: understanding what matters to patients, predicting patient choices, estimating the utility generated by treatment benefits, estimating the willingness to pay for treatment benefits, and informing distributional considerations. Summarizing the literature on these use cases, we recommend circumstances in which PP can add value to HTA and the further research and guidance that is required to support the …

Background Benefit–risk assessments for medicinal products and devices have advanced significantly over the past decade. The purpose of this study was to characterize the extent to which the life sciences industry is utilizing quantitative benefit–risk assessment (qBRA) methods. Methods Semi-structured interviews were conducted with a sample of industry professionals working in drug and/or medical device benefit–risk assessments (n = 20). Questions focused on the use, timing, and impact of qBRA; implementation challenges; and future plans. Interviews were recorded, transcribed, and coded for thematic analysis. Results While most surveyed companies had applied qBRA, application was limited to a small number of assets—primarily to support internal decision-making and regulatory submissions. Positive …

Globally, epilepsy is the most common chronic neurological disorder. The incidence in sub-Saharan Africa is 2-3 times higher than that in high income countries. Infection by Onchocerca volvulus may be an underlying risk factor for the high burden and based upon epidemiological associations, has been proposed to cause a group of disorders—Onchocerca associated epilepsies (OAE) like nodding syndrome (NS). To improve our understanding of the disease spectrum, we described the clinical, electroencephalographic (EEG) and magnetic resonance imaging (MRI) features of children with epilepsy and sero-positive for Onchocerca volvulus (possible OAEs other than nodding syndrome). Twenty-nine children and adolescents with non-nodding syndrome OAE in northern Uganda were enrolled. A diagnosis of OAE was made in patients with epilepsy and seizure onset after age 3 years, no reported exposure to perinatal severe febrile illness or traumatic brain injury, no syndromic epilepsy diagnosis and a positive Ov-16 ELISA test. Detailed clinical evaluation including psychiatric, diagnostic EEG, a diagnostic brain MRI (in 10 patients) and laboratory testing were performed. Twenty participants (69%) were male. The mean age was 15.9 (standard deviation [SD] 1.9) years while the mean age at seizure onset was 9.8 (SD 2.9) years. All reported normal early childhood development. The most common clinical presentation was a tonic-clonic seizure. The median number of seizures was 2 (IQR 1–4) in the previous month. No specific musculoskeletal changes, or cranial nerve palsies were reported, neither were any vision, hearing and speech …

Epidemiological studies suggest a link between onchocerciasis and various forms of epilepsy, including nodding syndrome (NS). The aetiopathology of onchocerciasis associated epilepsy remains unknown. This case-control study investigated potential risk factors that may lead to NS and other forms of non-nodding epilepsy (OFE) in northern Uganda. We consecutively recruited 154 persons with NS (aged between 8 and 20 years), and age-frequency matched them with 154 with OFE and 154 healthy community controls. Participants’ socio-demography, medical, family, and migration histories were recorded. We tested participants for O. volvulus serum antibodies. The 154 controls were used for both OFE and NS separately to determine associations. We recruited 462 people with a median age of 15 years (IQR 14, 17); 260 (56.4%) were males. Independent risk factors associated with the development of NS were the presence of O. volvulus antibodies [aOR 8.79, 95% CI (4.15–18.65), p-value < 0.001] and preterm birth [aOR 2.54, 95% CI (1.02–6.33), p-value = 0.046]. Risk factors for developing OFE were the presence of O. volvulus antibodies [aOR 8.83, 95% CI (4.48–17.86), p-value < 0.001] and being born in the period before migration to IDP camps [aOR 4.28, 95% CI (1.20–15.15), p-value = 0.024]. In conclusion, O. volvulus seropositivity was a risk factor to develop NS and OFE; premature birth was a potential co-factor. Living in IDP camps was not a risk factor for developing NS or OFE.

Background Studies recommend randomising the order of attributes in discrete choice experiments (DCEs) to avoid bias; however, in a benefit–risk setting, this may increase the cognitive burden of respondents who compare the benefits and risks of treatments, or may affect their decision-making process. Based on these concerns, this paper explored attribute ordering effects in a benefit–risk DCE. Method Attribute ordering effects were explored in a large pilot DCE relating to the medical treatment of insomnia. Participants were randomised to one of three presentation orders: (1) benefits were presented before risks (BR); (2) risks were presented before benefits (RB); (3) all attributes were randomised (RN). For the RB and BR presentation orders, attributes were randomised within benefits and risks. Responses were assessed in three ways. First …

This study reports on the application of a Portfolio Decision Analysis (PDA) to support investment decisions of a non-profit funder of vaccine technology platform development for rapid response to emerging infections. A value framework was constructed via document reviews and stakeholder consultations. Probability of Success (PoS) data was obtained for 16 platform projects through expert assessments and stakeholder portfolio preferences via a Discrete Choice Experiment (DCE). The structure of preferences and the uncertainties in project PoS suggested a non-linear, stochastic value maximization problem. A simulation-optimization algorithm was employed, identifying optimal portfolios under different budget constraints. Stochastic dominance of the optimization solution was tested via mean-variance and mean-Gini statistics, and its robustness via rank probability analysis in a Monte Carlo simulation. Project PoS estimates were low and substantially overlapping. The DCE identified decreasing rates of return to investing in single platform types. Optimal portfolio solutions reflected this non-linearity of platform preferences along an efficiency frontier and diverged from a model simply ranking projects by PoS-to-Cost, despite significant revisions to project PoS estimates during the review process in relation to the conduct of the DCE. Large confidence intervals associated with optimization solutions suggested significant uncertainty in portfolio valuations. Mean-variance and Mean-Gini tests suggested optimal portfolios with higher expected values were also accompanied by higher risks of not achieving those values despite stochastic dominance of …

Objective Nodding syndrome is a poorly understood epileptic encephalopathy characterized by a unique seizure type—head nodding—and associated with Onchocerca volvulus infection. We hypothesized that altered immune activation in the cerebrospinal fluid (CSF) and plasma of children with nodding syndrome may yield insights into the pathophysiology and progression of this seizure disorder. Method We conducted a case‐control study of 154 children (8 years or older) with long‐standing nodding syndrome and 154 healthy age‐matched community controls in 3 districts of northern Uganda affected by nodding syndrome. Control CSF samples were obtained from Ugandan children in remission from hematological malignancy during routine follow‐up. Markers of immune activation and inflammation (cytokines and chemokines) and complement activation (C5a) were measured in plasma and CSF using …

Background Patient preference information is increasingly being used to inform decision making; however, further work is required to support the collection of preference information in rare diseases. This study illustrates the use of direct preference elicitation methods to collect preference data from small samples in the context of early decision making to inform the development of a product for the treatment of immunoglobulin A nephropathy. Method An interview-based swing weighting approach was used to elicit preferences from 40 patients in the US and China. Attributes were identified through a background review, expert engagement and patient focus groups. Participants completed a series of tasks that involved ranking, rating and scoring improvements in the attributes to obtain attribute swing weights and partial value functions. The preference …

IntroductionIn March 2020 the World Health Organisation (WHO) released a Global Research Roadmap in an effort to coordinate and accelerate the global research response to combat COVID-19 based on deliberations of 400 experts across the world. Three months on, the disease and our understanding have both evolved significantly. As we now tackle a pandemic in very different contexts and with increased knowledge, we sought to build on the work of the WHO to gain a more current and global perspective on these initial priorities. MethodsWe undertook a mixed methods study seeking the views of the global research community to i) assess which of the early WHO roadmap priorities are still most pressing; ii) understand whether they are still valid in different settings, regions or countries; and iii) identify any new emerging priorities. ResultsThematic analysis of the significant body of combined data shows the WHO roadmap is globally relevant, however, new important priorities have emerged, in particular, pertinent to low and lower-middle income countries (less resourced countries), where health systems are under significant competing pressures. We also found a shift from prioritising vaccine and therapeutic development towards a focus on assessing the effectiveness, risks, benefits and trust in the variety of public health interventions and measures. Our findings also provide insight into temporal nature of these research priorities, highlighting the urgency of research that can only be undertaken within the period of virus transmission, as well as other important research questions but which can be answered outside the transmission period …

Background and Aims Anaemia is a common complication of chronic kidney disease (CKD) that is associated with fatigue, shortness of breath, and lethargy. CKD anaemia is commonly treated with oral or intravenous (IV) iron and IV or subcutaneous (SC) erythropoiesis-stimulating agents (ESAs). The objectives of this study were to understand patients’ experiences with CKD anaemia and their preferences related to treatment. Method Qualitative 60-minute semi-structured interviews were conducted with ESA-treated adult CKD patients with anaemia, either non–dialysis-dependent (ND) or dialysis-dependent (DD), and with practicing nephrologists in France, Germany, Spain, the UK, and Japan. The patients’ interviews, appropriately tailored for ND and DD patients, comprised three sections: 1) patients’ views on the burden of the disease and its treatment; 2) discussion of …

Background: Since the 2000s, rates of remission and overall survival (OS) in patients with Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) have improved thanks to combination therapy with tyrosine kinase inhibitors (TKIs) and conventional chemotherapy. The aim of this study was to elicit relative preferences for risks and benefits of first-line treatment with TKI-chemotherapy combinations in adult Ph+ ALL patients.Material and Methods: Between February and April 2020, adult patients in the US with self-reported Ph+ ALL completed an online discrete choice experiment (DCE) comprising 12 experimental and 2 internal validity choice tasks. Each task asked participants to choose between 2 hypothetical treatments comprising different levels of benefits and risks. The DCE was pilot tested and refined through interviews with 5 patients to ensure that the attributes and levels were understood …

Understanding the functional role of proteins expressed by Plasmodium falciparum is an important step toward unlocking potential targets for the development of therapeutic or diagnostic interventions. The armadillo (ARM) repeat protein superfamily is associated with varied functions across the eukaryotes. Therefore, it is important to understand the role of members of this protein family in Plasmodium biology. The Plasmodium falciparum armadillo repeats only (PfARO; Pf3D7_0414900) and P. falciparum merozoite organizing proteins (PfMOP; Pf3D7_0917000) are armadillo-repeat containing proteins previously characterized in P. falciparum. Here, we describe the characterization of another ARM repeat-containing protein in P. falciparum, which we have named the P. falciparum Merozoites-Associated Armadillo repeats protein (PfMAAP). Antibodies raised to three different synthetic peptides of PfMAAP show apical staining of free merozoites and those within the mature infected schizont. We also demonstrate that the antibodies raised to the PfMAAP peptides inhibited invasion of erythrocytes by merozoites from different parasite isolates. In addition, naturally acquired human antibodies to the N- and C- termini of PfMAAP are associated with a reduced risk of malaria in a prospective cohort analysis.

Healthcare decisions, whether they are made by individuals (such as physicians or patients), in committees on behalf of the general population, or by pharmaceutical companies making strategic decisions about their pipelines, invariably require choices between different courses of actions characterized by multiple and often conflicting objectives, and may involve a variety of stakeholders with different goals. In these circumstances, multicriteria decision analysis (MCDA) can help to avoid suboptimal choices. This chapter provides a brief overview of MCDA and its applications in healthcare decision making, summarizes the steps involved in conducting an MCDA, and illustrates these with an MCDA used to support individuals to choose between contraceptive methods.

Background Cutaneous leishmaniasis (CL) is a disease that often affects exposed skin areas and may heal leaving lifelong scars. Patients’ expectations from treatment are rarely considered in drug development for CL. An initiative aiming to address shortcomings in clinical trial design and conduct for CL treatments involving the researchers’ community is on-going. This manuscript presents patient-preferred outcomes for CL and an assessment on how to consider these in the conduct of future trials. Methodology/Principal findings We report preferred treatment outcomes by 74 patients with confirmed CL in endemic regions of Brazil, Burkina Faso, Colombia, Iran, Morocco, Peru and Tunisia during individual in-depth interviews. Beyond outcomes customarily considered in trials (such as lesion appearance and adverse events), patients talked about a large number of outcomes related to quality of life, such as pain, scar formation, and others affecting their work and daily activities. They also reported fears around getting rid of the parasite, disease recurrence, and possible sequelae. Conclusions/Significance The study results provide a rich insight into important outcomes for CL treatments, as well as related topics, from the perspective of a diverse patient population. Among the outcomes identified, we argue that those related to quality of life as well as recurrence should be included to a greater extent for assessment in clinical trials, and discuss the suitability of measurement instruments such as the Dermatology Quality of Life Index (DLQI). Interviews also point out the potential need to address concerns related to parasitological cure or scar …

MethodsAttributes and levels were selected based on a review of clinical studies and qualitative research on patients. Computer-assisted, interview-based swing weighting exercises were piloted in a focus group with five participants each from the US and China. Preferences were then elicited in interviews with twenty-five patients in the US and fifteen patients in China. Consistency tests were used to assess internal validity. Qualitative data were collected on the reasons for patients’ preferences.ResultsPreference consistency: The weights for one attribute were elicited twice. The difference between initial and consistency test weights was not statistically significant (p< 0.1), although this may partly reflect the small sample sizes. Trade-offs: Qualitative data were used to demonstrate the validity of interpreting participants’ ratings as trade-offs. Using the partial value function for end-stage renal disease as an example …

Introduction Emerging data from Africa indicates remarkably low numbers of reported COVID-19 deaths despite high levels of disease transmission. However evolution of these trends as the pandemic progresses remains unknown. More certain are the devastating long-term impacts of the pandemic on health and development evident globally. Research tailored to the unique needs of African countries is crucial. UKCDR and GloPID-R have launched a tracker of funded COVID-19 projects mapped to the WHO research priorities and research priorities of Africa and less-resourced countries and published a baseline analysis of a Living Systematic Review (LSR) of these projects. Methods In-depth analyses of the baseline LSR for COVID-19 funded research projects in Africa (as of 15th July 2020) to determine the funding landscape and alignment of the projects to research priorities of relevance to Africa. Results The limited COVID-19 related research across Africa appears to be supported mainly by international funding, especially from Europe, although with notably limited funding from United States-based funders. At the time of this analysis no research projects funded by an African-based funder were identified in the tracker although there are several active funding calls geared at research in Africa and there may be funding data which has not been made publicly available. Many projects mapped to the WHO research priorities and 5 particular gaps in research funding were identified namely investigating the role of children in COVID-19 transmission; effective modes of community engagement; health systems research; communication of …

ObjectiveThis study examines European decision makers' consideration and use of quantitative preference data.MethodsThe study reviewed quantitative preference data usage in 31 European countries to support marketing authorization, reimbursement, or pricing decisions. Use was defined as: agency guidance on preference data use, sponsor submission of preference data, or decision-maker collection of preference data. The data could be collected from any stakeholder using any method that generated quantitative estimates of preferences. Data were collected through: (1) documentary evidence identified through a literature and regulatory websites review, and via key opinion leader outreach; and (2) a survey of staff working for agencies that support or make healthcare technology decisions.ResultsPreference data utilization was identified in 22 countries and at a European level. The most prevalent use (19 …

ObjectivesLow-dose aspirin (LDA; 100mg), indicated as an antiplatelet for prevention of cardiovascular (CV) events, has been found to have preventative effect on colorectal cancer (CRC). This study assessed heterogeneity in patient preferences for efficacy including CV and CRC prevention, as well as safety outcomes associated with LDA in primary and secondary prevention of CV events in Italy.MethodsIndividuals in Italy eligible for LDA treatment completed a discrete choice experiment (DCE) to elicit preferences for LDA benefits (myocardial infarction prevention, ischaemic stroke and CRC) and risks (gastrointestinal bleeding, peptic ulcer, intracranial bleeding and severe allergic reaction). Participants were divided into primary prevention cohort (PPC) and secondary prevention cohort (SPC) which were analysed separately using latent class logit models.ResultsA total of 1,005 participants completed the DCE …

PP data quantifies how patients make trade-offs involved in treatment decisions. Decision makers are increasingly interested in using quantitative PP data to support their decisions. For instance, the US Food and Drug Administration’s (FDA) Center for Devices and Radiological Health (CDRH) encourages manufacturers to submit PP data to support its benefit-risk assessment. 2 Health technology assessment (HTA) often also involves the use of quantitative preference data. However, HTA agencies have tended to use general population preferences to estimate utility

IntroductionIn March 2020, the WHO released a Global Research Roadmap in an effort to coordinate and accelerate the global research response to combat COVID-19 based on deliberations of 400 experts across the world. Three months on, the disease and our understanding have both evolved significantly. As we now tackle a pandemic in very different contexts and with increased knowledge, we sought to build on the work of the WHO to gain a more current and global perspective on these initial priorities.MethodsWe undertook a mixed methods study seeking the views of the global research community to (1) assess which of the early WHO roadmap priorities are still most pressing; (2) understand whether they are still valid in different settings, regions or countries; and (3) identify any new emerging priorities.ResultsThematic analysis of the significant body of combined data shows the WHO roadmap is globally …

BACKGROUND: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL), an aggressive disease with historically poor survival in adults, is treated with tyrosine kinase inhibitors (TKI) plus chemotherapy. Choosing a TKI involves considering a variety of factors, including the benefits and risks of each therapy. This study aims to understand patients' preferences for these benefits and risks, and how this varies between patients.METHODS: In a US-based study conducted between February and April 2020, adult patients (≥ 18 years) with self-reported Ph+ALL (newly diagnosed and relapsed/refractory) completed an online discrete choice experiment (DCE) comprising 12 experimental and 2 internal validity choice tasks. For each task, patients were asked to choose between 2 hypothetical treatments with different levels of benefits and risks. Attributes and levels in the DCE included overall survival …