Joint epidemic and spatio-temporal approach for modelling disease outbreaks

When forecasting epidemics, the main interests lie in understanding the determinants of transmission and predicting who is likely to become infected next. However, for vector-borne diseases, data availability and alteration can constitute an obstacle to doing so: climate change and globalized trade contribute to the expansion of vector habitats to different territories and hence the distribution of many diseases. As a consequence, in the face of a rapidly changing environmental and ecological climatic conditions, previously well-fitted models might become obsolete soon. The demand for precise forecast and prediction of the spread of a disease requires a model that is flexible with respect to the availability of vector data, unobserved random effects and only partially observed data for diseases incidence. Thus, we introduce a combination of a mechanistic SIR model with principled data-based methods from geostatistics. We allow flexibility by replacing a parameter of a continuous-time mechanistic model with a random effect, that is assumed to stem from a spatial Gaussian process. By employing Bayesian inference techniques, we identify points in space where transmission (as opposed to simply incidence) is unusually high or low compared to a national average. We explore how well the spatial random effect can be recovered within a mechanistic model and only partially observed outbreak data available. To this end, we extended the Python probabilistic programming library PyMC3 with our own sampler to effectively impute missing infection and removal time data

Automatic classification of farms and traders in the pig production chain

The trade in live pigs is an essential risk factor in the spread of animal diseases. Traders play a key role in the trade network, as they are logistics hubs and responsible for large animal movements. In order to implement targeted control measures in case of a disease outbreak, it is hence strongly advisable to use information about the holding type in the pig production chain. However, in many datasets the types of the producing farms or the fact whether the agent is a trader are unknown. In this paper we introduce two indices that can be used to identify the position of a producing farm in the pig production chain and more importantly, identify traders. This was realized partially through a novel dynamic programming algorithm. Analyzing the pig trade network in Germany from 2005 to 2007, we demonstrate that our algorithm is very sensitive in detecting traders. Since the methodology can easily be applied to trade networks in other countries with similar infrastructure and legislation, we anticipate its use for augmenting the datasets in further network analyses and targeting control measures. For further usage, we have developed an R package which can be found in the supplementary material to this manuscript

Effectiveness and cost-effectiveness of four different strategies for SARS-CoV-2 surveillance in the general population (CoV-Surv Study): study protocol for a two-factorial randomized controlled multi-arm trial with cluster sampling

Background: To achieve higher effectiveness in population-based SARS-CoV-2 surveillance and to reliably predict the course of an outbreak, screening, and monitoring of infected individuals without major symptoms (about 40% of the population) will be necessary. While current testing capacities are also used to identify such asymptomatic cases, this rather passive approach is not suitable in generating reliable population-based estimates of the prevalence of asymptomatic carriers to allow any dependable predictions on the course of the pandemic. Methods: This trial implements a two-factorial, randomized, controlled, multi-arm, prospective, interventional, single-blinded design with cluster sampling and four study arms, each representing a different SARS-CoV-2 testing and surveillance strategy based on individuals' self-collection of saliva samples which are then sent to and analyzed by a laboratory. The targeted sample size for the trial is 10,000 saliva samples equally allocated to the four study arms (2500 participants per arm). Strategies differ with respect to tested population groups (individuals vs. all household members) and testing approach (without vs. with pre-screening survey). The trial is complemented by an economic evaluation and qualitative assessment of user experiences. Primary outcomes include costs per completely screened person, costs per positive case, positive detection rate, and precision of positive detection rate. Discussion: Systems for active surveillance of the general population will gain more importance in the context of pandemics and related disease prevention efforts. The pandemic parameters derived from such active surveillance with routine population monitoring therefore not only enable a prospective assessment of the short-term course of a pandemic, but also a more targeted and thus more effective use of local and short-term countermeasures. Trial registration: ClinicalTrials.gov DRKS00023271. Registered November 30, 2020, with the German Clinical Trials Register (Deutsches Register Klinischer Studien

Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data

BACKGROUND: Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests. METHODS: In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337. FINDINGS: We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15-66) for AlereLAM, 61% (95% Crl 25-88) for Xpert, and 32% (95% Crl 10-55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies. INTERPRETATION: AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples. FUNDING: FIND, the Global Alliance for Diagnostics

Addressing the diagnostic gap in hypertension through possible interventions and scale-up: A microsimulation study

Background Cardiovascular diseases (CVDs) are the leading cause of mortality globally with almost a third of all annual deaths worldwide. Low- and middle-income countries (LMICs) are disproportionately highly affected covering 80% of these deaths. For CVD, hypertension (HTN) is the leading modifiable risk factor. The comparative impact of diagnostic interventions that improve either the accuracy, the reach, or the completion of HTN screening in comparison to the current standard of care has not been estimated. Methods and findings This microsimulation study estimated the impact on HTN-induced morbidity and mortality in LMICs for four different scenarios: (S1) lower HTN diagnostic accuracy; (S2) improved HTN diagnostic accuracy; (S3) better implementation strategies to reach more persons with existing tools; and, lastly, (S4) the wider use of easy-to-use tools, such as validated, automated digital blood pressure measurement devices to enhance screening completion, in comparison to the current standard of care (S0). Our hypothetical population was parametrized using nationally representative, individual-level HPACC data and the global burden of disease data. The prevalence of HTN in the population was 31% out of which 60% remained undiagnosed. We investigated how the alteration of a yearly blood pressure screening event impacts morbidity and mortality in the population over a period of 10 years. The study showed that while improving test accuracy avoids 0.6% of HTN-induced deaths over 10 years (13,856,507 [9,382,742; 17,395,833]), almost 40 million (39,650,363 [31,34,233, 49,298,921], i.e., 12.7% [9.9, 15.8]) of the HTN-induced deaths could be prevented by increasing coverage and completion of a screening event in the same time frame. Doubling the coverage only would still prevent 3,304,212 million ([2,274,664; 4,164,180], 12.1% [8.3, 15.2]) CVD events 10 years after the rollout of the program. Our study is limited by the scarce data available on HTN and CVD from LMICs. We had to pool some parameters across stratification groups, and additional information, such as dietary habits, lifestyle choice, or the blood pressure evolution, could not be considered. Nevertheless, the microsimulation enabled us to include substantial heterogeneity and stochasticity toward the different income groups and personal CVD risk scores in the model. Conclusions While it is important to consider investing in newer diagnostics for blood pressure testing to continuously improve ease of use and accuracy, more emphasis should be placed on screening completion. In a micro-simulation study, Lisa Koeppel and co-authors explore the comparative impact of interventions for addressing the diagnostic gap in hypertension screening in low- and middle-income countries. Author summary Why was this study done? Cardiovascular diseases (CVDs) are the leading cause of mortality globally, affecting low- and middle-income countries (LMICs) disproportionally highly. Hypertension (HTN) is the leading modifiable risk factor for CVDs. The diagnosis of HTN and thus the access to treatment is hampered by the necessity of at least one repeated measurement for a final diagnosis and the operator-dependent variability of blood pressure measurement. It is unclear which strategies would be the most impactful to close the diagnostic gap: more accurate, easy-to-use and/or more scalable tools or better implementation strategies to reach more persons with existing tools. What did the researchers do and find? We developed a stochastic microsimulation model that examines the impact of possible diagnostic interventions and implementation strategies on HTN-induced morbidity and mortality in LMICs. The different scenarios were applied over a period of 10 years and affected the individual risk of experiencing a CVD event. While improving test accuracy avoids only 0.6% of HTN-induced deaths over 10 years, scaling up test coverage and completion can avoid almost 40 million HTN-induced CVD events and 14 million (13.7%) related deaths. What do these findings mean? This simulation demonstrates the importance of increasing the coverage of testing for HTN and the improvement of screening completion over diagnostic accuracy of HTN testing. Strategies to narrow the diagnostic gap in HTN should put more emphasis on screening completion

Addressing the diagnostic gap in hypertension through possible interventions and scale-up: A microsimulation study.

BackgroundCardiovascular diseases (CVDs) are the leading cause of mortality globally with almost a third of all annual deaths worldwide. Low- and middle-income countries (LMICs) are disproportionately highly affected covering 80% of these deaths. For CVD, hypertension (HTN) is the leading modifiable risk factor. The comparative impact of diagnostic interventions that improve either the accuracy, the reach, or the completion of HTN screening in comparison to the current standard of care has not been estimated.Methods and findingsThis microsimulation study estimated the impact on HTN-induced morbidity and mortality in LMICs for four different scenarios: (S1) lower HTN diagnostic accuracy; (S2) improved HTN diagnostic accuracy; (S3) better implementation strategies to reach more persons with existing tools; and, lastly, (S4) the wider use of easy-to-use tools, such as validated, automated digital blood pressure measurement devices to enhance screening completion, in comparison to the current standard of care (S0). Our hypothetical population was parametrized using nationally representative, individual-level HPACC data and the global burden of disease data. The prevalence of HTN in the population was 31% out of which 60% remained undiagnosed. We investigated how the alteration of a yearly blood pressure screening event impacts morbidity and mortality in the population over a period of 10 years. The study showed that while improving test accuracy avoids 0.6% of HTN-induced deaths over 10 years (13,856,507 [9,382,742; 17,395,833]), almost 40 million (39,650,363 [31,34,233, 49,298,921], i.e., 12.7% [9.9, 15.8]) of the HTN-induced deaths could be prevented by increasing coverage and completion of a screening event in the same time frame. Doubling the coverage only would still prevent 3,304,212 million ([2,274,664; 4,164,180], 12.1% [8.3, 15.2]) CVD events 10 years after the rollout of the program. Our study is limited by the scarce data available on HTN and CVD from LMICs. We had to pool some parameters across stratification groups, and additional information, such as dietary habits, lifestyle choice, or the blood pressure evolution, could not be considered. Nevertheless, the microsimulation enabled us to include substantial heterogeneity and stochasticity toward the different income groups and personal CVD risk scores in the model.ConclusionsWhile it is important to consider investing in newer diagnostics for blood pressure testing to continuously improve ease of use and accuracy, more emphasis should be placed on screening completion

Fig 4 -

Mean numbers of deaths related to HTN-induced CVD events per year and their 95% credible intervals for the different scenarios for the population of LMICs (S0: Base case, S1: Lower accuracy, S2: Improved accuracy, S3: Increased coverage, S4: Increased coverage and screens completed). CVD, cardiovascular disease; HTN, hypertension; LMIC, low- and middle-income country.</p

Members of the HPACC Consortium.

(DOCX)</p

Characteristics of the simulated population at initiation.

Characteristics of the simulated population at initiation.</p