scholarly journals Using viral load and epidemic dynamics to optimize pooled testing in resource-constrained settings

2021 ◽  
Vol 13 (589) ◽  
pp. eabf1568 ◽  
Author(s):  
Brian Cleary ◽  
James A. Hay ◽  
Brendan Blumenstiel ◽  
Maegan Harden ◽  
Michelle Cipicchio ◽  
...  
Keyword(s):  
Time Course ◽  
Resource Constraints ◽  
Group Testing ◽  
Individual Identification ◽  
Pooling Designs ◽  
Viral Kinetics ◽  
Viral Loads ◽  
Pooled Testing ◽  
Epidemic Dynamics ◽  
Resource Limited

Virological testing is central to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containment, but many settings face severe limitations on testing. Group testing offers a way to increase throughput by testing pools of combined samples; however, most proposed designs have not yet addressed key concerns over sensitivity loss and implementation feasibility. Here, we combined a mathematical model of epidemic spread and empirically derived viral kinetics for SARS-CoV-2 infections to identify pooling designs that are robust to changes in prevalence and to ratify sensitivity losses against the time course of individual infections. We show that prevalence can be accurately estimated across a broad range, from 0.02 to 20%, using only a few dozen pooled tests and using up to 400 times fewer tests than would be needed for individual identification. We then exhaustively evaluated the ability of different pooling designs to maximize the number of detected infections under various resource constraints, finding that simple pooling designs can identify up to 20 times as many true positives as individual testing with a given budget. Crucially, we confirmed that our theoretical results can be translated into practice using pooled human nasopharyngeal specimens by accurately estimating a 1% prevalence among 2304 samples using only 48 tests and through pooled sample identification in a panel of 960 samples. Our results show that accounting for variation in sampled viral loads provides a nuanced picture of how pooling affects sensitivity to detect infections. Using simple, practical group testing designs can vastly increase surveillance capabilities in resource-limited settings.

scholarly journals Efficient prevalence estimation and infected sample identification with group testing for SARS-CoV-2

2020 ◽  
Author(s):  
Brian Cleary ◽  
James A. Hay ◽  
Brendan Blumenstiel ◽  
Stacey Gabriel ◽  
Aviv Regev ◽  
...  
Keyword(s):  
Resource Constraints ◽  
Large Population ◽  
Group Testing ◽  
Individual Identification ◽  
Viral Kinetics ◽  
Community Screening ◽  
Identification Rate ◽  
Individual Level ◽  
Viral Loads ◽  
Prevalence Estimation

The ongoing pandemic of SARS-CoV-2, a novel coronavirus, caused over 3 million reported cases of coronavirus disease 2019 (COVID-19) and 200,000 reported deaths between December 2019 and April 20201. Cases and deaths will increase as the virus continues its global march outward. In the absence of effective pharmaceutical interventions or a vaccine, wide-spread virological screening is required to inform where restrictive isolation measures should be targeted and when they can be lifted2–6. However, limitations on testing capacity have restricted the ability of governments and institutions to identify individual clinical cases, appropriately measure community prevalence, and mitigate transmission. Group testing offers a way to increase efficiency, by combining samples and testing a small number of pools7–9. Here, we evaluate the effectiveness of group testing designs for individual identification or prevalence estimation of SARS-CoV-2 infection when testing capacity is limited. To do this, we developed mathematical models for epidemic spread, incorporating empirically measured individual-level viral kinetics to simulate changing viral loads in a large population over the course of an epidemic. We used these to construct representative populations and assess pooling strategies for community screening, accounting for variability in viral load samples, dilution effects, changing prevalence and resource constraints. We confirmed our group testing framework through pooled tests on de-identified human nasopharyngeal specimens with viral loads representative of the larger population. We show that group testing designs can both accurately estimate overall prevalence using a small number of measurements and substantially increase the identification rate of infected individuals in resource-limited settings.

scholarly journals HYPER: Group testing via hypergraph factorization applied to COVID-19

2021 ◽  
Author(s):  
David Hong ◽  
Rounak Dey ◽  
Xihong Lin ◽  
Brian Cleary ◽  
Edgar Dobriban
Keyword(s):  
Large Scale ◽  
Resource Constraints ◽  
Group Testing ◽  
Viral Kinetics ◽  
Online Tool ◽  
Constrained Environments ◽  
Substantial Resource ◽  
The Face ◽  
Important Challenge ◽  
Global Nature

AbstractLarge scale screening is a critical tool in the life sciences, but is often limited by reagents, samples, or cost. An important challenge in screening has recently manifested in the ongoing effort to achieve widespread testing for individuals with SARS-CoV-2 infection in the face of substantial resource constraints. Group testing methods utilize constrained testing resources more efficiently by pooling specimens together, potentially allowing larger populations to be screened with fewer tests. A key challenge in group testing is to design an effective pooling strategy. The global nature of the ongoing pandemic calls for something simple (to aid implementation) and flexible (to tailor for settings with differing needs) that remains efficient. Here we propose HYPER, a new group testing method based on hypergraph factorizations. We provide characterizations under a general theoretical model, and exhaustively evaluate HYPER and proposed alternatives for SARS-CoV-2 screening under realistic simulations of epidemic spread and within-host viral kinetics. We demonstrate that HYPER performs at least as well as other methods in scenarios that are well-suited to each method, while outperforming those methods across a broad range of resource-constrained environments, and being more flexible and simple in design, and taking no expertise to implement. An online tool to implement these designs in the lab is available at http://hyper.covid19-analysis.org.

scholarly journals Viral loads observed under competing strain dynamics

2021 ◽  
Author(s):  
James A Hay ◽  
Lee Kennedy-Shaffer ◽  
Michael J Mina
Keyword(s):  
Growth Rates ◽  
Population Distribution ◽  
Surveillance Systems ◽  
Sample Collection ◽  
Viral Kinetics ◽  
Cross Sectional ◽  
Viral Loads ◽  
Epidemic Dynamics ◽  
Routine Surveillance ◽  
Plausible Mechanism

A plausible mechanism for the increased transmissibility of SARS-CoV-2 variants of concern (VOCs) results from VOC infections causing higher viral loads in infected hosts. However, investigating this hypothesis using routine RT-qPCR testing data is challenging because the population-distribution of viral loads changes depending on the epidemic growth rate; lower cycle threshold (Ct) values for a VOC lineage may simply reflect increasing incidence relative to preexisting lineages. To understand the extent to which viral loads observed under routine surveillance systems reflect viral kinetics or population dynamics, we used a mathematical model of competing strain dynamics and simulated Ct values for variants with different viral kinetics. We found that comparisons of Ct values obtained under random cross-sectional surveillance were highly biased unless samples were obtained at times when the variants had comparable growth rates. Conversely, comparing Ct values from symptom-based testing was largely unaffected by epidemic dynamics, and accounting for the time between symptom onset and sample collection date further reduced the risk of statistical errors. Finally, we show how a single cross-sectional sample of Ct values can be used to jointly estimate differences in viral kinetics and epidemic growth rates between variants. Epidemic dynamics should be accounted for when investigating strain-specific viral kinetics using virologic surveillance data, and findings should be corroborated with longitudinal viral kinetics studies.

scholarly journals Pooled testing with replication as a mass testing strategy for the COVID-19 pandemics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Julius Žilinskas ◽  
Algirdas Lančinskas ◽  
Mario R. Guarracino
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Group Testing ◽  
Testing Strategy ◽  
Testing Technique ◽  
Testing Procedures ◽  
Pooled Testing ◽  
Replication Scheme ◽  
Speed Up ◽  
Multiple Patients

AbstractDuring the COVID-19 pandemic it is essential to test as many people as possible, in order to detect early outbreaks of the infection. Present testing solutions are based on the extraction of RNA from patients using oropharyngeal and nasopharyngeal swabs, and then testing with real-time PCR for the presence of specific RNA filaments identifying the virus. This approach is limited by the availability of reactants, trained technicians and laboratories. One of the ways to speed up the testing procedures is a group testing, where the swabs of multiple patients are grouped together and tested. In this paper we propose to use the group testing technique in conjunction with an advanced replication scheme in which each patient is allocated in two or more groups to reduce the total numbers of tests and to allow testing of even larger numbers of people. Under mild assumptions, a 13 ×  average reduction of tests can be achieved compared to individual testing without delay in time.

scholarly journals High-Potency Human Immunodeficiency Virus Vaccination Leads to Delayed and Reduced CD8+ T-Cell Expansion but Improved Virus Control

2005 ◽  
Vol 79 (15) ◽  
pp. 10059-10062 ◽  
Author(s):  
Miles P. Davenport ◽  
Lei Zhang ◽  
Ansuman Bagchi ◽  
Arthur Fridman ◽  
Tong-Ming Fu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Cell Expansion ◽  
Virus Infections ◽  
Significant Delay ◽  
Viral Kinetics ◽  
Cell Numbers ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
T Cell Expansion

ABSTRACT CD8+ T lymphocytes are thought to play an important role in the control of acute and chronic human immunodeficiency virus infections. However, there is a significant delay between infection and the first observed increase in virus-specific CD8+ T-cell numbers. Prior to this time, viral kinetics are not significantly different between controls and vaccinees. Surprisingly, higher initial virus-specific CD8+ T-cell numbers lead to a longer delay prior to initial CD8+ T-cell expansion, and slower CD8+ T-cell increases. Nevertheless, higher initial CD8+ T-cell numbers were associated with reduced peak and chronic viral loads and reduced CD4+ T-cell depletion.

scholarly journals A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Luiza A. Castro-Jorge ◽  
Carla D. Pretto ◽  
Asa B. Smith ◽  
Oded Foreman ◽  
Kelly E. Carnahan ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Time Course ◽  
Interleukin 1 ◽  
Adenovirus Type ◽  
Mouse Strains ◽  
Complex Nature ◽  
Type I ◽  
Viral Loads ◽  
The Brain

ABSTRACT Interleukin-1β (IL-1β), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 −/− mice). Il1r1 −/− mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1β production (Pycard −/− mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 −/− mice). Pycard −/− and Unc93b1 −/− mice showed lower survival (similar to Il1r1 −/− mice) than control mice but, unlike Il1r1 −/− mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 −/− mice had a very different inflammatory profile from infected Il1r1 −/− and Pycard −/− mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 −/− mice. A time course of infection of control and Il1r1 −/− mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-β signaling may result in increased neuroinflammation. IMPORTANCE The investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis.

scholarly journals Outcomes of retained and disengaged pregnant women living with HIV in Uganda

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251413
Author(s):  
Agnes N. Kiragga ◽  
Ellon Twinomuhwezi ◽  
Grace Banturaki ◽  
Marion Achieng ◽  
Juliet Nampala ◽  
...  
Keyword(s):  
Post Partum ◽  
Urban Environments ◽  
Hiv Viral Load ◽  
Viral Loads ◽  
Women Living With Hiv ◽  
Resource Limited ◽  
Increased Risk ◽  
Exposed Infant ◽  
Public Clinics ◽  
Living With Hiv

Introduction Loss-to-follow-up among women living with HIV (WLWHIV) may lead to unfavorable outcomes for both mother and exposed infant. This study traced WLWHIV disengaged from care and their infants and compared their outcomes with those retained in care. Methods The study included WLWHIV who initiated ART during pregnancy at six public clinics in Uganda. A woman was defined as disengaged (DW) if she had not attended her 6-week post-partum visit by 10 weeks after her estimated date of delivery. DW were matched with retained women (RW) by age and duration on ART. Nurse counselors traced all selected DW via telephone and community visits to assess vital status, infant HIV sero-status and maternal HIV viral load through blood draws. Results Between July 2017 and July 2018, 734 women (359 DW and 375 RW) were identified for the study. Tracing was attempted on 349 DW and 160 (44.6%) were successfully located and enrolled in the study. They were matched with 162 RW. Among DW, 52 (32.5%) transferred to another health facility. Very few DW, 39.0% were HIV virally suppressed (<1000 copies/ml) compared to RW 89.5%, P<0.001). Among 138 babies born to DW, 4.3% tested positive for HIV compared to 1.4% among babies born to RW (P = 0.163). Conclusion Pregnant and breastfeeding WLWHIV who disengage from care are difficult to find in urban environments. Many have detectable viral loads, leading to the potential for an increased risk of MTCT. Efforts to reduce disengagement from care are critical for the successful elimination of MTCT in resource-limited settings.

scholarly journals Adenovirus Viral Kinetics and Mortality in Ex Vivo T Cell-Depleted Hematopoietic Cell Transplant Recipients With Adenovirus Infection From a Single Center

2020 ◽  
Vol 222 (7) ◽  
pp. 1180-1187
Author(s):  
Yeon Joo Lee ◽  
Jiaqi Fang ◽  
Phaedon D Zavras ◽  
Susan E Prockop ◽  
Farid Boulad ◽  
...  
Keyword(s):  
T Cell ◽  
Ex Vivo ◽  
Area Under The Curve ◽  
Absolute Lymphocyte Count ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Viral Kinetics ◽  
Cox Models ◽  
Viral Loads

Abstract Background We report on predictors of adenovirus (ADV) viremia and correlation of ADV viral kinetics with mortality in ex vivo T-cell depleted (TCD) hematopoietic cell transplant (HCT). Methods T cell-depleted HCT recipients from January 1, 2012 through September 30, 2018 were prospectively monitored for ADV in the plasma through Day (D) +100 posttransplant or for 16 weeks after the onset of ADV viremia. Adenovirus viremia was defined as ≥2 consecutive viral loads (VLs) ≥1000 copies/mL through D +100. Time-averaged area under the curve (AAUC) or peak ADV VL through 16 weeks after onset of ADV viremia were explored as predictors of mortality in Cox models. Results Of 586 patients (adult 81.7%), 51 (8.7%) developed ADV viremia by D +100. Age &lt;18 years, recipient cytomegalovirus seropositivity, absolute lymphocyte count &lt;300 cells/µL at D +30, and acute graft-versus-host disease were predictors of ADV viremia in multivariate models. Fifteen (29%) patients with ADV viremia died by D +180; 8 of 15 (53%) died from ADV. Peak ADV VL (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.52–3.33) and increasing AAUC (HR, 2.95; 95% CI, 1.83–4.75) correlated with mortality at D +180. Conclusions In TCD HCT, peak ADV VL and ADV AAUC correlated with mortality at D +180. Our data support the potential utility of ADV viral kinetics as endpoints in clinical trials of ADV therapies.

Asymptotics of pooling design performance

1999 ◽  
Vol 36 (04) ◽  
pp. 951-964
Author(s):  
J. K. Percus ◽  
O. E. Percus ◽  
W. J. Bruno ◽  
D. C. Torney
Keyword(s):  
Group Testing ◽  
Performance Criterion ◽  
Expected Number ◽  
Pooling Design ◽  
Pooling Designs ◽  
Parametric Control ◽  
Expected Performance ◽  
Qualitative Effect ◽  
Pooling Strategy ◽  
Asymptotic Forms

We analyse the expected performance of various group testing, or pooling, designs. The context is that of identifying characterized clones in a large collection of clones. Here we choose as performance criterion the expected number of unresolved ‘negative’ clones, and we aim to minimize this quantity. Technically, long inclusion–exclusion summations are encountered which, aside from being computationally demanding, give little inkling of the qualitative effect of parametric control on the pooling strategy. We show that readily-interpreted re-summation can be performed, leading to asymptotic forms and systematic corrections. We apply our results to randomized designs, illustrating how they might be implemented for approximating combinatorial formulae.

scholarly journals Evaluation of Five International HBV Treatment Guidelines: Recommendation for Resource-Limited Developing Countries Based on the National Study in Nepal

2020 ◽  
Vol 27 (1) ◽  
pp. 3-13
Author(s):  
Sundar Khadka ◽  
Roshan Pandit ◽  
Subhash Dhital ◽  
Jagat Bahadur Baniya ◽  
Surendra Tiwari ◽  
...  
Keyword(s):  
Developing Countries ◽  
Viral Load ◽  
Treatment Guidelines ◽  
Developed Countries ◽  
World Health ◽  
National Study ◽  
Viral Loads ◽  
Resource Limited ◽  
Number Of Patients ◽  
Who Guideline

Hepatitis B virus (HBV) infects the liver, causing cirrhosis and cancer. In developed countries, five international guidelines have been used to make a decision for the management of patients with chronic HBV infection. In this review, since the guidelines were established by clinical and epidemiological data of developed countries, we aimed to evaluate whether (1) HBV patient profiles of developing countries are similar to developed countries, and (2) which guideline can be applicable to resource-limited developing countries. First, as an example of the most recent data of HBV infections among developing countries, we evaluated the national HBV viral load study in Nepal, which were compared with the data from other developing countries. In Nepal, the highest number of patients had viral loads of 20–2000 IU/mL (36.7%) and belonged to the age group of 21–30 years; HBV epidemiology in Nepal, based on the viral loads, gender, and age groups was similar to those of not only other developing countries but also developed countries. Next, we reviewed five international HBV treatment guidelines of the World Health Organization (WHO), American Association for the Study of Liver Diseases (AASLD), National Institute for Health and Care Excellence (NICE), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL). All guidelines require the viral load and alanine aminotransferase (ALT) levels for decision making. Although four guidelines recommend elastography to assess liver cirrhosis, the WHO guideline alternatively recommends using the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), which is inexpensive and conducted routinely in most hospitals. Therefore, in resource-limited developing countries like Nepal, we recommend the WHO guideline for HBV treatment based on the viral load, ALT, and APRI information.

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