Browsing by Author "Murphy, Gary"

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    Comparison of cross-sectional HIV incidence assay results from dried blood spots and plasma
    (Public Library of Science, 2017-02-23) Schlusser, Katherine E.; Pilcher, Christopher; Kallas, Esper G.; Santos, Breno R.; Deeks, Steven G.; Facente, Shelley; Keating, Sheila M.; Busch, Michael P.; Murphy, Gary; Welte, Alex; Quinn, Thomas; Eshleman, Susan H.; Laeyendecker, Oliver
    Background: Assays have been developed for cross-sectional HIV incidence estimation using plasma samples. Large scale surveillance programs are planned using dried blood spot (DBS) specimens for incidence assessment. However, limited information exists on the performance of HIV cross-sectional incidence assays using DBS. Methods: The assays evaluated were: Maxim HIV-1 Limiting Antigen Avidity EIA (LAg-Avidity), Sedia HIV-1 BED-Capture EIA (BED-CEIA), and CDC modified BioRad HIV-1/2 Plus O Avidity-based Assay (CDC-BioRad Avidity) using pre-determined cutoff values. 100 matched HIV-1 positive plasma and DBS samples, with known duration of infection, from the Consortium for the Evaluation and Performance of HIV Incidence Assays repository were tested. All assays were run in duplicate. To examine the degree of variability within and between results for each sample type, both categorical and continuous results were analyzed. Associations were assessed with Bland Altman, R2 values and Cohen’s kappa coefficient (ĸ). Results: Intra-assay variability using the same sample type was similar for all assays (R2 0.96 to 1.00). The R2 values comparing DBS and plasma results for LAg-Avidity, BED-CEIA, and CDC-BioRad Avidity were 0.96, 0.94, and 0.84, respectively. The concordance and ĸ values between DBS and plasma for all three assays were >87% and >0.64, respectively. The Bland-Altman analysis showed significant differences between plasma and DBS samples. For all three assays, a higher number of samples were classified as recent infections using DBS samples. Conclusions: DBS and plasma sample results were highly correlated. However, when compared to plasma, each assay performed somewhat differently in DBS at the lower and higher ends of the dynamic range. DBS samples were more likely to be classified as recently infected by all three assays, which may lead to overestimation of incidence in surveys using performance criteria derived for plasma samples.
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    Infection staging and incidence surveillance applications of high dynamic range diagnostic immuno-assay platforms
    (Wolters Kluwer, 2017-12) Grebe, Eduard; Welte, Alex; Hall, Jake; Keating, Sheila; Facente, Shelley; Marson, Kara; Martin, Jeffrey; Little, Susan; Price, Matthew; Kallas, Esper; Busch, Michael; Pilcher, Christopher; Murphy, Gary; Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA); South African Centre for Epidemiological Modelling and Analysis (SACEMA)
    Background: Custom HIV staging assays, including the Sedia HIV-1 Limiting Antigen (LAg) Avidity EIA and avidity modifications of the Ortho VITROS anti-HIV-1+2 and Abbott ARCHITECT HIV Ag/Ab Combo assays, are used to identify “recent” infections in clinical settings and for cross-sectional HIV incidence estimation. However, the high dynamic range of chemiluminescent platforms allows differentiating recent and long-standing infection on signal intensity, and this raises the prospect of using unmodified diagnostic assays for infection timing and surveillance applications. Methods: We tested a panel of 2500 well-characterized specimens with estimable duration of HIV infection with the 3 assays and the unmodified ARCHITECT. Regression models were used to estimate mean durations of recent infection (MDRIs), contextspecific false-recent rates (FRRs) and correlation between diagnostic signal intensity and LAg measurements. Hypothetical epidemiological scenarios were constructed to evaluate utility in surveillance applications. Results: Over a range of MDRIs (reflecting recency discrimination thresholds), a diluted ARCHITECT-based RITA produced lower FRRs than the VITROS platform (FRR z 0.5% and 1.5%, respectively at MDRI z 200 days), and the unmodified diagnostic ARCHITECT produces incidence estimates with comparable precision to LAg (relative SE z 17.5% and 15%, respectively at MDRIz 200 days). ARCHITECT S/CO measurements were highly correlated with LAg optical density measurements (r = 0.80), and values below 200 are strongly predictive of LAg recency and duration of infection less than 1 year. Conclusions: Low quantitative measurements from the unmodified ARCHITECT obviate the need for additional recency testing, and its use is feasible in clinical staging and incidence surveillance applications.
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    Interpreting HIV diagnostic histories into infection time estimates : analytical framework and online tool
    (BMC (part of Springer Nature), 2019-10-26) Grebe, Eduard; Facente, Shelley N.; Bingham, Jeremy; Pilcher, Christopher D.; Powrie, Andrew; Gerber, Jarryd; Priede, Gareth; Chibawara, Trust; Busch, Michael P.; Murphy, Gary; Kassanjee, Reshma; Welte, Alex
    Background: It is frequently of epidemiological and/or clinical interest to estimate the date of HIV infection or time-since-infection of individuals. Yet, for over 15 years, the only widely-referenced infection dating algorithm that utilises diagnostic testing data to estimate time-since-infection has been the ‘Fiebig staging’ system. This defines a number of stages of early HIV infection through various standard combinations of contemporaneous discordant diagnostic results using tests of different sensitivity. To develop a new, more nuanced infection dating algorithm, we generalised the Fiebig approach to accommodate positive and negative diagnostic results generated on the same or different dates, and arbitrary current or future tests – as long as the test sensitivity is known. For this purpose, test sensitivity is the probability of a positive result as a function of time since infection. Methods: The present work outlines the analytical framework for infection date estimation using subject-level diagnostic testing histories, and data on test sensitivity. We introduce a publicly-available online HIV infection dating tool that implements this estimation method, bringing together 1) curatorship of HIV test performance data, and 2) infection date estimation functionality, to calculate plausible intervals within which infection likely became detectable for each individual. The midpoints of these intervals are interpreted as infection time ‘point estimates’ and referred to as Estimated Dates of Detectable Infection (EDDIs). The tool is designed for easy bulk processing of information (as may be appropriate for research studies) but can also be used for individual patients (such as in clinical practice). Results: In many settings, including most research studies, detailed diagnostic testing data are routinely recorded, and can provide reasonably precise estimates of the timing of HIV infection. We present a simple logic to the interpretation of diagnostic testing histories into infection time estimates, either as a point estimate (EDDI) or an interval (earliest plausible to latest plausible dates of detectable infection), along with a publicly-accessible online tool that supports wide application of this logic. Conclusions: This tool, available at https://tools.incidence-estimation.org/idt/, is readily updatable as test technology evolves, given the simple architecture of the system and its nature as an open source project.
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    Performance comparison of the Maxim and Sedia Limiting Antigen Avidity assays for HIV incidence surveillance
    (Public Library of Science, 2019-07-26) Sempa, Joseph B.; Welte, Alex; Busch, Michael P.; Hall, Jake; Hampton, Dylan; Facente, Shelley N.; Keating, Sheila M.; Marson, Kara; Parkin, Neil; Pilcher, Christopher D.; Murphy, Gary; Grebe, Eduard
    Background: Two manufacturers, Maxim Biomedical and Sedia Biosciences Corporation, supply CDC-approved versions of the HIV-1 Limiting Antigen Avidity EIA (LAg) for detecting ‘recent’ HIV infection in cross-sectional incidence estimation. This study assesses and compares the performance of the two assays for incidence surveillance. Methods: We ran both assays on a panel of 2,500 well-characterized HIV-1-infected specimens. We analysed concordance of assay results, assessed reproducibility using repeat testing and estimated mean durations of recent infection (MDRIs) and false-recent rates (FRRs) for a range of normalized optical density (ODn) thresholds, alone and in combination with viral load thresholds. We defined three hypothetical surveillance scenarios, similar to the Kenyan and South African epidemics, and a concentrated epidemic. These scenarios allowed us to evaluate the precision of incidence estimates obtained by means of various recent infection testing algorithms (RITAs) based on each of the two assays. Results: The Maxim assay produced lower ODn values than the Sedia assay on average, largely as a result of higher calibrator readings (mean OD of 0.749 vs. 0.643), with correlation of normalized readings lower (R2 = 0.908 vs. R2 = 0.938). Reproducibility on blinded control specimens was slightly better for Maxim. The MDRI of a Maxim-based algorithm at the ‘standard’ threshold (ODn ≤1.5 & VL >1,000) was 201 days (95% CI: 180,223) and for Sedia 171 (152,191). The difference Differences in MDRI were estimated at 32.7 (22.9,42.8) and 30.9 days (21.7,40.7) for the two algorithms, respectively. Commensurately, the Maxim algorithm had a higher FRR in treatment-naive subjects (1.7% vs. 1.1%). The two assays produced similar precision of incidence estimates in the three surveillance scenarios. Conclusions: Differences between the assays can be primarily attributed to the calibrators supplied by the manufacturers. Performance for surveillance was extremely similar, although different thresholds were optimal (i.e. produced the lowest variance of incidence estimates) and at any given ODn threshold, different estimates of MDRI and FRR were obtained. The two assays cannot be treated as interchangeable: assay and algorithm-specific performance characteristic estimates must be used for survey planning and incidence estimation.