Change‐point models to estimate the limit of detection

May, Ryan; Chu, Haitao; Ibrahim, Joseph G.; Hudgens, Michael G.; Lees, Abigail C.

doi:10.1002/sim.5872

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…We determined that our HIV RNA PCR assay could detect the difference between 1 copy and ≥10 copies using dilutions of an HIV RNA internal standard [24]. Detectable PCR signal less than 10 copies (1–9 copies) was treated in all analyses as 5 copies.…”

Section: Methodsmentioning

confidence: 99%

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

Archin

Liberty

Kashuba

et al. 2012

Nature

1,035

1,069

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Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection [1]. Inducing the expression of latent genomes within resting CD4+ T cells is the primary strategy to clear this reservoir [2]. While histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA or vorinostat, VOR) can disrupt HIV-1 latency in vitro [3–5], the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients.Therefore we isolated the circulating resting CD4+ T cells of patients in whom viremia was fully suppressed by antiretroviral therapy (ART), and directly studied the effect of VOR in this latent reservoir. In each of eight patients studied, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4+ cells (mean increase 4.8-fold). This is the first demonstration that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in man, provides proof-of-concept for HDAC inhibitors as a new therapeutic class, and defines a precise approach to test novel strategies to directly attack and eradicate latent HIV infection.

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Section: Methodsmentioning

confidence: 99%

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

Archin

Liberty

Kashuba

et al. 2012

Nature

1,035

1,069

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“…When working with concentration values a decision is made on how to set the appropriate level-of-detection (LOD) for each analyte25. However, the inverse procedure of going from fluorescence to concentration, via the inverse 5PL curve, also has limits (top/bottom), beyond which no concentration values can be obtained.…”

Section: Resultsmentioning

confidence: 99%

“…This assumption may not be strictly true for the observed fluorescence responses for a given platform; as automatic calibration steps during setup yields a highly reproducible signal output even across different instruments 23 . Recently, we have argued that for statistical differential analysis and for reproducibility fluorescence values are the better choice and they alleviate the concern of determining levels of detection 15 17 22 24 25 . It this report a xMAP suspension bead-based immunoassay format is used to demonstrate fluorescence based data analysis, however the methodological techniques used here are generic and applicable to other immunoassay platforms that use typical sigmoidal/ logistic concentration curves to map fluorescence to concentration values.…”

mentioning

confidence: 99%

The Statistical Value of Raw Fluorescence Signal in Luminex xMAP Based Multiplex Immunoassays

Breen

Tan

Khan

2016

Sci Rep

101

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Tissue samples (plasma, saliva, serum or urine) from 169 patients classified as either normal or having one of seven possible diseases are analysed across three 96-well plates for the presences of 37 analytes using cytokine inflammation multiplexed immunoassay panels. Censoring for concentration data caused problems for analysis of the low abundant analytes. Using fluorescence analysis over concentration based analysis allowed analysis of these low abundant analytes. Mixed-effects analysis on the resulting fluorescence and concentration responses reveals a combination of censoring and mapping the fluorescence responses to concentration values, through a 5PL curve, changed observed analyte concentrations. Simulation verifies this, by showing a dependence on the mean florescence response and its distribution on the observed analyte concentration levels. Differences from normality, in the fluorescence responses, can lead to differences in concentration estimates and unreliable probabilities for treatment effects. It is seen that when fluorescence responses are normally distributed, probabilities of treatment effects for fluorescence based t-tests has greater statistical power than the same probabilities from concentration based t-tests. We add evidence that the fluorescence response, unlike concentration values, doesn’t require censoring and we show with respect to differential analysis on the fluorescence responses that background correction is not required.

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“…Such out-of-range values in concentration-based analysis are frequently imputed by maximum likelihood estimations, extrapolation or substitution thereby increasing the risk of obtaining inaccurate estimations and false conclusions 29 , 30 , 31 , 32 , 33 , 34 . Several studies have shown that fluorescence values do not have out-of-range problems, and that fluorescence-based analysis has higher statistical power than concentration-based analysis, is a better choice for statistical differential analyses and reproducibility, and that background correction is not required [ 28 , 33 , 35 , 36 ]. The use of fluorescence intensity values for our discriminant analysis is relatively novel.…”

Section: Discussionmentioning

confidence: 99%

A three-marker protein biosignature distinguishes tuberculosis from other respiratory diseases in Gambian children

et al. 2020

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Background Our study aimed to identify a host cytokine biosignature that could distinguish childhood tuberculosis (TB) from other respiratory diseases (OD). Methods Cytokine responses in prospectively recruited children with symptoms suggestive of TB were measured in whole blood assay supernatants, harvested after overnight incubation, using a Luminex platform. We used logistic regression models with Least Absolute Shrinkage and Selection Operator (LASSO) penalty to identify the optimal biosignature associated with confirmed TB disease in the training set. We subsequently assessed its performance in the test set. Findings Of the 431 children included in the study, 44 had bacteriologically confirmed TB, 60 had clinically diagnosed TB while 327 had OD. All children were HIV-negative. Application of LASSO regression models to the training set ( n = 260) resulted in the combination of IL-1ra, IL-7 and IP-10 from unstimulated samples as the optimally discriminant cytokine biosignature associated with bacteriologically confirmed TB. In the test set ( n = 171), this biosignature distinguished children diagnosed with TB disease, irrespective of microbiological confirmation, from OD with area under the receiver operator characteristic curve (AUC) of 0•74 (95% CI: 0•67, 0•81), and demonstrated sensitivity and specificity of 72•2% (95% CI: 60•4, 82•1%) and 75•0% (95% CI: 64•9, 83•4%) respectively, with its performance independent of their age group and their age- and sex-adjusted nutritional status. Interpretation This novel biosignature of childhood TB derived from unstimulated supernatants is promising. Independent validation with further optimisation will improve its performance and translational potential. Funding Steinberg Fellowship (McGill University); Grand Challenges Canada; MRC Program Grant.

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Change‐point models to estimate the limit of detection

Cited by 6 publications

References 23 publications

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

The Statistical Value of Raw Fluorescence Signal in Luminex xMAP Based Multiplex Immunoassays

A three-marker protein biosignature distinguishes tuberculosis from other respiratory diseases in Gambian children

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