scholarly journals Confirmatory cut point has limited ability to make accurate classifications in immunogenicity assays

Bioanalysis ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 245-256
Author(s):  
Robert J Kubiak ◽  
Rosalinda HGP Arends ◽  
Nancy Lee ◽  
Meina Liang ◽  
Jianchun Zhang ◽  
...  
Keyword(s):  
Competitive Inhibition ◽  
Cut Points ◽  
Limited Ability ◽  
Cut Point ◽  
Confirmatory Assay ◽  
Drug Naïve ◽  
Point Determination ◽  
Antidrug Antibodies ◽  
Immunogenicity Assays

Aim: Competitive inhibition with excess unlabeled drug is used to confirm the presence of antidrug antibodies (ADA) in study samples. We evaluated specific and nonspecific responses from both drug-naive and drug-treated subjects to identify conditions required by the confirmatory assay to make accurate ADA classifications. Results: Nonspecific signal measured in drug-naive samples used to determine assay cut points was uniformly low and close to the screening cut point. Confirmatory assays performed on incurred study samples with nonspecific responses significantly above the level observed during cut point determination resulted in incorrect ADA classifications. Conclusion: Intensity of confirmatory response should be proportional to the screening response and therefore, to ensure accurate ADA classifications, the confirmatory responses cannot be considered as independent but need to be evaluated in relation to the screening responses.

Statistical methods of screening cut point determination in immunogenicity studies

Bioanalysis ◽  
2021 ◽  
Author(s):  
Meiyu Shen ◽  
Tianjiao Dai
Keyword(s):  
Random Effect ◽  
Random Effect Model ◽  
Covariance Structure ◽  
Repeated Measurements ◽  
Sources Of Uncertainty ◽  
Cut Point ◽  
Effect Model ◽  
Point Determination ◽  
Antidrug Antibodies ◽  
Immunogenicity Study

Background: Currently, screening cut point (CP) calculated from an assay validation with replicates are applied to an immunogenicity study with nonreplicates, for which the antidrug antibodies rate is determined. IID treats the replicate of a sample as coming from another independent sample. AVE uses average results from each sample across runs but inter-assay variability is reduced. Therefore, we propose a random effect model (REM) for calculating CP. Materials & method: We investigate impact of noncompatibility design between validation and immunogenicity studies on CP and compare these methods. Conclusion: IID may not fit for use when replicates’ variability dominates all sources of uncertainty. REM considers covariance structure of repeated measurements. CP by REM is smaller than that by IID but larger than that by AVE.

Non-Normal Random Effects Models for Immunogenicity Assay Cut Point Determination

2014 ◽  
Vol 25 (2) ◽  
pp. 295-306 ◽  
Author(s):  
Jianchun Zhang ◽  
Binbing Yu ◽  
Lanju Zhang ◽  
Lorin Roskos ◽  
Laura Richman ◽  
...  
Keyword(s):  
Random Effects ◽  
Random Effects Models ◽  
Cut Point ◽  
Point Determination ◽  
Immunogenicity Assay

Addressing drug effects on cut point determination for an anti-drug antibody assay

2012 ◽  
Vol 384 (1-2) ◽  
pp. 152-156 ◽  
Author(s):  
Maria D.F.S. Barbosa ◽  
Carol R. Gleason ◽  
Kelli R. Phillips ◽  
Flora Berisha ◽  
Bruce Stouffer ◽  
...  
Keyword(s):  
Drug Effects ◽  
Antibody Assay ◽  
Cut Point ◽  
Point Determination

P4-075: LUMIPULSE® G TOTAL TAU TO β-AMYLOID 1-42 RATIO CUT-POINT DETERMINATION FOR AMYLOID ELIGIBILITY SCREENING

2006 ◽  
Vol 14 (7S_Part_27) ◽  
pp. P1463-P1463
Author(s):  
June Kaplow ◽  
Manu Vandijck ◽  
Roger Moonen ◽  
Bart De Decker ◽  
Jim Zhao ◽  
...  
Keyword(s):  
Cut Point ◽  
Total Tau ◽  
Β Amyloid ◽  
Point Determination

scholarly journals Multiple Testing, Cut-Point Optimization, and Signs of Publication Bias in Prognostic FDG–PET Imaging Studies of Head and Neck and Lung Cancer: A Review and Meta-Analysis

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1030
Author(s):  
Malene M. Clausen ◽  
Ivan R. Vogelius ◽  
Andreas Kjær ◽  
Søren M. Bentzen
Keyword(s):  
Lung Cancer ◽  
Head And Neck ◽  
Publication Bias ◽  
Pet Imaging ◽  
Fdg Pet ◽  
Prognostic Value ◽  
Statistical Tests ◽  
Meta Analysis ◽  
Cut Points ◽  
Cut Point

Positron emission tomography (PET) imaging with 2-deoxy-2-[18F]-fluorodeoxyglucose (FDG) was proposed as prognostic marker in radiotherapy. Various uptake metrics and cut points were used, potentially leading to inflated effect estimates. Here, we performed a meta-analysis and systematic review of the prognostic value of pretreatment FDG–PET in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), with tests for publication bias. Hazard ratio (HR) for overall survival (OS), disease free survival (DFS), and local control was extracted or derived from the 57 studies included. Test for publication bias was performed, and the number of statistical tests and cut-point optimizations were registered. Eggers regression related to correlation of SUVmax with OS/DFS yielded p = 0.08/p = 0.02 for HNSCC and p < 0.001/p = 0.014 for NSCLC. No outcomes showed significant correlation with SUVmax, when adjusting for publication bias effect, whereas all four showed a correlation in the conventional meta-analysis. The number of statistical tests and cut points were high with no indication of improvement over time. Our analysis showed significant evidence of publication bias leading to inflated estimates of the prognostic value of SUVmax. We suggest that improved management of these complexities, including predefined statistical analysis plans, are critical for a reliable assessment of FDG–PET.

scholarly journals EBF recommendation on practical management of critical reagents for antidrug antibody ligand-binding assays

Bioanalysis ◽  
2019 ◽  
Vol 11 (19) ◽  
pp. 1787-1798 ◽  
Author(s):  
Susanne Pihl ◽  
Barry WA van der Strate ◽  
Michaela Golob ◽  
Janka Ryding ◽  
Laurent Vermet ◽  
...  
Keyword(s):  
Life Cycle ◽  
Ligand Binding ◽  
Crucial Role ◽  
Binding Assays ◽  
Antidrug Antibody ◽  
Regulatory Guidelines ◽  
Minimum Requirements ◽  
Antidrug Antibodies ◽  
Immunogenicity Assays

Immunogenicity (ISI) assays are required to measure antidrug antibodies that are generated against biotherapeutic modalities. As for any ligand-binding assays, critical reagents (CR) play a crucial role in immunogenicity assays, as the robustness and reliability of an assay are defined by the quality and long-term availability of these reagents. The current regulatory guidelines do not provide clear directions on how to implement and verify lot-to-lot changes of CR during an assay life cycle, or the acceptance criteria that should be used when implementing new lots of CR. These aspects were extensively discussed within the European Bioanalysis Forum community. In this paper, CR for immunogenicity assays are identified and the minimum requirements for introducing new lots of CR in immunogenicity assays are described.

scholarly journals C-Reactive Protein and Ferritin Are Associated With Organ Dysfunction and Mortality in Hospitalized Children

2019 ◽  
Vol 58 (7) ◽  
pp. 752-760 ◽  
Author(s):  
Christopher M. Horvat ◽  
Jamie Bell ◽  
Sajel Kantawala ◽  
Alicia K. Au ◽  
Robert S. B. Clark ◽  
...  
Keyword(s):  
High Risk ◽  
Hospital Mortality ◽  
Organ Dysfunction ◽  
Risk Groups ◽  
Hospitalized Children ◽  
Inpatient Mortality ◽  
C Reactive Protein ◽  
Cut Points ◽  
Cut Point ◽  
Reactive Protein

Our objective was to determine if C-reactive protein (CRP) and ferritin values alone and in combination are associated with mortality among hospitalized children. All hospitalized patients at our institution with a CRP or ferritin assay in 2015 and 2016 were included. Area under the receiver operating curves (AUROC) were examined, optimal cut-points determined, and patients were stratified into low-, intermediate-, or high-risk groups based on elevation of zero, one, or both biomarkers. A total of 14 928 CRP and 653 ferritin values were obtained, with both obtained for 172 patients. AUROC for maximum CRP value was 0.76 (0.68-0.85) with a cut-point of 7.1 mg/dL for in-hospital mortality and 0.90 (0.83-0.98) for maximum ferritin with a cut-point of 373 ng/mL. Elevation of both ferritin and CRP was associated with the highest inpatient mortality (21.7%) and greatest organ dysfunction, followed by either biomarker alone. Additional prospective study of these biomarkers in combination is warranted.

scholarly journals Concurrent and discriminant validity of ActiGraph waist and wrist cut-points to measure sedentary behaviour, activity level, and posture in office work

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Roman P. Kuster ◽  
Maria Hagströmer ◽  
Daniel Baumgartner ◽  
Wilhelmus J. A. Grooten
Keyword(s):  
Sedentary Behaviour ◽  
Discriminant Validity ◽  
Roc Curves ◽  
Activity Level ◽  
Kappa Statistics ◽  
Office Work ◽  
Cut Points ◽  
Cut Point ◽  
Task Effects ◽  
Estimation Equations

Abstract Background Sedentary Behaviour (SB) gets an increasing attention from ergonomics and public health due to its associated detrimental health effects. A large number of studies record SB with ActiGraph counts-per-minute cut-points, but we still lack valid information about what the cut-points tell us about office work. This study therefore analysed the concurrent and discriminant validity of commonly used cut-points to measure SB, activity level, and posture. Methods Thirty office workers completed four office tasks at three workplaces (conventional chair, activity-promoting chair, and standing desk) while wearing two ActiGraphs (waist and wrist). Indirect calorimetry and prescribed posture served as reference criteria. Generalized Estimation Equations analysed workplace and task effects on the activity level and counts-per-minute, and kappa statistics and ROC curves analysed the cut-point validity. Results The activity-promoting chair (p < 0.001, ES ≥ 0.66) but not the standing desk (p = 1.0) increased the activity level, and both these workplaces increased the waist (p ≤ 0.003, ES ≥ 0.63) but not the wrist counts-per-minute (p = 0.74) compared to the conventional chair. The concurrent and discriminant validity was higher for activity level (kappa: 0.52–0.56 and 0.38–0.45, respectively) than for SB and posture (kappa ≤0.35 and ≤ 0.19, respectively). Furthermore, the discriminant validity for activity level was higher for task effects (kappa: 0.42–0.48) than for workplace effects (0.13–0.24). Conclusions ActiGraph counts-per-minute for waist and wrist placement were – independently of the chosen cut-point – a measure for activity level and not for SB or posture, and the cut-points performed better to detect task effects than workplace effects. Waist cut-points were most valid to measure the activity level in conventional seated office work, but they showed severe limitations for sit-stand desks. None of the placements was valid to detect the increased activity on the activity-promoting chair. Caution should therefore be paid when analysing the effect of workplace interventions on activity level with ActiGraph waist and wrist cut-points.

Are Current Body Mass Index Referenced Pedometer Step-Count Recommendations Applicable to US Youth?

2008 ◽  
Vol 5 (5) ◽  
pp. 665-674 ◽  
Author(s):  
Michael W. Beets ◽  
Guy C. Le Masurier ◽  
Aaron Beighle ◽  
David A. Rowe ◽  
Charles F. Morgan ◽  
...  
Keyword(s):  
Physical Activity ◽  
Body Mass Index ◽  
Cross Validation ◽  
Healthy Weight ◽  
Activity Data ◽  
Cut Points ◽  
Cut Point ◽  
Us Children ◽  
Unhealthy Weight ◽  
Current Body Mass Index

Background:The purpose of this study was to cross-validate international BMI-referenced steps/d cut points for US girls (12,000 steps/d) and boys (15,000 steps/d) 6 to 12 years of age.Methods:Secondary pedometer-determined physical activity data from US children (N = 1067; 633 girls and 434 boys, 6 to 12 years) were analyzed. Using international BMI classifications, cross-validation of the 12,000 and 15,000 steps/d cut points was examined by the classification precision, sensitivity, and specificity for each age–sex stratum.Results:For girls (boys) 6 to 12 years, the 12,000 (15,000) steps/d cut points correctly classified 42% to 60% (38% to 67%) as meeting (achieved steps/d cut point and healthy weight) and failing (did not achieve steps/d cut point and overweight). Sensitivity ranged from 55% to 85% (64% to 100%); specificity ranged from 23% to 62% (19% to 50%).Conclusion:The utility of pedometer steps/d cut points was minimal in this sample given their inability to differentiate among children who failed to achieve the recommended steps/d and exhibited an unhealthy weight. Caution, therefore, should be used in applying previous steps/d cut points to US children.

scholarly journals Validation of the short Mood and Feelings Questionnaire in young adulthood

2021 ◽  
Author(s):  
Olga Eyre ◽  
Rhys Bevan Jones ◽  
Sharifah Shameem Agha ◽  
Robyn E Wootton ◽  
Ajay K Thapar ◽  
...  
Keyword(s):  
Young Adults ◽  
Sensitivity And Specificity ◽  
Young Adulthood ◽  
Early Adulthood ◽  
Well Being ◽  
The Self ◽  
Depression Symptoms ◽  
Cut Points ◽  
Cut Point ◽  
Dsm 5

AbstractBackgroundDepression often onsets in adolescence and is associated with recurrence in adulthood. There is a need to identify and monitor depression symptoms across adolescence and into young adulthood. The short Mood and Feelings Questionnaire (sMFQ) is commonly used to measure depression symptoms in adolescence but has yet to be validated in young adulthood. This study aimed to (1) examine whether the sMFQ is a valid assessment of depression in young adults, and (2) identify cut-points that best capture a DSM-5 diagnosis of depression at age 25.MethodsThe sample included young people who took part in the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 25 (n=4098). Receiver Operating Characteristic analyses were used to examine how well the self-rated sMFQ discriminates between cases and non-cases of DSM-5 Major Depressive Disorder (MDD) classified using the self-rated Development and Well Being Assessment. Sensitivity and specificity values were used to identify cut-points on the sMFQ.ResultsThe sMFQ had high accuracy for discriminating MDD cases from non-cases at age 25. The commonly used cut-point in adolescence (≥12) performed well at this age, best balancing sensitivity and specificity. However, a lower cut-point (≥10) may be appropriate in some contexts, e.g. for screening, when sensitivity is favoured over specificity.LimitationsALSPAC is a longitudinal population cohort that suffers from non-random attrition.ConclusionsThe sMFQ is a valid measure of depression in young adults in the general population. It can be used to screen for and monitor depression across adolescence and early adulthood.

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