A bridging immunogenicity assay for anti-cabiralizumab antibodies: overcoming the low assay cut point and drug tolerance challenges

Bioanalysis ◽  
2021 ◽  
Author(s):  
Long Yuan ◽  
Carol R Gleason ◽  
Dennis Stocker ◽  
Li Li ◽  
Jim X Shen ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Drug Tolerance ◽  
Normal Serum ◽  
Acid Dissociation ◽  
Reagent Concentration ◽  
Acid Pretreatment ◽  
Cut Points ◽  
Cut Point ◽  
Immunogenicity Assay ◽  
Assay Conditions

Background: To support the clinical studies of cabiralizumab, an immunogenicity assay for detecting anti-cabiralizumab antibodies is required. Results: Strategies were developed to overcome two major bioanalytical challenges: poor drug tolerance of the anti-drug antibodies assay and very low cut point observed in the screening and confirmatory assays. By using acid dissociation (400 mM glycine solution at pH 2.0), drug tolerance of 200 μg/ml drug was achieved for both the screening and confirmatory assays. Effects of biological matrix (disease state vs normal serum) and assay conditions (capture/detector reagent concentration, minimum required dilution, acid pretreatment) on assay cut points were systematically evaluated. Conclusion: A bridging immunogenicity assay for detecting anti-cabiralizumab antibodies in human serum has been successfully developed, validated and applied to clinical studies.

scholarly journals High ionic strength dissociation assay (HISDA) for high drug tolerant immunogenicity testing

Bioanalysis ◽  
2020 ◽  
Author(s):  
Gregor Jordan ◽  
Alexander Pöhler ◽  
Florence Guilhot ◽  
Meike Zaspel ◽  
Roland F Staack
Keyword(s):  
Ionic Strength ◽  
Acid Treatment ◽  
Structural Integrity ◽  
Drug Tolerance ◽  
High Ionic Strength ◽  
Acid Dissociation ◽  
High Drug ◽  
Overnight Incubation ◽  
Antidrug Antibody ◽  
High Doses

Aim: Antidrug antibody (ADA) assessment may be challenged in studies that involve the administration of high doses of biotherapeutics and/or with long half-lives. In such cases, ADA assays with optimized drug tolerance are desired. Material & Methods: We evaluated the use of MgCl2 to develop high ionic strength dissociation assays in two investigational examples (bridging enzyme-linked immunosorbent ADA assays) to attain high drug tolerance while maintaining best possible structural integrity of ADAs. Results: Both ADA-bridging assays treated with MgCl2 showed improved drug tolerance and higher signal-to-blank values compared with overnight incubation or acid treatment. Conclusion: The use of MgCl2 treatment in ADA-bridging assays provides a sensitive, drug tolerant and easy-to-use alternative in cases where acid dissociation is not possible or unwanted.

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

Anti-drug Antibody Assay Conditions Significantly Impact Assay Screen and Confirmatory Cut-Points

2019 ◽  
Vol 21 (4) ◽  
Author(s):  
Boris Gorovits ◽  
Ying Wang ◽  
Liang Zhu ◽  
Marcela Araya ◽  
John Kamerud ◽  
...  
Keyword(s):  
Antibody Assay ◽  
Cut Points ◽  
Assay Conditions

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 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.

scholarly journals The Diagnostic Value of the Short Physical Performance Battery for Sarcopenia

2020 ◽  
Author(s):  
Steven Phu ◽  
Ben Kirk ◽  
Ebrahim Bani Hassan ◽  
Sara Vogrin ◽  
Jesse Zanker ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Physical Performance ◽  
Older Persons ◽  
High Sensitivity ◽  
Diagnostic Value ◽  
Community Dwelling ◽  
Short Physical Performance Battery ◽  
Clinical Settings ◽  
Cut Points ◽  
Cut Point

Abstract BACKGROUND: Sarcopenia is defined as the age-related loss of muscle mass, strength and physical performance. The original European Working Group on Sarcopenia in Older Persons (EWGSOP1) definition, and its revision (EWGSOP2), provide new cut-points and alternate measures for sarcopenia diagnosis. However, sarcopenia is rarely diagnosed in clinical settings owing to its labour-intensive screening process. Given the Short Physical Performance Battery (SPPB) is a quick, easily administrable and objective measure of muscle strength and physical performance, both of which are key components of sarcopenia, this study examined the diagnostic value of the SPPB for this muscle disease.METHODS: A cross-sectional analysis of 294 community-dwelling older persons (≥65 years) was conducted. Appendicular lean body mass [(ALM) divided by height squared (ALM/h 2 )], muscle strength (handgrip/sit to stand), and physical performance [gait speed, timed up and go (TUG) and SPPB] were assessed using validated procedures, while participants were diagnosed with sarcopenia following the EWGSOP1 and EWGSOP2 criteria. Diagnostic ability of the SPPB independently and combined with ALM/h 2 for sarcopenia was determined using area under the curve (AUC). Potential cut-points were identified, and sensitivity and specificity calculated.RESULTS: Prevalence of sarcopenia ranged from 4 to 16% depending on the definition. The SPPB demonstrated moderate (AUC = 0.644-0.770) value in diagnosing sarcopenia, and a cut-point of ≤8points in SPPB performance resulted in high sensitivity (82-100%) but low specificity (36-41%) for diagnosing those with severe sarcopenia.CONCLUSIONS: The SPPB displayed acceptable value in diagnosing older adults with severe sarcopenia. Moreover, the high sensitivity of the SPPB when using the cut-point of ≤8 suggests it may be a favourable screening tool for sarcopenia in clinical settings where ALM measurements are not available.

Data-Derived Treatment Duration Goal for Cervical Cancer: Should 8 Weeks Remain the Target in the Era of Concurrent Chemoradiation?

2017 ◽  
pp. 1-15 ◽  
Author(s):  
Julian C. Hong ◽  
Jonathan Foote ◽  
Gloria Broadwater ◽  
Julie A. Sosa ◽  
Stephanie Gaillard ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Treatment Duration ◽  
Cross Validation ◽  
Recursive Partitioning ◽  
Hazard Ratio ◽  
Recursive Partitioning Analysis ◽  
Rank Test ◽  
Cut Points ◽  
Cut Point ◽  
Lower Stage

Purpose Prior studies have demonstrated the importance of treatment duration (TD) in radiation therapy (RT) for cervical cancer, with an 8-week goal based primarily on RT alone. This study uses a contemporary cohort to estimate the time point by which completion of chemoradiation therapy is most critical. Patients and Methods The National Cancer Database was queried for women with nonmetastatic cervical cancer diagnosed from 2004 to 2012 who underwent chemotherapy, external beam RT, and brachytherapy. Data-derived TD cut points for overall survival (OS) were computed by using recursive partitioning analysis with bootstrapped aggregation (bagging) and 10-fold cross-validation. Models were independently trained with 70% of the population and validated on 30% of the population by log-rank test with and without propensity matching. Multivariable Cox proportional hazards regression was performed for the entire cohort. Results In all, 7,355 women were identified with a median TD of 57 days. Bagged recursive partitioning analysis converged to a mean cut point of 66.6 days (median, 64.5 days; interquartile range, 63.5 to 68.5 days). Cross-validation yielded a cut point of 63.3 days. Both cut points differentiated OS in validation. Younger age, recent diagnosis, geographic region, nongovernment insurance, shorter distance to treatment facility, metropolitan location, lower comorbidity, squamous cell carcinoma, lower stage, negative lymph nodes, and shorter TD were independently associated with longer OS. With adjustment, TD within the mean cut point (64.9 days; hazard ratio, 0.79; 95% CI, 0.73 to 0.87) and 56 days (hazard ratio, 0.87; 95% CI, 0.80 to 0.95) were associated with longer OS. Exploratory stratification suggested increasing OS detriment beyond 64 days. Conclusion Shorter chemoradiation TD in cervical cancer is associated with longer survival, and TD should be minimized as much as possible. The data-derived cut point was distributed around 64 days, with a continuous relationship between shorter TD and longer OS.

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