Test Performance Criteria Research Articles

Evaluation of the clinical assessment scale for autoimmune encephalitis (CASE) in a retrospective cohort and a systematic review

BackgroundAutoimmune encephalitis (AE) poses significant challenges in clinical management, requiring effective monitoring tools for therapeutic success and relapse detection. This study aims to assess the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) as compared to the modified Rankin scale (mRS) in evaluating AE patients and to determine the real-world adoption of the CASE score.MethodsA retrospective cohort study was conducted on 20 AE patients, assessing clinical data including symptomatology, diagnostic findings, and therapeutic regimens. Furthermore, we performed a systematic review on the test performance criteria and the real-world use of the CASE score.ResultsThe CASE score showed a higher sensitivity in detecting clinical changes compared to the mRS, with a significant correlation between the two scales throughout the disease course (r = 0.85, p < 0.01). A systematic review of 150 articles revealed widespread adoption of the CASE score, especially in Asian populations, demonstrating high reliability and internal consistency.DiscussionDespite limitations such as retrospective design and small sample size, our findings underscore the CASE score's utility in both clinical practice and research settings. The CASE score emerges as a valuable tool for monitoring AE patients, offering improved sensitivity over existing scales like the mRS. Further validation studies in diverse populations are warranted to establish its broader applicability and inform future therapeutic interventions.

Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders.

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.

Feasibility study of wire arc additive manufactured P91 steel by cold metal transfer deposition

The objective of this study was to analyze and evaluate the feasibility of utilizing Wire Arc Additive Manufacturing (WAAM) technology for the constructing components made from P91 steel, which is widely used material for high-temperature applications. The utilization of the Cold Metal Transfer (CMT) method enables the deposition of thin steel walls by virtue of its low heat input. Samples collected from the deposited wall have been tested in two different microstructural conditions, in the as-built (AB) condition and in a normalized and tempered (NT) condition. The latter condition is the microstructural state commonly employed for producing components used in power plants. This post-deposition heat treatments (PDHT) comprise a normalization process conducted at 1050 °C for 40 min, followed by a tempering step at 760 °C for 2 h. The results of mechanical testing and microstructural characterization were then compared against the established standards for commercial P91 steel. SEM-EDAX, XRD, and EBSD analyses were employed to conduct a comprehensive microstructural examination of the samples. The hardness of the AB samples ranged from 384 to 439 HV, while the NT samples had a hardness range of 205 to 223 HV. In terms of tensile strength, the AB samples demonstrated a range of 1064 to 1266 MPa, whereas the NT samples exhibited a range of 635 to 626 MPa. These results were found to be consistent with the observed strong texture and grain orientations in the {001} and {111} planes, as revealed by the EBSD analysis. The NT components demonstrated significant strength, ductility, hardness, and toughness compared to the specified ASTM standards. Based on the test performance and feasibility criteria, this process has significant potential as an additive manufacturing method suitable for complex boiler components.

Comparison of Bond Strength Evaluation Methods Between Pavement Layers

Tack coats are generally used to facilitate a bonding between pavement layers in construction of hot-mix asphalt pavements and overlays. The goal of applying a tack coat material is to ensure the new or consecutive pavement layers respond monolithically under loading and avoid premature failure caused by debonding, mat slippage, or fatigue cracking. Multiple different in-situ and laboratory tests have been developed to evaluate bond strength of tack coat materials under tension, shear, and mixed-mode loading mechanisms. However, there is no universally accepted bond strength test method or performance criteria for tack coats within the United States. While some specifying agencies have gained familiarity and comfort with a particular bond strength test, a gap exists for many states that have not adopted a testing procedure. The objective of this paper is to compare current and newly developed tack coat bond strength tests to help determine which is most indicative in predicting field performance. Field cores from four different pavement sections with varying traffic loading conditions and early bond strength performance were sampled and tested in the laboratory using four different bond strength evaluation methods. Statistical analysis of bond strength testing results shows a strong linear correlation between pull-off and shear strength testing. Meanwhile, a novel approach to tack coat bond testing under cyclic tensile loading was explored and showed appreciable discrimination between sample locations and agreement with early field performance.

Diagnostic Value of Tracheal Wash Cytology for Monitoring Exercise-Induced Pulmonary Hemorrhage in Thoroughbred Racehorses

Lower airway cytology has been proposed as a complementary diagnostic method to confirm the presence and quantifying the severity of exercise-induced pulmonary hemorrhage (EIPH). Bronchoalveolar lavage is usually preferred over tracheal wash (TW), yet the need for sedation imposes as a limitation for active sport horses in addition to be a highly invasive technique. This study aims to evaluate the diagnostic value of TW with Total Hemosiderin Score (THS) for monitoring EIPH in active Thoroughbred racehorses. A sampling of 47 randomly selected Thoroughbreds were endoscopically examined for EIPH grading 30 to 60 minutes after competing in an official race and then classified as Group 1 (EIPH-negative), Group 2 (EIPH-positive) or Group 3 (furosemide users). Tracheal wash fluids (TWFs) were collected from 24 to 30 hours later and smears were stained for differential cell count and hemosiderophage grading and counting to calculate THS. Differential cell counts were compared by the median test. Comparisons between mean THS values by EIPH grade and by group were compared by the Mann-Whitney test and ANOVA, respectively. Test performance criteria were determined with a contingency table. It was not possible to establish a THS cut-off point but statistical results showed that, at THS stand view, all groups had similar results despite their EIPH grades. Most animals showed no signs of neutrophilic inflammation, but haemosiderophages were found even on a first-time runner from Group 1. Thus, TW can detect evidence of lung bleeding even on horses with no history of EIPH. The implementation of TW analysis to diagnose EIPH in racehorses is promising, as TW is both low-cost and a less invasive tool.

Evaluation of Two Rapid Antigenic Tests for the Detection of SARS-CoV-2 in Nasopharyngeal Swabs.

(1) Background: In the current context of the COVID-19 crisis, there is a need for fast, easy-to-use, and sensitive diagnostic tools in addition to molecular methods. We have therefore decided to evaluate the performance of newly available antigen detection kits in “real-life” laboratory conditions. (2) Methods: The sensitivity and specificity of two rapid diagnostic tests (RDT)—the COVID-19 Ag Respi-Strip from Coris Bioconcept, Belgium (CoRDT), and the coronavirus antigen rapid test cassette from Healgen Scientific, LLC, USA (HeRDT)—were evaluated on 193 nasopharyngeal samples using RT-PCR as the gold standard. (3) Results: The sensitivity obtained for HeRDT was 88% for all collected samples and 91.1% for samples with Ct ≤ 31. For the CoRDT test, the sensitivity obtained was 62% for all collected samples and 68.9% for samples with Ct ≤ 31. (4) Conclusions: Despite the excellent specificity obtained for both kits, the poor sensitivity of the CoRDT did not allow for its use in the rapid diagnosis of COVID-19. HeRDT satisfied the World Health Organization’s performance criteria for rapid antigen detection tests. Its high sensitivity, quick response, and ease of use allowed for the implementation of HeRDT at the laboratory of the University Hospital of Liège.

Maternal infections: revisiting the need for screening in pregnancy.

The decision to implement screening for infections during pregnancy depends upon epidemiological, economic, therapeutic and test performance criteria. It therefore varies with public health priorities from country to country. When screening is implemented, the first trimester has become the best time slot to build individual care pathways in this field. This is most relevant for evaluating the risk of embryonic consequences, planning diagnostic testing, initiating primary or secondary prevention and optimising the accuracy of ultrasound follow-up. This article is a critical appraisal of epidemiological data and current international screening recommendations for infections in pregnancy. TWEETABLE ABSTRACT: Screening for infections in pregnancy: a critical review of current epidemiological evidence and international guidelines.

Development, validation and feasibility study of a remote basic skills assessment for wheelchair service providers

Aim The purpose of this study was to develop, validate and conduct a feasibility study of three remote basic skills assessment modalities for wheelchair service providers (WSP) including an online case study quiz (m1), an in-person skills assessment (m2) and a video conference skills assessment (m3). Methods We conducted a literature review; developed and validated 3 basic skills assessments; and conducted a feasibility study of each modality. Results The literature review revealed that a validated remote basic skills assessment for WSP that reflects all World Health Organization (WHO) 8 wheelchair service provision steps did not exist. We recruited a total of 12 participants for the feasibility study. Two participants dropped out of the study prior to completing a second testing modality. Related to test performance, the results show that our first hypothesis was rejected because only m1 mean score was comparable to the International Society of Wheelchair Professionals (ISWP) Basic Knowledge Test (SD = 0.44). This is in contrast with the Wilcoxon signed-rank test results that show a statistically significant difference between these two modalities. We are therefore not confident that the knowledge test was an appropriate comparison to m1 skills assessment. Hypothesis two was not rejected. The feasibility results reveal 86% success. Conclusion M1, 2 and 3 have the potential to serve as remote basic skills assessments. However, according to both test performance and feasibility criteria, we believe that m2 has the highest potential to be included in certification processes for basic wheelchair service providers, like the one offered by ISWP. IMPLICATIONS FOR REHABILITATION A universal remote basic skills assessment that can be accessed across the globe, especially in remote locations where a skilled and experienced provider is not available, is needed. Such test can be an asset to training or professional organisations like ISWP as a way to test WSP competency or to warrant certification. WSP clinical knowledge and skills are essential for the prescription of an appropriate wheelchair to avoid physical harm, abandonment of the device and unnecessary expenses. Properly prescribed wheelchairs allow people with impaired mobility to gain increased ability to perform ADLs, participate in communities, and reduce secondary medical complications such as upper limb repetitive strain injuries, pain, and/or pressure sores.

On the “Invisible Inventory Conundrum” in RFID‐Equipped Supply Chains: A Data Science Approach to Assessing Tag Performance

Recent trade reports suggest that RFID implementation continues to lag lofty projections. A primary concern is that, despite the high cost of implementing RFID systems, realized read‐rates fall short of expectations. This results in the invisible inventory conundrum whereby tagged merchandise may still not be accurately represented in inventory records. Drawing from data science to address this issue, we ask: How can directed data mining models be used to identify laboratory test performance criteria for RFID tags that operate reliably across the idiosyncratic facilities (i.e., unique DCs, warehouses, and stores) that comprise apparel retailers’ supply chains? We investigate this question by advancing a methodology that integrates laboratory test performance data, field tests of RFID tags fixed to apparel items and scanned under normal operating conditions, and the application of five directed data mining models to the integrated data set of laboratory and field test results. Our analyses of 45,416 observations show that two directed data mining models may identify—with near‐100% accuracy—laboratory test criteria that discriminate tags having 99% or greater read‐rates in the field. Accordingly, our study validates a generalizable methodology for identifying technical performance standards for tags that operate reliably within apparel retailers’ supply chains.

Rehabilitation Practice Patterns Following Anterior Cruciate Ligament Reconstruction: A Survey of Physical Therapists.

Recovery from anterior cruciate ligament reconstruction (ACLR) requires an intensive course of postoperative rehabilitation. Although guidelines outlining evidence-based rehabilitation recommendations have been published, actual practice patterns of physical therapists are unknown. To analyze the current landscape of clinical practice as it pertains to rehabilitation progression and the use of time and objective criteria in rehabilitation following ACLR. In this cross-sectional study, an online survey was distributed to members of the Academy of Orthopaedic Physical Therapy, the American Academy of Sports Physical Therapy, and the Private Practice Section of the American Physical Therapy Association between January and March 2017. The study analyzed a sample of 1074 responses. Supervised physical therapy was reported to last 5 months or less by 56% of survey respondents. The most frequent time frames for activity progression were 3 to 4 months (58%) for jogging, 4 to 5 months (50%) for modified sports activity, and 9 to 12 months (40%) for unrestricted sports participation. More than 80% of respondents reported using strength and functional measures during rehabilitation. Of those physical therapists who assessed strength, 56% used manual muscle testing as their only means of strength testing. Single-limb hop testing (89%) was the most frequently reported measure used to allow patients to begin modified sports activity following ACLR. Performance criteria for strength and functional tests varied significantly across all phases of rehabilitation. The 45% of respondents who reported using patient-reported outcome measures indicated that just under 10% of those measures involved fear or athletic confidence scales. Considerable variation in practice exists among American Physical Therapy Association members regarding rehabilitation following ACLR. This variability in practice may contribute to suboptimal outcomes and confusion among practitioners and patients. J Orthop Sports Phys Ther 2018;48(10):801-811. Epub 22 May 2018. doi:10.2519/jospt.2018.8264.

Validation of the abrasion resistance test protocols and performance criteria of EN13595: The probability of soft tissue injury to motorcycle riders by abrasion resistance of their clothing

IntroductionMotorcyclists represent an increasing proportion of road users globally and are increasingly represented in crash statistics. Soft tissue injuries are the most common type of injuries to crashed motorcyclists. These injuries can be prevented through the use of protective clothing designed for motorcycle use. However, the quality of such clothing is not controlled in many countries around the world. A European Standard was developed to assess the performance of clothing but as this is not mandatory, clothing certified to this Standard is difficult to obtain. Given the importance of this Standard, and that it has been validated only once, further validation work is required. MethodsIn-depth crash investigation data were used to investigate the relationship between the abrasion resistance performance of clothing and real-world injury outcome. Clothing was collected from riders who crashed on public roads in Sydney and Newcastle, Australia. This clothing was tested according to the EU Standard and the time to hole was recorded. Hospital medical records were reviewed and the association between a rider suffering a soft tissue injury and the time-to-hole for the garment was examined. ResultsThe probability of soft tissue injury for Level 1 Standard garments was between 40–60%, but more than 60% of garments tested failed to meet the minimum requirement. ConclusionsThe findings of this study provide qualified support for the Standard, with a marginal association between time-to-hole and injury being found. Practical ImplicationsThis work supports the need for improved safety performance and an increased number of high performing garments being available to motorcyclists.

Detection and identification of Xanthomonas arboricola pv. pruni from symptomless plant material: results of an Italian test performance study

Xanthomonas arboricola pv. pruni, the causal agent of bacterial spot disease of stone fruits, is a regulated quarantine pathogen in the European Union, listed as an A2 pest by the European and Mediterranean Plant Protection Organization (EPPO). Because detection and identification of this pathogen is key for its management and to ensure the production of pest free propagation material, it should be based on reliable tests, in particular when dealing with symptomless material. The current EPPO diagnostic Standard (PM 7/64) does not provide specific molecular methods for detection of this pest. The present paper summarizes the results of a test‐performance study (TPS) to validate, at a national level, a detection procedure for this bacterium. A working group was established in order to evaluate the performance criteria for tests included in the current EPPO Standard, and for a conventional PCR. On the basis of the obtained performance criteria, a diagnostic procedure was elaborated and then applied to perform an inter‐laboratory comparison. Screening tests for the detection of the bacterium on symptomless plant material based on IF and/or PCR were proposed, in parallel with isolation on agar media. For identification two methods were suggested: a molecular test or IF. This paper reports on the results of the TPS and proposes a flow diagram for the detection and identification of X. arboricola pv. pruni.

Evaluation of a novel algorithm for primary mass casualty triage by paramedics in a physician manned EMS system: a dummy based trial.

BackgroundThe Amberg-Schwandorf Algorithm for Primary Triage (ASAV) is a novel primary triage concept specifically for physician manned emergency medical services (EMS) systems. In this study, we determined the diagnostic reliability and the time requirements of ASAV triage.MethodsSeven hundred eighty triage runs performed by 76 trained EMS providers of varying professional qualification were included into the study. Patients were simulated using human dummies with written vital signs sheets. Triage results were compared to a standard solution, which was developed in a modified Delphi procedure. Test performance parameters (e.g. sensitivity, specificity, likelihood ratios (LR), under-triage, and over-triage) were calculated. Time measurements comprised the complete triage and tagging process and included the time span for walking to the subsequent patient. Results were compared to those published for mSTaRT. Additionally, a subgroup analysis was performed for employment status (career/volunteer), team qualification, and previous triage training.ResultsFor red patients, ASAV sensitivity was 87%, specificity 91%, positive LR 9.7, negative LR 0.139, over-triage 6%, and under-triage 10%. There were no significant differences related to mSTaRT. Per patient, ASAV triage required a mean of 35.4 sec (75th percentile 46 sec, 90th percentile 58 sec). Volunteers needed slightly more time to perform triage than EMS professionals. Previous mSTaRT training of the provider reduced under-triage significantly. There were significant differences in time requirements for triage depending on the expected triage category.ConclusionsThe ASAV is a specific concept for primary triage in physician governed EMS systems. It may detect red patients reliably. The test performance criteria are comparable to that of mSTaRT, whereas ASAV triage might be accomplished slightly faster. From the data, there was no evidence for a clinically significant reliability difference between typical staffing of mobile intensive care units, patient transport ambulances, or disaster response volunteers. Up to now, there is no clinical validation of either triage concept. Therefore, reality based evaluation studies are needed.

Electromagnetic Compatibility Tests of Mining Mobile Inspection Robot/Badania Kompatybilności Elektromagnetycznej Górniczego Mobilnego Robota Inspekcyjnego

Abstract The articles presents the methodology and results of electromagnetic compatibility tests conducted on a non-commercial prototype of the Mining Mobile Inspection Robot. The tests were carried out in an accredited laboratory of the Institute of Innovative Technologies EMAG in compliance with European standards harmonized with the 2004/108/EC (EMC) directive. In the article the testing stands were characterized along with the test types, performance criteria and test results. The testing methodology and the selection of standards can be a pattern to conduct electromagnetic compatibility tests for similar products designed for the mining industry.

Inter‐laboratory trial of a standardized sediment contact test with the aquatic plant Myriophyllum aquaticum (ISO 16191)

A whole-sediment toxicity test with Myriophyllum aquaticum has been developed by the German Federal Institute of Hydrology and standardized within the International Organization for Standardization (ISO; ISO 16191). An international ring-test was performed to evaluate the precision of the test method. Four sediments (artificial, natural) were tested. Test duration was 10 d, and test endpoint was inhibition of growth rate (r) based on fresh weight data. Eighteen of 21 laboratories met the validity criterion of r ≥ 0.09 d(-1) in the control. Results from 4 tests that did not conform to test-performance criteria were excluded from statistical evaluation. The inter-laboratory variability of growth rates (20.6%-25.0%) and inhibition (26.6%-39.9%) was comparable with the variability of other standardized bioassays. The mean test-internal variability of the controls was low (7% [control], 9.7% [solvent control]), yielding a high discriminatory power of the given test design (median minimum detectable differences [MDD] 13% to 15%). To ensure these MDDs, an additional validity criterion of CV ≤ 15% of the growth rate in the controls was recommended. As a positive control, 90 mg 3,5-dichlorophenol/kg sediment dry mass was tested. The range of the expected growth inhibition was proposed to be 35 ± 15%. The ring test results demonstrated the reliability of the ISO 16191 toxicity test and its suitability as a tool to assess the toxicity of sediment and dredged material.

Retrospective audit of the widal test for diagnosis of typhoid Fever in pediatric patients in an endemic region.

Although typhoid fever is confirmed by culture of Salmonella Typhi, Widal test is widely used in India but little information exists about its reliability. We examined the performance of Widal test in our hospital for diagnosis of typhoid fever in children. Hundred consecutive pediatric in-patients for whom, the Widal test was requested were grouped into four categories: widal positive and clinically consistent with typhoid fever (Group 1; n=42), widal negative but clinically consistent (Group 2, n=12), widal positive but not clinically consistent (Group 3, n=12) and widal negative and also not clinically consistent (Group 4, n=34). The results were analyzed by the test performance criteria, namely, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) using culture-confirmed typhoid fever cases as the "true positives". We found that 7/100 patients had culture-proven typhoid fever. Using a cut off ≥ 50 for O agglutinins or ≥100 for H agglutinins, the Widal test gave a sensitivity of 71.43%, specificity of 47.31%, and a positive predictive value of 09.25% and a negative predictive value of 95.65%. The Widal test is an easy, inexpensive and relatively non-invasive but is not reliable in our set up because of a low PPV. There is a need for a more efficient rapid diagnostic test for typhoid fever.

Racial/ethnic subgroup differences in cognitive ability test range restriction: Implications for differential validity.

Recent meta-analyses demonstrated that the observed correlation between cognitive ability test scores and performance criteria was lower for Black and Hispanic subgroups than for Asian and White subgroups in college admissions, civilian employment, and military domains (i.e., differential validity). Given mean score differences between racial/ethnic subgroups, these observed validities may have been confounded by subgroup differences in range restriction. The present study draws on data from hundreds of cognitive ability test validity studies including more than 1 million persons to investigate whether Asian, Black, Hispanic, and White subgroups have differed in amounts of range restriction. We first replicated observed differential validity results and also extended them by presenting the first meta-analytic evidence that observed cognitive ability test validity is lower for the Hispanic subgroup in civilian employment settings. All subgroups were approximately equivalently restricted in range in college admissions and civilian employment domains, but the Black subgroup was more restricted in range than the White subgroup in military studies. In all 3 domains, any differences in range restriction could not account for observed validity differences between subgroups. We also provide estimates of range-restriction-corrected validities; Black and Hispanic subgroups' corrected validities were 11.3-18.0% lower than White corrected validities across domains.

A uniform methodology to establish test parameters for watertightness testing: Part I: A critical review

Many of the standards and codes related to watertightness of building components in use today have a long history and in most cases their roots were conceived decades ago. Irrespective of the broad spectrum of research on wind loads, rainfall and wind driven rain (WDR) intensity, little information is available concerning the scientific basis for watertightness test methods or performance criteria. This paper provides an overview of existing methodologies to establish test conditions and a critical review of calculation methods for wind and WDR loads on buildings, from the viewpoint of establishing test parameters for watertightness testing. The operative standard in the field of structural engineering is extended with a gust model to calculate wind loads for varying configurations, return periods and gust lengths, and model implications are discussed. A state-of-the-art on intensity–duration–frequency curves of horizontal rainfall intensity is given, and a new approach to accommodate conflicting models is presented. Furthermore, based on recent advances in WDR research, an adapted semi-empirical model is suggested to calculate extreme WDR intensities on building façades. For two locations boundary conditions for watertightness testing were calculated based on datasets extending over 10 years of 10-min averaged values. Finally, constraints and challenges in extreme value analysis in respect to cut-off values, fitting algorithms, goodness-of-fit (GOF) criteria and co-occurrence of rain and wind are discussed.

Analytical Validation of the Oncotype DX Genomic Diagnostic Test for Recurrence Prognosis and Therapeutic Response Prediction in Node-Negative, Estrogen Receptor–Positive Breast Cancer

Oncotype DX is a clinically validated, high-complexity, multianalyte reverse transcription-PCR genomic test that predicts the likelihood of breast cancer recurrence in early-stage, node-negative, estrogen receptor-positive breast cancer. The Recurrence Score (RS) provides a more accurate, reproducible measure of breast cancer aggressiveness and therapeutic responsiveness than standard measures. Individualized patient management requires strict performance criteria for clinical laboratory tests. We therefore investigated the analytical performance of the assay. Assays used a pooled RNA sample from fixed paraffin-embedded tissues to evaluate the analytical performance of a 21-gene panel with respect to amplification efficiency, precision, linearity, and dynamic range, as well as limits of detection and quantification. Performance variables were estimated from assays carried out with sample dilutions. In addition, individual patient samples were used to test the optimized assay for reproducibility and sources of imprecision. Assay results defined acceptable operational performance ranges, including an estimated maximum deviation from linearity of <1 cycle threshold (C(T)) units over a > or =2000-fold range of RNA concentrations, with a mean quantification bias of 0.3% and CVs of 3.2%-5.7%. An analysis of study design showed that assay imprecision contributed by instrument, operator, reagent, and day-to-day baseline variation was low, with SDs of <0.5 C(T). The analytical and operational performance specifications defined for the Oncotype DX assay allow the reporting of quantitative RS values for individual patients with an SD within 2 RS units on a 100-unit scale.

Achieving quality reproducible results and maintaining compliance in molecular diagnostic testing of human papillomavirus.

Laboratories contemplating either the addition of new molecular tests or modifying methods approved by the Food and Drug Administration for human papillomavirus testing should be aware of a variety of procedural, performance, and regulatory issues surrounding such activity. Diagnostic medical laboratory testing in the United States is regulated by the Centers for Medicare and Medicaid Services, an agency formerly known as the Health Care Finance Administration. The regulatory vehicle of the Centers for Medicare and Medicaid Services is manifested in the Clinical Laboratory Improvement Amendments (CLIA). The CLIA program has put into place specific regulations for laboratory quality control, which includes specific recommendations for method validation. Regulations that must be followed regarding personnel, quality control, quality assurance, method validation, and proficiency testing depend on the complexity category of the individual test. All molecular diagnostic tests, including those for human papillomavirus, are considered high complexity. The Centers for Medicare and Medicaid Services retains the authority to allow private, national accreditation organizations to "deem" that a laboratory is compliant with CLIA '88 requirements. Accreditation organizations, such as the Joint Commission for Accreditation of Hospitals, the Commission on Office Laboratory Accreditation, and the College of American Pathologists (CAP), as well as several state medical laboratory-accrediting agencies, possess the authority to deem laboratories as "CLIA-approved." The CAP, through its Laboratory Accreditation Program, has promoted standards for laboratory performance and method validation. In general, guidelines set forth in the CAP Laboratory Accreditation Program checklists specify that all clinical laboratory testing must essentially meet those requirements defined for high-complexity testing under CLIA '88, including test validation standards, reportable/reference ranges, performance criteria, and proficiency testing.