Regulatory compliance vs. NEXUS quality for laboratory tests

In the U.S., all clinical laboratory testing is regulated by the Clinical Laboratory Improvement Amendments (CLIA) (). The CLIA link test quality and adherence to a body of testing regulations intended to ensure accurate, reliable, and timely patient test results. The goal of the CLIA legislation was to ensure a minimum, fundamental level of quality. In the context of “NEXUS,” quality must “go beyond getting the ‘right’ answer on the ‘right’ patient that can be interpreted against ‘right’ reference values. CLIA regulations with specific minimum, performance requirements, or safeguards, are designed to prevent testing errors. The US Institute of Medicine found that testing processes fail as a result of human error, lack of documentation, and lack of test management. In the latest (2004) interpretations of CLIA regulations, the minimum quality control requirement continues to be analyzing at least two external, liquid quality control materials per test per day. In 1995, we proposed that the responsibility for achieving quality test results shifts from the sole purview of the laboratory director to an “alliance” of laboratory professionals, manufacturers, and regulators. The EQC (equivalent quality control) concept as proposed is a positive step in achieving this alliance. With the obvious lack of scientific and statistical robustness, EQC falls far short of ensuring quality. Achieving the “NEXUS Vision” for quality laboratory testing will not come solely from laboratory professionals. The NEXUS is about how to ensure the full-quality assessment of the testing process – pre-analytical, analytical, and post-analytical.Presented at the 10th Conference Quality in the Spotlight, March 2005, Antwerp, Belgium.     

Cardiac markers: a clear cause for point-of-care testing

Point-of-care testing (POCT) in patients with ischemic heart disease is driven by the time-critical need for fast, specific, and accurate results to initiate therapy instantly. According to current guidelines, the results of the cardiac marker testing should be available to the physician within 30 min (“vein-to-brain” time) to initiate therapy within 60–90 min (“door-to-needle” time) after the patient has arrived at the emergency room or intensive care unit. This article reviews the current efforts to meet this goal (1) by implementing POCT of established biochemical markers such as cardiac troponins, creatine kinase MB, and myoglobin, in accelerated diagnosis and management workflow schemes, (2) by improving current POCT methods to obtain more accurate, more specific, and even faster tests through the integration of optical and electrochemical sensor technology, and (3) by identifying new markers for the very early and sensitive detection of myocardial ischemia and necrosis. Furthermore, the specific requirements for cardiac POCT in regard to analytical performance, comparability, and diagnostic sensitivity/specificity are discussed. For the future, the integration of new immunooptical and electrochemical chip technology might speed up diagnosis even further. However, every new development will have to meet the stringent method validation criteria set for corresponding central laboratory testing.     

Quality in point-of-care testing: taking POC to the next level

Point-of-care testing (POCT) is a complex system with many opportunities for error. Delivering quality POCT requires multidisciplinary coordination and an understanding of the preanalytic, analytic, and postanalytic processes that are necessary to deliver a test result and take clinical action. Most errors in laboratory testing occur in the pre and postanalytical phases and many mistakes that are referred to as lab error are actually due to poor communication, actions by others involved in the testing process, or poorly designed processes outside the laboratory's control. POCT requires significant operator interaction with analysis and documentation of calibration and quality control, unlike other medical devices. Clinicians often interpret POCT as equivalent to core laboratory testing, only faster, and mistakenly utilize the results interchangeably despite the differences in test methodologies. Taking quality of POCT to the next level involves looking beyond the analytical phase and integration of POCT into the entire pathway of patient care to understand how POCT relates to medical decision-making at specific points during the patient's care. A systematic review of the literature by the National Academy of Clinical Biochemistry is currently being conducted to draft guidelines for best practice that link the use of POCT to improved patient outcomes.Presented at the 10th Conference Quality in the Spotlight, March 2005, Antwerp, Belgium.     

Urine dry reagent strip “error” rates using different reading methods

 The need for “quality” in near patient testing (NPT) has been acknowledged since the mid 1980s. The commonest biochemical NPT device is the dry reagent strip or “dipstick” for urinalysis. Dipsticks may be read in three ways, against the color chart printed along the side of the bottle, using a benchreader (the color chart printed on a flat card) or using an electronic reader. This report uses the results of a urinalysis quality assurance (QA) program, over 1998, to evaluate the “error” rates which occur using the three different reading methods. The QA samples are buffered aqueous solutions which are “spiked” to give concentrations midway between two color blocks for each analyte. Results are scored as ±1 if a color block adjacent to the target value, ±2 for results two color blocks (defined as “error”) and ±3 for results three color blocks (defined as “gross error”) from the target value. Analysis of the results show that the error rates are similar reading visually by either method, but greatly reduced when read electronically. Some persisting errors when using the electronic reader are explained by observation studies. The study highlights the value of a urinalysis QA program for NPT urinalysis in understanding the error rates of this simple but ubiquitous test. Received: 10 July 2000 / Accepted: 10 July 2000     

Quality and timeliness in medical laboratory testing

In terms of testing, modern laboratory medicine can be divided into centralized testing in central laboratories and point-of-care testing (POCT). Centralized laboratory medicine offers high-quality results, as guaranteed by the use of quality management programs and the excellence of the staff. POCT is performed by clinical staff, and so such testing has moved back closer to the patient. POCT has the advantage of shortening the turnaround time, which potentially benefits the patient. However, the clinical laboratory testing expertise of clinical staff is limited. Consequently, when deciding which components of laboratory testing must be conducted in central laboratories and which components as POCT (in relation to quality and timeliness), it will be medical necessity, medical utility, technological capabilities and costs that will have to be ascertained. Provided adequate quality can be guaranteed, POCT is preferable, considering its timeliness, when testing vital parameters. It is also preferred when the central laboratory cannot guarantee the delivery of results of short turn-around-time (STAT) markers within 60 or (even better) 30 min. POCT should not replace centralized medical laboratory testing in general, but it should be used in cases where positive effects on patient care have been clearly demonstrated.     

Reference intervals of serum folate and vitamin B12 developed from data of healthy subjects

 In this study the reference intervals for folate and vitamin B₁₂ were estimated according to the National Committee for Clinical Laboratory Standards Approved Guideline C28-A and International Federation of Clinical Chemistry recommendations. The study included 155 women and 124 men between ages 18–40. The health status was confirmed by history, physical examination and a questionnaire. The central 95% reference intervals of serum folate and vitamin B12 for women, determined non-parametrically, were found to be 3.9–18.1 ng/ml and 101–666.7 pg/ml, respectively. The reference values of serum folate and vitamin B12 for men were also found to be 2,5–17.6 ng/ml and 100–699.57 pg/ml, respectively. We did not observe subclass differences between females and males. Received: 15 April 2000 · Accepted: 15 April 2000     

Is CLIA 2003 the quality alliance envisioned between manufacturers,laboratory professionals,and regulatory agencies?

The Clinical Laboratory Improvement Amendments of 1988 (CLIA88) had a groundbreaking effect on laboratory professionals, instrument and reagent manufacturers, and regulators in the United States, and by association, worldwide. CLIA88 defined new levels of responsibility for all three of these stakeholders in modern laboratory testing. As a result, we envisioned a CLIA-driven approach to regulations, which in effect, created a three-member quality alliance. In 2003, the long awaited CLIA updates to the quality control and quality assurance requirements were published. The revisions in CLIA 2003 will herald an era in which manufactures take responsibility for meeting new standards of quality (improved accuracy and precision or reduced total allowable error) in the clinical laboratory and, especially, at point of care where testing is performed by non-laboratorians. The European (Bureau International des Poids ed Mesures) efforts at traceability, the National Committee of Clinical Laboratory Standards efforts at estimating total allowable error, and the new CLIA 2003 quality systems approach for quality requirements return to the fundamental concepts of accuracy to assess the efficacy of clinical laboratory testing.Presented at the 8th Conference on Quality in the Spotlight, 17–18 March 2003, Antwerp, Belgium     

Standardization of pH measurements based on the ion interaction approach

The Pitzer method was used to calculate the pH values on the conventional and “true” scales for the TRIS—TRIS·HCl−NaCl−H₂O buffer system in the 0–40 °C temperature region and 0–4 NaCl molality interval. This buffer can be used as a standard for pH measurements in a wide range of ionic strengths. The conventional scale is used in cells without a salt bridge. The “true” scale is recommended for pH measurements using cells with a salt bridge. At the same concentrations of the buffer solution, the “true” scale is essentially transformed into the scale of the National Bureau of Standards (NBS) of the USA. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 676–680, April, 2000.     

Can the progress in quality management tools for POC tame the fiends from Pandora's box?

POCT provides the opportunity to significantly improve the overall quality of blood testing in an organization. The design of the product, the redesign of the testing process and the tools used to manage a completely distributed testing process, are key to the quality implementation of POCT. Both theoretical considerations and practical outcomes are discussed in this paper, using the i-STAT^® System as an example of a POCT system.     

Quality assurance of qualitative analysis in the framework of the European project ’MEQUALAN’

 The European Commission has supported the G6MA-CT-2000–01012 project on ”Metrology of Qualitative Chemical Analysis” (MEQUALAN), which was developed during 2000–2002. The final result is a document produced by a group of scientists with expertise in different areas of chemical analysis, metrology and quality assurance. One important part of this document deals, therefore, with aspects involved in analytical quality assurance of qualitative analysis. This article shows the main conclusions reported in the document referring to the implementation of quality principles in qualitative analysis: traceability, reliability (uncertainty), validation, and internal/external quality control for qualitative methods. Received: 15 October 2002 Accepted: 20 October 2002 This paper is a summary of the Quality Assurance section included in the final report of the MEQUALAN project. The authors of this paper correspond to the members of the MEQUALAN Consortium. One of them (K.H.) does not fully agree with some parts of the text. Correspondence to A. Ríos     

Predictive values instead of normal ranges: less data, more information

Diagnostic strategies can have various goals at two levels: to facilitate the diagnostic process on the cognitive level, and to serve considerations on the level of the doctor–patient relationship. Requests for laboratory tests could be intended to exclude a disease or to affirm the presence of disease. Thirdly, tactical motives to smoothen the negotiations between doctor and patient probably seem to be important as well. These three intentions differ in prior probability, should lead to different sets of tests, and to different interpretations. Even the cut-off points should differ. This leads to three different decision strategies, both at requesting, as at interpreting the results. Following this line of thought, post-test probabilities are more suitable than normal ranges. Excluding strategy: this is the most prevalent. However, the disadvantage of an excluding strategy (prior 1–5%) is a false-positive result. A positive test result should lead to follow-up by wait and see or by repeated testing. More extensive testing usually is not a very sensible strategy. In practice, physicians simply ignore slightly abnormal values. Mentally they put the cut-off points for normality more broader. The number of tests is small. Confirmative strategy: the disadvantage of a confirmative intention (prior 10–30%) is a false-negative result. Follow-up without testing, repeated testing, or even accepting marginal normal results as abnormal is a proper strategy. The number of tests is moderate to high. Tactical strategy: the tactical intention strategy to reassure the patient – or avoid referrals – could lead to ignoring all slightly positive test results by choosing a higher cut-off point. Actually, considering the usual insignificant diagnostic gain when testing for tactical reasons, all test results are clinically insignificant, unsuspected outliers excluded. Here, a very limited set of tests should be chosen. The laboratory test is the currency in mutual trading medical expectations and relationship considerations between doctor and patient. The number of tests is minimal. If the physician chooses a strategy, a limited range of prior probability is chosen. Then a possibly computerized algorithm produces a “Value (posterior probability)” as test result, replacing “Value (normal ranges)”. Thus one number less on the lab form, yielding more significant information.Presented at the 10th Conference Quality in the Spotlight, March 2005, Antwerp, Belgium     

Keeping the spotlight on quality from a distance

 Maintaining the quality of testing in remote locations can be demanding of laboratory resources in terms of daily visits to instruments and providing support outside of normal working hours. Recently technology and software solutions have appeared to reduce this burden for laboratory scientists dramatically. The AVL Auto QC unit, in conjunction with OMNILink software, allow laboratory staff to perform many quality control and maintenance procedures on instruments in wards and medical units from a PC in the central laboratory. Assessment of this technology and software in the Special Baby Care Unit at Bradford Royal Infirmary has demonstrated many benefits including reduction in ward visits, better support out of hours, regular quality control checks, and improved analytical quality. Received: 15 April 2000 · Accepted: 15 April 2000     

Quality targets in dipstick urinalysis

Point of care testing (POCT) of urine has been practiced for many centuries. It has come particularly into its own in the second half of the 20th century with the development of tablet- and later dipstick-testing systems. Unfortunately, it has become embedded in clinical practice outside the laboratory, missing the development of the quality culture that has developed inside the laboratory. Analysis of the results of a Urine Quality Assurance Programme demonstrate the value and the need for this quality culture.     

Proficiency testing as tool for ISO 17025 implementation in National Public Health Laboratory: a mean for improving efficiency

Public Health Laboratories (PHL) as part of Public Health Services are involved in law enforcement and ensuring food and water quality. The laboratories had to go through an organizational and monetary change imposed by the growing and changing needs of the state of Israel. The laboratories had to become more modern and to implement new and more sophisticated testing methods. Another requirement was to perform a steadily increasing number of tests and to be more flexible towards customers’ demands. Yet, the budget was not changed accordingly, as the Public Service to which the laboratories belong to do not respond to changing needs. Management realization was that the accreditation process could be used as a tool to achieve organizational and cultural change. Understanding and transformation were required throughout the organization, including management. Proficiency testing is performed for all testing methods in all areas even for non-accredited tests such as clinical tests. Proficiency testing was used as a tool for organizational culture change. It is a great index with game elements, that gives employees and managers the possibility for comparison, fixing problems and corrective action. The demands of ISO 17025 made it necessary to change peoples’ attitudes and views on both professional and communication levels. Laboratory quality consists now on the four main principles, described in the 5M&E model which is typical to small organizations and which ensures a constantly improving system: ”Policy statement”, ”Machine”, ”Material”, ”Measurement”, ”Method”, ”Manpower”, and ”Environment” targeted to achieve ”Quality upgrade”. Slowly we succeeded in providing better and more reliable services and have increased our income on what would hopefully become our way to financial independence. We hope this process would provide the Ministry of Health with a better chance to public health using the same financial sources. Received: 25 October 2000 Accepted: 12 December 2000     

Intramolecular S···O chalcogen bond in thioindirubin

Results of X-ray diffraction study and quantum-chemical calculations revealed that molecular conformation of thioindirubin molecule creates suitable conditions for formation of intramolecular C–H···O and S···O interactions. Analysis of molecular electrostatic potential (MEP) demonstrates existence of two areas of positive MEP (σ-holes) in the outermost part of the sulfur atom on the continuation of the lines of the C–S bonds. One of these σ-holes is oriented toward region of negative MEP around the oxygen atom of carbonyl group. Such situation corresponds to formation of σ-hole or chalcogen bond. Existence of both types of bonding interactions is confirmed by topological analysis of electron density distribution using “Atoms in Molecules” (AIM) theory. Energies of the C–H···O hydrogen bond and the S···O σ-hole bond derived from AIM and NBO theories are very close.     

Quantitative analysis of eletriptan in human plasma by HPLC-MS/MS and its application to pharmacokinetic study

Authors developed a simple, sensitive, selective, rapid, rugged, and reproducible liquid chromatography–tandem mass spectrometry method for the quantification of eletriptan (EP) in human plasma using naratriptan (NP) as an internal standard (IS). Chromatographic separation was performed on Ascentis Express C18, 50 × 4.6 mm, 2.7 μm column. Mobile phase was composed of 0.1% formic acid: methanol (40:60 v/v), with 0.5 mL/min flow rate. Drug and IS were extracted by liquid–liquid extraction. EP and NP were detected with proton adducts at m/z 383.2→84.3 and 336.2→97.8 in multiple reaction monitoring (MRM) positive mode, respectively. The method was validated with the correlation coefficients of (r ²) ≥ 0.9963 over a linear concentration range of 0.5–250.0 ng/mL. This method demonstrated intra- and inter-day precision within 1.4–9.2% and 4.4–5.5% and accuracy within 96.8–103% and 98.5–99.8% for EP. This method is successfully applied in the bioequivalence study of 24 human volunteers.     

Performance of uncertainty evaluation strategies in a food proficiency scheme

A study of the performance of different uncertainty evaluation strategies among 163 voluntary respondents from food proficiency schemes is presented. Strategies included use of: single-laboratory validation data, quality control data, past proficiency testing data, reproducibility data, a measurement equation and the dispersion of replicate observations on the test material. Most performed reasonably well, but the dispersion of replicate observations underestimated uncertainty by a factor of approximately 3. Intended compliance with accreditation requirements was associated with significantly improved uncertainty evaluation performance, while intended compliance with the ISO “Guide to the expression of uncertainty in measurement” had no significant effect. Substituting estimates based on the Horwitz or Horwitz–Thompson models or on PT target standard deviation for the respondents’ own estimates of uncertainty led to a marked reduction in poor zeta scores and significant improvement in dispersion of zeta scores.     

Key requirements for introducing quality assurance in measurement laboratories

 The implementation of a quality assurance system is fraught with difficulties. However, these difficulties may be overcome if the laboratory uses suitable means to facilitate the process. It is necessary to mobilise the intelligence and energy of all members of the laboratory. In order to command adherence, the project must be shared, and this necessitates a major effort by all concerned. Communication is a major factor in obtaining the support of all parties. Six important steps must be distinguished: – Defining quality policy – Creating awareness, information, training – Creating a quality structure – Establishing a deadline for obtaining accreditation – Progressive implementation – Experimentation and validation. Even if the task of obtaining and maintaining accreditation remains difficult, it clearly promotes a minimum level of organisation and stepwise progress in quality assurance. The laboratory must keep improving its quality system, using European Standard EN 45001 as an effective management model. Received: 9 April 1997 · Accepted: 11 September 1997