Over the last few years, hepatitis C virus (HCV) infection has emerged as one of the most significant causes of chronic liver disease worldwide, with estimated prevalence ranging from 2.2 to 3.0%. Since January 2011, the Infectious Diseases Department of San Raffaele Scientific Institute in Milan carried out a prevention programme called ‘EASY test project’, to diagnose the HCV infection. In these four years a total of 35,000 subjects have been approached to inform them about HCV infection and other sexually transmitted diseases. Of the total eligible volunteers, 6500 (18,6% of contacted subjects) performed HCV tests on saliva and completed the interview in the alternative ‘street lab’. We believe that increasing awareness of these alternative tests among individuals at risk and providers may be an appropriate strategy to increase the number of people who know their serological status and who could be linked to care and engaged in care!
by M.R. Parisi, Dr L. Soldini, Dr G. Vidoni, Dr K. Schlusnus, Dr F. Dorigatti, and Prof. A. Lazzarin
Background
Over the last few years, hepatitis C virus (HCV) infection has emerged as one of the most significant causes of chronic liver disease worldwide, with estimated prevalence ranging from 2.2 to 3.0% (1).
In our country, the proportion of subjects infected with HCV is approximately 2% of the general population with a gradient that increases from the north to the south and the islands and with age (60% of patients with hepatitis C are over 65 years old). It is estimated that about 1 million people in Italy are ill with hepatitis C (2).
As acute HCV infection is usually asymptomatic, early diagnosis is rare. Those people who are developing chronic infection, even though undiagnosed, may suffer serious liver damage. In fact, a significant proportion of HCV infected subjects will ultimately progress to liver cirrhosis and/or hepatocellular carcinoma, making chronic HCV infection a major health problem (3, 4).
Despite the excellent accuracy of the tests currently available for the detection of anti-HCV antibodies (anti-HCV), the delay in reporting the results, the need for specialized equipment for processing the samples and interpreting the results, as well as the need to transfer individuals to sample collection and processing centres, limit their use as screening tools. Serologic points-of-care tests (POCTs) have several advantages, namely that they require little specialized apparatus, can be brought to the individuals who are to be tested and allow diagnosis in as little as a few minutes in different clinical settings (5). These advantages might be translated into increased testing opportunity and, ultimately, identification of more patients who could benefit from antiviral treatment (6). Over the last few years, several tests for rapid detection of anti-HCV have been developed and are currently in use in various countries; however, only recently, the first POCT was approved by the U.S. Food and Drug Administration (7). The investigation of the diagnostic accuracy of POCTs and rapid tests for the detection of anti-HCV is a highly relevant topic. As well as the great importance of the issue in terms of public health, there is a lack of studies evaluating the performance of several of the currently used tests.
EASY test project
Since January 2011, the Infectious Diseases Department of San Raffaele Scientific Institute in Milan carried out a Prevention Program called “EASY test project”, using the new oral test (rapid and non-invasive) the OraQuick® HCV Rapid Antibody Test (OraSure technologies, Inc.) to diagnose the HCV infection. The test is a single-use, immunoassay for the qualitative detection of antibodies to hepatitis C virus (anti-HCV) in oral fluid, fingerstick whole blood, venipuncture whole blood and plasma specimens. The HCV rapid test received the FDA approval for use with oral fluid on 28 June 2010.
The clinical sensitivity and specificity of the OraQuick HCV test using oral fluid were 97.8% (95% confidence interval [CI]) and 100% (95% CI, 98.4-100%), respectively (8).
The main objective of the project is to evaluate the acceptability of an alternative, free and anonymous HCV test offer, available in different settings (in Points of Care, STDs Prevention clinics and General Practitioner surgeries) (9, 10). Furthermore, contacting the ‘hard-to-reach’ people with this anonymous and free test offer could reduce or stop this public health problem, by making an easy link to healthcare.
Subjects who underwent the test were asked to complete an anonymous questionnaire, through which it has been possible to collect a series of data on risk behaviours of the population tested. The questionnaire was devised with the intention of collecting demographic and risk behaviour data, as well as previous HCV/HIV testing experience, information about sex, drug use, educational level, nationality, general behaviours, use of HIV/HCV prevention services, previous surgical practices, invasive diagnostic practices, dental cares, tattoos or sexually transmitted diseases. Post-test counselling has been provided to all HCV reactive and non-reactive subjects, by the Infectious Diseases Department physicians involved in the study. The test was been carried out by a biologist or a practitioner, following the manufacturer’s procedures.
If the HCV oral test provided a preliminary positive result, a venipuncture was performed immediately for standard test confirmation, supported by the post-test counselling.
The results were received in two working days. At this point, the HCV-positive patient was contacted directly by the infectious diseases specialist for the visit and the diagnostic procedures to define the liver disease status and eventually to start the treatment, according to the guidelines for when HCV viral load and genotype are identified.
In these four years a total of 35,000 subjects have been approached to inform them about HCV infection and other sexually transmitted diseases. Of the total eligible volunteers, 6500 (18.6%) performed HCV tests on saliva and completed the interview in the alternative ‘street lab’. From the questionnaires we know that this initiative has been much appreciated.
Discussion
In recent years, advances in detection technology made available a range of POCTs for different infectious diseases. It is now possible to screen and diagnose those conditions at primary healthcare settings, using minimally invasive tests. In the present study, a new POCT for HCV infection has been performed on oral fluid. The use of oral fluid is an attractive alternative based on the fact that collection of plasma or serum samples requires equipment and training, and is more time consuming.
The FDA-approved OraQuick HCV Rapid Antibody Test (OraSure Technologies) is one of the most studied rapid tests for the diagnosis of HCV infection.
The development of rapid alternative tests for the diagnosis of HCV infection is to facilitate access to testing to reduce the individual risk of disease progression and social costs.
Despite the excellent sensitivity and specificity of third-generation enzyme immunoassays (EIAs), the turnaround time for reporting test results is at least one day, thereby making it difficult to deliver the results to tested individuals at first visit. Rapid tests are formatted such that they do not require complicated instrumentation or testing by skilled technical staff. They potentially generate results within an hour and therefore may be used for point-of-care testing. Rapid tests are obviously more expensive than conventional immunoassays and are not designed for testing large batches of specimens. However, in no-clinical settings and laboratories that conduct low-volume testing, adoption of rapid oral testing can be cost-effective. CDC guidelines formulated for confirming screening anti-HCV results remain to be refined to accommodate rapid anti-HCV testing. It is important to emphasize that OraQuick HCV test has not been approved for general screening. A positive result of a rapid anti-HCV positive test is indicative of the presence of anti-HCV and, again, does not indicate active infection (11).
We successfully conducted this rapid HCV testing and counselling programme with the goal of spreading the use of saliva test anonymously and free of charge. We aim to facilitate access to testing in alternative settings, in order to understand if the ‘hard-to access’ population would access salivary rapid testing versus the conventional settings.
Increasing awareness of these alternative tests among individuals at risk and providers may be an appropriate strategy to increase the number of people who know their serological status and who could be linked to care and engaged in care!
The recent introduction of rapid oral HCV antibody test could completely change the HCV diagnosis approach by facilitating the possibility of testing millions of people worldwide (in particular in the developing countries).
For these reasons, we hope the oral-fluid based rapid HCV tests could become the ‘gold standard’ to facilitate the HCV screening access and become the standard of care and the basis for the national HCV testing algorithm in many countries with spread HCV epidemic, also in the dental care surgeries.
References
1. Lavanchy D. The global burden of hepatitis C. Liver Int. 2009; 29: 74–81.
2. Istituto Superiore di Sanita (ISS). Available at: www.iss.it.
3. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997; 26: 15S–20S.
4. Hutin Y, Kitler M, Dore G, Perz J, Armstrong G, Dusheiko G, et al. Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol. 2004; 44: 20–29.
5. Ferreira-Gonzales A, Shiffman ML. Use of diagnostic testing for managing hepatitis C virus infection. Semin Liver Dis. 2004; 24: 9–18.
6. Tucker JD, Bien CH, Peeling RW. Point-of-care testing for sexually transmitted infections: recent advances and implications for disease control. Curr Opin Infect Dis. 2013; 26: 73–79.
7. Food and Drug Administration. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfClia/detail
8. OraQuick HCV Rapid Antibody Test. Available from:
http://www.fda.gov/MedicalDevices/productsandMedicalProcedures/DeviceApprovalsandClearances/Recently-approved-Devices
9. Parisi MR, Soldini L, Di Perri G, Tiberi S, Lazzarin A, et al. Offer of rapid testing and alternative biological samples as practical tools to implement HIV screening programs. New Microbiol. 2009; 32(4): 391–396.
10. Parisi MR, Soldini L, Vidoni GM, Clemente F, Mabellini C, Belloni T, Nozza S, Brignolo L, Negri S, Rusconi S, Schlusnus K, Dorigatti F, Lazzarin A. Cross-sectional study of community serostatus to highlight undiagnosed HIV infections with oral fluid HIV-1/2 rapid test in non-conventional settings. New Microbiol. 2013; 36(2): 121–132.
11. Center for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Available from: http://www.cdc.gov/hepatitis/hcv/Management.htm.
The authors
Maria Rita Parisi*1 MSc, Laura Soldini2 MD, Gianmarino Vidoni3 MD, Karin Schlusnus4 PhD, Fernanda Dorigatti2 MD, Adriano Lazzarin1 MD
1Division of Immunology, Transplantation and Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
2Laboraf Diagnostic and Research OSR S.p.A., San Raffaele Scientific Institute, Milan, Italy
3Prevention Department, Reference Centre for HIV and STDs, Local Public Health Unit, Milan, Italy
4ANLAIDS Lombardia Onlus, Milan, Italy
*Corresponding author
E-mail: parisi.mariarita@hsr.it
HCV infection: recent advances of an alternative screening approach
, /in Featured Articles /by 3wmediaOver the last few years, hepatitis C virus (HCV) infection has emerged as one of the most significant causes of chronic liver disease worldwide, with estimated prevalence ranging from 2.2 to 3.0%. Since January 2011, the Infectious Diseases Department of San Raffaele Scientific Institute in Milan carried out a prevention programme called ‘EASY test project’, to diagnose the HCV infection. In these four years a total of 35,000 subjects have been approached to inform them about HCV infection and other sexually transmitted diseases. Of the total eligible volunteers, 6500 (18,6% of contacted subjects) performed HCV tests on saliva and completed the interview in the alternative ‘street lab’. We believe that increasing awareness of these alternative tests among individuals at risk and providers may be an appropriate strategy to increase the number of people who know their serological status and who could be linked to care and engaged in care!
by M.R. Parisi, Dr L. Soldini, Dr G. Vidoni, Dr K. Schlusnus, Dr F. Dorigatti, and Prof. A. Lazzarin
Background
Over the last few years, hepatitis C virus (HCV) infection has emerged as one of the most significant causes of chronic liver disease worldwide, with estimated prevalence ranging from 2.2 to 3.0% (1).
In our country, the proportion of subjects infected with HCV is approximately 2% of the general population with a gradient that increases from the north to the south and the islands and with age (60% of patients with hepatitis C are over 65 years old). It is estimated that about 1 million people in Italy are ill with hepatitis C (2).
As acute HCV infection is usually asymptomatic, early diagnosis is rare. Those people who are developing chronic infection, even though undiagnosed, may suffer serious liver damage. In fact, a significant proportion of HCV infected subjects will ultimately progress to liver cirrhosis and/or hepatocellular carcinoma, making chronic HCV infection a major health problem (3, 4).
Despite the excellent accuracy of the tests currently available for the detection of anti-HCV antibodies (anti-HCV), the delay in reporting the results, the need for specialized equipment for processing the samples and interpreting the results, as well as the need to transfer individuals to sample collection and processing centres, limit their use as screening tools. Serologic points-of-care tests (POCTs) have several advantages, namely that they require little specialized apparatus, can be brought to the individuals who are to be tested and allow diagnosis in as little as a few minutes in different clinical settings (5). These advantages might be translated into increased testing opportunity and, ultimately, identification of more patients who could benefit from antiviral treatment (6). Over the last few years, several tests for rapid detection of anti-HCV have been developed and are currently in use in various countries; however, only recently, the first POCT was approved by the U.S. Food and Drug Administration (7). The investigation of the diagnostic accuracy of POCTs and rapid tests for the detection of anti-HCV is a highly relevant topic. As well as the great importance of the issue in terms of public health, there is a lack of studies evaluating the performance of several of the currently used tests.
EASY test project
Since January 2011, the Infectious Diseases Department of San Raffaele Scientific Institute in Milan carried out a Prevention Program called “EASY test project”, using the new oral test (rapid and non-invasive) the OraQuick® HCV Rapid Antibody Test (OraSure technologies, Inc.) to diagnose the HCV infection. The test is a single-use, immunoassay for the qualitative detection of antibodies to hepatitis C virus (anti-HCV) in oral fluid, fingerstick whole blood, venipuncture whole blood and plasma specimens. The HCV rapid test received the FDA approval for use with oral fluid on 28 June 2010.
The clinical sensitivity and specificity of the OraQuick HCV test using oral fluid were 97.8% (95% confidence interval [CI]) and 100% (95% CI, 98.4-100%), respectively (8).
The main objective of the project is to evaluate the acceptability of an alternative, free and anonymous HCV test offer, available in different settings (in Points of Care, STDs Prevention clinics and General Practitioner surgeries) (9, 10). Furthermore, contacting the ‘hard-to-reach’ people with this anonymous and free test offer could reduce or stop this public health problem, by making an easy link to healthcare.
Subjects who underwent the test were asked to complete an anonymous questionnaire, through which it has been possible to collect a series of data on risk behaviours of the population tested. The questionnaire was devised with the intention of collecting demographic and risk behaviour data, as well as previous HCV/HIV testing experience, information about sex, drug use, educational level, nationality, general behaviours, use of HIV/HCV prevention services, previous surgical practices, invasive diagnostic practices, dental cares, tattoos or sexually transmitted diseases. Post-test counselling has been provided to all HCV reactive and non-reactive subjects, by the Infectious Diseases Department physicians involved in the study. The test was been carried out by a biologist or a practitioner, following the manufacturer’s procedures.
If the HCV oral test provided a preliminary positive result, a venipuncture was performed immediately for standard test confirmation, supported by the post-test counselling.
The results were received in two working days. At this point, the HCV-positive patient was contacted directly by the infectious diseases specialist for the visit and the diagnostic procedures to define the liver disease status and eventually to start the treatment, according to the guidelines for when HCV viral load and genotype are identified.
In these four years a total of 35,000 subjects have been approached to inform them about HCV infection and other sexually transmitted diseases. Of the total eligible volunteers, 6500 (18.6%) performed HCV tests on saliva and completed the interview in the alternative ‘street lab’. From the questionnaires we know that this initiative has been much appreciated.
Discussion
In recent years, advances in detection technology made available a range of POCTs for different infectious diseases. It is now possible to screen and diagnose those conditions at primary healthcare settings, using minimally invasive tests. In the present study, a new POCT for HCV infection has been performed on oral fluid. The use of oral fluid is an attractive alternative based on the fact that collection of plasma or serum samples requires equipment and training, and is more time consuming.
The FDA-approved OraQuick HCV Rapid Antibody Test (OraSure Technologies) is one of the most studied rapid tests for the diagnosis of HCV infection.
The development of rapid alternative tests for the diagnosis of HCV infection is to facilitate access to testing to reduce the individual risk of disease progression and social costs.
Despite the excellent sensitivity and specificity of third-generation enzyme immunoassays (EIAs), the turnaround time for reporting test results is at least one day, thereby making it difficult to deliver the results to tested individuals at first visit. Rapid tests are formatted such that they do not require complicated instrumentation or testing by skilled technical staff. They potentially generate results within an hour and therefore may be used for point-of-care testing. Rapid tests are obviously more expensive than conventional immunoassays and are not designed for testing large batches of specimens. However, in no-clinical settings and laboratories that conduct low-volume testing, adoption of rapid oral testing can be cost-effective. CDC guidelines formulated for confirming screening anti-HCV results remain to be refined to accommodate rapid anti-HCV testing. It is important to emphasize that OraQuick HCV test has not been approved for general screening. A positive result of a rapid anti-HCV positive test is indicative of the presence of anti-HCV and, again, does not indicate active infection (11).
We successfully conducted this rapid HCV testing and counselling programme with the goal of spreading the use of saliva test anonymously and free of charge. We aim to facilitate access to testing in alternative settings, in order to understand if the ‘hard-to access’ population would access salivary rapid testing versus the conventional settings.
Increasing awareness of these alternative tests among individuals at risk and providers may be an appropriate strategy to increase the number of people who know their serological status and who could be linked to care and engaged in care!
The recent introduction of rapid oral HCV antibody test could completely change the HCV diagnosis approach by facilitating the possibility of testing millions of people worldwide (in particular in the developing countries).
For these reasons, we hope the oral-fluid based rapid HCV tests could become the ‘gold standard’ to facilitate the HCV screening access and become the standard of care and the basis for the national HCV testing algorithm in many countries with spread HCV epidemic, also in the dental care surgeries.
References
1. Lavanchy D. The global burden of hepatitis C. Liver Int. 2009; 29: 74–81.
2. Istituto Superiore di Sanita (ISS). Available at: www.iss.it.
3. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997; 26: 15S–20S.
4. Hutin Y, Kitler M, Dore G, Perz J, Armstrong G, Dusheiko G, et al. Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol. 2004; 44: 20–29.
5. Ferreira-Gonzales A, Shiffman ML. Use of diagnostic testing for managing hepatitis C virus infection. Semin Liver Dis. 2004; 24: 9–18.
6. Tucker JD, Bien CH, Peeling RW. Point-of-care testing for sexually transmitted infections: recent advances and implications for disease control. Curr Opin Infect Dis. 2013; 26: 73–79.
7. Food and Drug Administration. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfClia/detail
8. OraQuick HCV Rapid Antibody Test. Available from:
http://www.fda.gov/MedicalDevices/productsandMedicalProcedures/DeviceApprovalsandClearances/Recently-approved-Devices
9. Parisi MR, Soldini L, Di Perri G, Tiberi S, Lazzarin A, et al. Offer of rapid testing and alternative biological samples as practical tools to implement HIV screening programs. New Microbiol. 2009; 32(4): 391–396.
10. Parisi MR, Soldini L, Vidoni GM, Clemente F, Mabellini C, Belloni T, Nozza S, Brignolo L, Negri S, Rusconi S, Schlusnus K, Dorigatti F, Lazzarin A. Cross-sectional study of community serostatus to highlight undiagnosed HIV infections with oral fluid HIV-1/2 rapid test in non-conventional settings. New Microbiol. 2013; 36(2): 121–132.
11. Center for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Available from: http://www.cdc.gov/hepatitis/hcv/Management.htm.
The authors
Maria Rita Parisi*1 MSc, Laura Soldini2 MD, Gianmarino Vidoni3 MD, Karin Schlusnus4 PhD, Fernanda Dorigatti2 MD, Adriano Lazzarin1 MD
1Division of Immunology, Transplantation and Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
2Laboraf Diagnostic and Research OSR S.p.A., San Raffaele Scientific Institute, Milan, Italy
3Prevention Department, Reference Centre for HIV and STDs, Local Public Health Unit, Milan, Italy
4ANLAIDS Lombardia Onlus, Milan, Italy
*Corresponding author
E-mail: parisi.mariarita@hsr.it
The Longitude Prize 2014
, /in Featured Articles /by 3wmediaThe Longitude Prize was originally offered by the British Government to anyone who could come up with a simple method for determining a ship’s longitude when at sea. John Harrison received funding from the Board of Longitude for his work on chronometers, and his name is still the one associated with having solved this problem.
In 2014, the British Prime Minister, David Cameron, launched a new version of the prize, which is being developed and run by Nesta, the UK’s innovation foundation. Six potential themes were announced, including:
The category chosen (by public vote) to receive the modern prize was that of antibiotic resistance.
The discovery, development and use of antibiotics has been one of the great successes of modern medicine. However, the rise of antibiotic resistance (already warned of by Sir Alexander Fleming in his Nobel Prize winner’s lecture in 1945) threatens to render existing antibiotics useless and no new class of drugs has been discovered since the 1980s. Quotes can easily be found from organizations such as the World Health Organization (WHO), the US Centers for Disease Control and Prevention (CDC) and many senior scientists ranging from the ‘grim future’ to the ‘apocalypse’ of returning to life without antibiotics.
In order to fight antimicrobial resistance, the inappropriate use of antibiotics has to be prevented. To target this, the challenge set by the Longitude Prize committee is to create a ‘cheap, accurate, rapid and easy-to-use point of care test kit’ that will indicate if antibiotics are necessary, and if so which to prescribe. The kit should deliver results within 30 minutes and devices with built-in data recording and transmission capacities will be favoured.
There are of course technical hurdles, such as selecting the right targets for detection, how to detect them (what sample preparation has to happen?) and how to achieve the desired performance (of size/portability, speed, low cost per test, data transmission). However, POC devices do already exist and are in use. Notably, a mobile phone linked test for blindness (the portable eye examination kit or Peek) that allows eye tests to be carried out anywhere on earth. This is particularly advantageous in resource-poor settings. For example in Nigeria, even though less than 50% of the population has access to clean drinking water, 80% of people have mobile phones.
Collaboration between the different fields of medicine, microbiology, biochemistry, engineering and physics will be needed to address these technical issues. This is another aspect where the modern Longitude Prize is echoing the original – the solution can come from anywhere, not necessarily the expected sources. Again, examples of this have been seen in other areas recently. Jack Andraka, born in 1997 has been dubbed the ‘teen prodigy of pancreatic cancer’ for his development of promising early detection test for pancreatic cancer. In 2012, Brittany Wenger, at the age of 17, won the Google Sciences Fair grand prize for a breast cancer diagnosis app. One thing though is certain – innovation will be needed.
For more information see the Longitude Prize 2014 website: https://longitudeprize.org/
External Quality Assessment (EQA) for trace element measurements in clinical laboratories
, /in Featured Articles /by 3wmediaExternal Quality Assessment (EQA) is the cornerstone of quality assurance and method validation in clinical testing labs in the UK, ensuring that the results of patient investigations are reliable and comparable wherever they are produced. In this article we focus specifically on EQA for laboratories performing trace element measurements, although many of the points are applicable to the wider pathology areas.
by S.-J. Bainbridge and Dr C. F. Harrington
Introduction
External Quality Assessment (EQA), also termed proficiency testing (PT), involves the regular distribution of test materials to participating laboratories so that they may evaluate their analytical performance against a peer-group, detect any accuracy or other problems that may develop with the assay and so improve the results that they produce. The key elements that differentiate EQA from PT include: education and support; identification of method poor performance; and method evaluation [1].
Historically clinical science was one of the first disciplines to realize the usefulness of EQA and take steps to implement schemes that would be of use in the hospital laboratory. The first proficiency survey of UK clinical pathology laboratories was reported in 1953 and revealed a wide spectrum of results for the common tests [2]. Further surveys in the 1950s and 60s confirmed the need for regular PT. In 1969, the National Quality Control Scheme was initiated by the Wolfson Research Laboratories, Birmingham and involved the distribution of specimens every 14 days [2]. This is now known as the UK National External Quality Assessment Scheme (UKNEQAS) and is responsible for about 30 different schemes.
In 2013, the importance of EQA in the NHS pathology services was emphasized by Dr Ian Barnes in a Department of Health review into quality assurance [3]. The review assessed current NHS quality assurance frameworks and governance mechanisms for pathology services. It gathered a diverse range of evidence: examining expectations of pathology services; identifying areas for improvement; and recommending a system-wide way forward. It recommended strengthening and standardizing the current quality assurance structures that are in place, which are based on the Royal College of Pathologists (RCPath) Joint Working Group for Quality Assessment (JWGQA), which co-ordinates and oversees the standards and performance of EQA schemes for all schemes regardless of provider.
EQA for trace elements
The Trace Elements External Quality Assessment Scheme (TEQAS), which is part of UKNEQAS but based in Guildford, UK, was established in 1979 with distribution of specimens on a monthly schedule to UK hospital laboratories measuring copper and zinc in serum. During the next five years the scheme developed with inclusion of other participants and the introduction of additional analytes and specimen types. Following an international conference on Aluminium and Renal Disease in 1986, a two year arrangement was established with the EU Commission to fund participation in the serum aluminium programme for European laboratories involved with the monitoring of patients with chronic renal failure. An outcome of this work was the realization that analytical standards of performance for this measurement were very poor. In collaboration with the UK Department of Health it was proposed that the scheme should be linked to UKNEQAS in order to provide a mechanism for referral of poor performers to the Clinical Chemistry Advisory Panel. This link was formally established by the Advisory Committee on Analytical Laboratory Standards in 1988. The aims of TEQAS are consistent with the intentions of UK NEQAS, to:
The main TEQAS scheme provides EQA for: Al, Cr, Co, Cu, Se and Zn in serum; As, Cd, Cr, Co, Pb, Mg, Mn, Hg, Se, Tl and Zn in whole blood; and As, Cd, Cr, Co, Cu, Fe, Pb, Mn, Hg, Ni, Tl and Zn in urine. This operates on a monthly cycle, with the results from the measurement of two specimens being returned on-line on the last day of each month. The report is then available five days later to download. Two smaller schemes providing Al in dialysis fluid and Cu and Fe in solid matrices are also available, but have a more limited number of participants.
The main steps in the EQA process
For a better appreciation of the overall EQA scheme it is useful to divide it into a number of process-based areas as shown in Figure 1. The activities that comprise these areas are also shown. Some of these areas come under particular focus as part of ISO 17043:
Design
Appropriate design of the PT scheme ensures that participants will have paid for a service that provides high quality comparable test items that are representative of patient samples they would normally expect to analyse. These test items will have undergone thorough assessment procedures in accordance with acceptable statistics to ensure a homogenous and stable test item.
Materials
The participants can be assured that the materials used in the production of the PT samples have been ethically and legally obtained and that the competence of the suppliers have been evaluated and verified to ensure their products or services do not affect the quality of the PT scheme.
Evaluation
ISO 17043:2010 ensures the evaluation of the participants performance is conducted fairly and consistently guaranteeing they receive an accurate evaluation calculated from the use of robust statistical methods.
Knowledge and Experience
In addition to all this ISO 17043:2010 ensures that the operations of the PT scheme are carried out by personnel that have the training, skills and competence necessary to professionally carry out their assigned tasks. Participants can feel secure in knowing that they have access to the specialist knowledge and expertise in the field of trace element testing to be able to discuss any concerns they may have.
Establishment of performance criteria
Measurements of performance are based on deviations of results from target values, which are used to calculate a Z-score. As EQA has developed, various organizations have produced documents that summarize best practice. Those from authoritative international bodies include:
All these documents recommend that assessment of performance should be based upon calculation of a Z-score (or a derivative which takes uncertainty into consideration).
The Z-score is calculated as:
x-X/ SDPT
where x = laboratory result,
X = target value, and
SDPT = standard deviation for PT (also represented as σ)
The ‘standard deviation for PT’ is set by the scheme organizer but should ideally be a value that will allow the score to demonstrate whether or not the performance is fit for the purpose for which the assay is being used. It is recommended that this value be set so that a Z-score of up to ±2 indicates acceptable performance and a score of more than ±3 indicates unsatisfactory performance.
In the TEQAS scheme, we have used quality specifications based on biological variation for the ‘standard deviation for PT’ and the determination of these quality specifications has been published [5]. For assays where there is insufficient data to prepare specifications in this way we have produced values that are related to performance within the scheme during recent years.
The quality specifications and their corresponding SDPT for some illustrative elements are shown in Table 1. These are presented as either a percentage of the target value or a fixed value depending on the concentration of the target value, and the one used is whichever is the greater. This allows for the increase in imprecision at low concentrations and conforms to a ‘funnel’ shape.
Scheme accreditation
Accreditation is fast becoming a preferred mechanism for delivering confidence in UK Healthcare and with the application of BS EN ISO 15189:2012 into Medical Laboratories and its requirement for the laboratories to seek confirmation for confidence in their results, the need for EQA schemes in the relevant fields of medical laboratories is ever increasing. Participation in a suitable scheme can be an effective way of demonstrating the laboratories’ technical competence. ISO 15189:2012 requires laboratories to evaluate their PT providers and a recognized acceptable basis of their evaluation recommended by the UK Accreditation Service (UKAS) is the participation in PT schemes with those providers that have been accredited to ISO/IEC 17043:2010. This International Standard specifies criteria and the general requirements for the competence of the PT providers and their responsibility for all tasks in the development and operation of the PT scheme. Some of the main differences introduced with ISO 17043 are summarized in Table 2.
Assessment of conformance
When conducting an assessment of a PT scheme for conformance to ISO 17043:2010, the assessors will take a holistic approach looking at the management system as a whole. The assessment will include areas such as scheme organization, scheme management, evaluation processes, technical competence and impartiality and integrity. Each separate area of the PT scheme are all interlinked and therefore when accreditation is granted by the accreditation body (UKAS in the UK) it will not be given on a single fact but the overall competence of the PT provider. Accreditation to ISO 17043:2010 can be a hard and thorough task for PT providers to undertake but once accreditation is granted it provides the necessary assurance of a competent and professional scheme which can provide an open and honest service whilst maintaining confidentiality for all those participants enrolled in the scheme.
Summary
The 2013 Barnes review into quality assurance in the NHS pathology services reinforced the importance of quality assurance and this article has discussed the implications of recently introduced ISO standards for clinical pathology departments (ISO 15189:2012) as well as for EQA scheme providers (ISO 17043:2010). This strengthens and standardizes the systems used in clinical testing laboratories and ensures high quality and comparable results for patient tests.
References
1. James D, Ames D, Lopez B, Still R, Simpson W, Twomey. External quality assessment: best practice. J Clin Pathol. 2014; doi: 10.1136/jclinpath-2013-20621.
2. Bullock DG. External quality assessment schemes for clinical chemistry in the United Kingdom. Ann Ist Super Sanita 1995; 31: 61–69.
3. Barnes I. Pathology Quality Assurance Review 2014. www.england.nhs.uk/wp-content/uploads/2014/01/path-qa-review.pdf
4. Thompson M, Ellison SLR, Wood R. The International Harmonized Protocol for the proficiency testing of analytical chemistry laboratories (IUPAC Technical Report). Pure Appl Chem. 2006; 78: 145–196.
5. Arnaud J, Weber J-P, Weykamp CW, Parsons PJ, Angerer J, Mairiaux E, Mazarrasa O, Valkonen S, Meditto A, Patriarca M, Taylor A. Quality specifications for the determination of copper, zinc, and selenium in human serum or plasma: evaluation of an approach based on biological and analytical variation. Clin Chem. 2008; 54(11): 1892-1899.
6. Summary of ISO 15189 additional requirements. CPA UK Ltd, 2012. http://www.ukas.com/Library/Services/CPA/Summary%20of%20Idifferences%20betwen%20ISO%2015189%20&%20CPA.pdf
The authors
Sarah-Jane Bainbridge and Chris F. Harrington* PhD
TEQAS, Trace Element Centre, Surrey Research Park, Guildford GU2 7YD, UK
*Corresponding author
E-mail: Chris.harrington1@nhs.net
Molecular diagnostics – US industry seeks more regulation
, /in Featured Articles /by 3wmediaMolecular diagnostics is seen as the gateway to an era of personalized medicine. It detects DNA and RNA-level abnormalities that provoke and fuel most diseases. As a result, it offers precise diagnosis, determines the susceptibility of a patient to a specific disease and assesses his or her response to therapy. Moelcular diagnostics can also establish a patient’s prognosis over time far more scientifically than what is often no more than a physician’s informed guess.
Tailored therapy, patient convenience
The track record of molecular diagnostics is, on first sight, impressive.
For instance, FoundationOne, a molecular diagnostic test from Foundation Medicine, scans a patient’s tumour sample for changes in 238 genes that drive cancers, helping oncologists to “choose drugs targeted to the genetic profile of a patient’s tumour cells.”
Another example is Cologuard, from Exact Sciences, which screens stool samples for colorectal cancer. Apart from greater accuracy, the technique is far less invasive than colonoscopy. According to The Mayo Clinic, this will enable more people to get tested earlier and ‘revolutionize’ the fight against colorectal cancer.
Convenience in access is also central to tests from TrovaGene, which utilizes urine samples. Priority targets for the company include malignant melanoma, whose rate of spread makes early detection invaluable, but is also an especially difficult cancer to diagnose via traditional means.
Genomic Health: single-product trailblazer
A poster child of the molecular diagnostic revolution is Genomic Health. The company was founded 15 years ago to close the gap between genomic research and real-life benefits for cancer patients.
Based on the success of a single product, Oncotype Dx, the company has reached a market value of about $1 billion. Oncotype Dx predicts relapse rates of women with breast cancer and assesses benefits from different types of chemotherapy. Its scope has also been extended to prostate and colon cancer.
Targeting broad spectrum of diseases
New molecular diagnostic products, however, go beyond cancer to other challenging conditions. Rheumatoid arthritis is the focus for Crescendo Bioscience, which has developed a test for 12 different proteins in a blood sample of patients. Its metrics are the first to measure molecular activity of the disease and permits a quicker decision to screen for antibodies. The test, moreover, can determine the effectiveness of a cheap, generic steroid such as dexamethasone on a particular patient, as it can about the ineffectiveness of biotech drugs – whose costs range from $1,000 to $3,000 a month.
In some cases, research breakthroughs have allowed firms to offer tests for a variety of diseases out of the same platform. The tests from TrovaGene, for example, are based on proprietary cell-free nucleic acid (cf-NA) techniques – and can be used for cancer as well as infectious disease, organ transplantation and prenatal genetic testing.
Regulation holds key to building confidence
In spite of its strong case, the proponents of molecular diagnostics lament that current use is far below potential. Such arguments have reached fever pitch, especially in the US.
The reason seems ironical. The industry has been calling for more government regulation. An Op-Ed piece in ‘The Boston Globe’ in 2011 explains why. Due to the absence of clear approval policies, it notes, both payers and physicians lacked confidence about the reliability and accuracy of molecular diagnostics. The authors of the Op-Ed, Mara Aspinall, then CEO of an IP-rich molecular diagnostics company On-Q-ity, and Brook Byers of venture capital powerhouse Kleiner, Perkins, Caufield & Byers, were especially scathing about the decision by the Food and Drug Administration (FDA) “to regulate diagnostic tests as ‘medical devices’,” and proposed that molecular diagnostics requires both “new expertise and a new regulatory focus.”
These kind of concerns seemed prescient. Within two years, Aspinall’s On-Q-ity had folded. Following its demise, an industry analyst observed that molecular diagnostics faced similar concerns as therapeutics, but was confronted “by larger reimbursement and regulatory uncertainties.”
CLIA certification and reimbursement
Many molecular diagnostic tests on the US market have not been endorsed by the FDA, or been classified as eligible for Medicare. Indeed, tests approved by the FDA largely concern infectious diseases and companion diagnostics.
Most vendors have their products certified under the less stringent Clinical Laboratory Improvement Amendments (CLIA) standard. Some have succeeded in obtaining Medicare reimbursement, with only CLIA certification. However, this has been lengthy. For example, Crescendo’s rheumatoid arthritis test discussed previously was sold for three years, before being approved by Medicare.
Others have fared worse, in spite of successful products on the market. Foundation Medicine’s tumour test (see above) is neither FDA-approved, nor reimbursed by Medicare. As a result, the company has to negotiate with payers to get paid every time a patient is tested with its product.
Multiple, complex challenges
There are several layers in the underlying problem.
The first is the regulation of diagnostic tests as medical devices. As explained by ‘Expert Review of Molecular Diagnostics’, current regulatory systems were written to regulate a broader array of products, and “molecular diagnostics are now being fitted into that existing framework.” Though there will be overlaps, it is “appropriate to treat molecular diagnostics – properly defined – in a different manner to a group consisting of all other IVDs.” This is clearly not yet the case. A certification program at the University of California, San Diego, for example, notes: “Molecular diagnostics, or in vitro diagnostics …”.
A second regulatory challenge is that molecular diagnostics encompasses both test assays as well as instruments and equipment. The latter are more clearly akin to devices, assays far less so. However, a problem arises when instruments used in assay development are specifically referenced for approvals. A Draft Guidance from the FDA in April 2013 acknowledges such a limitation.
The third factor is the linkage between genomics research on biomarkers, which yields masses of data, but does not provide clinically useful information for real-world molecular diagnostics. This can only be achieved in a gray area between a research laboratory and a clinical laboratory.
Research use only versus diagnostics
The FDA regulates (in vitro) diagnostic kits explicitly designed for diagnostic use. In sharp contrast, research use only (RUO) products are unregulated. Their definition in FDA regulations covers labelling only and is sketchy, specifying that they should be “in the laboratory research phase of development and not represented as an effective in vitro diagnostic product.”
Biomarker assays are usually labelled RUO since their clinical use is unknown, until after their diagnostic effectiveness has been evaluated in a clinical laboratory. Some maintain this status indefinitely, staying outside FDA jurisdiction.
The regulatory problem arises once a clinical laboratory evaluation of a biomarker begins to move on its own course.
From in vitro to molecular diagnostics: difference in detail
As explained by Jeffrey Gibbs of the law firm Hyman, Phelps & McNamara, the roots of the RUO challenge date to the 1990s, when many RUO products began to be used by laboratories for clinical applications. At this time, companies labelled their in vitro assays and instruments as RUO but then promoted them for diagnostic use – in some cases, making specific claims too.
In 1997, the FDA sought to curb this practice with a regulation on analyte specific reagents (ASR), targeting the basic chemical components used in diagnostic assays. However, it became clear some years later that the ASR regulation was being used to camouflage sales of more complex products. In 2007, the FDA issued a guidance document on ASRs, prohibiting the combination of more than one active component.
This, as Mr. Gibbs states, was acceptable for in vitro diagnostics. It was clearly not so for molecular diagnostics, where, for example, a primer and probe pair need to be offered together. To cope with this, a number of companies relabelled their ASRs as (unregulated) RUOs.
In a draft guidance in 2011, the FDA proposed sanctioning companies for selling RUO diagnostic products to clinical labs. Of special concerned were ‘high-risk’ laboratory-developed tests (LDTs) impacting on major treatment decisions – attention to which strengthened in 2011 after the prestigious Duke University used faulty genomic markers to select therapy for cancer patients.
FDA steps in, but industry remains uncertain
The end of 2013 saw a series of major moves by the FDA, which will have a bearing on the shape of the molecular diagnostics industry in the years to come.
One was to shut down health-related genetic tests by direct-to-consumer firms, including market leader 23andMe, which has been selling kits and test results for carrier status, health risks, and drug response.
Another was to provide the first-ever FDA clearance of a next-generation sequencing (NGS) instrument and universal reagents, opening the way for tests to be cleared on their own merits. This may encourage a move by companies of their RUO products into the FDA process.
The FDA also issued a Final Guidance on how companies could market RUO and investigational use only (IUO) diagnostic tests and instruments, which several clinical laboratories had been using for LDTs.
In its Guidance, the FDA backed off from its plans two years before to sanction RUO product sales to clinical laboratories. However, it opens the way for enforcement – and another kind of uncertainty for molecular diagnostic companies, for some time to come.
The Guidance notes that if a manufacturer “were to assist in the validation or verification of the performance of a test for clinical diagnostic use that uses its RUO or IUO labelled IVD, that assistance would be considered to be evidence of a non-research or non-investigational intended use.”
The wording of the Final Guidance leaves considerable room for interpreting the marketing and sales behaviour of both vendors and clinical laboratories. These are likely to be taken up for enforcement actions by the FDA on a case-by-case basis.
As another recent commentary by law firm Hyman, Phelps & McNamara observes, the FDA “says it will take enforcement action based on the totality of the circumstances. What that actually means remains to be seen. As with most things with FDA, we will simply have to wait and see.”
Electronic health records and the lab
, /in Featured Articles /by 3wmediaTwo opposing agendas confront clinical labs in terms of electronic health records (EHRs): privacy/security on the one side, and interoperability, on the other. The former involves an inward push for isolation, while the latter tends to pull technology in the other direction.
There also is a major financial challenge. While healthcare providers have been given a host of incentives to adopt EHRs (especially in the US), labs have been pretty much left out on their own.
EHRs and lab systems populate different worlds
Clearly, lab-compatible EHR systems which meet both (privacy and interoperability) criteria promise the quickest returns. EHR developers have however shown little enthusiasm, until recently, to incorporate clinical lab requirements as a sufficient driver, while laboratory system vendors have tended to ignore EHRs or postpone taking them into account until EHR development has matured sufficiently.
US EHR adoption drives lab applications
In the US, this limbo is being shaken up by healthcare providers, who are compelling vendors to take account of their need for EHR-friendly clinical lab systems.
At end 2012, the US Centers for Disease Control and Prevention (CDC) released a survey which found 72 percent of office-based physicians using EHR systems, up from 48 percent in 2009 and 18 percent in 2001.
The reason for the dramatic increase in EHR adoption lies in the Meaningful Use requirements of the 2009 Health Information Technology for Economic and Clinical Health Act, also known as the HITECH Act. The Act provides billions of dollars in incentive payments through the Medicare and Medicaid programmes to increase physician adoption of EHR systems.
Clinical labs are now being lifted by the rising tide of EHR adoption. According to the US Office of the National Coordinator for Health Information Technology (ONC), the “availability of structured lab results within the EHR contributes to office efficiencies while also assisting providers in the ability to make real time decisions about the patient’s care.”
The ONC explicitly specifies the threshold for EHR-friendly clinical lab practices in Stage 1 – of over 40 percent of all lab test results ordered by a provider and incorporated in certified EHR technology as structured data.
Stage 2 Meaningful Use requirements, finalised in August 2012, increase the clinical lab results threshold to 50 percent. The ONC has subsequently announced plans to assess health information exchange (HIE) in clinical laboratories.
Labs left to own resources
While healthcare providers have the financial incentives of the HITECH Act, clinical labs have been left to their own resources to set up interfaces from their laboratory information systems (LIS) to providers.
Compounding this has been inconsistencies in the way different EHR systems generate lab test orders.
However, the alternative has been stark – to be left out of referrals from tests.
EHR systems remain heterogeneous
The US EHR landscape is however hardly uniform. As of September 2013, there were 3,652 non-enterprise certified ambulatory EHR software systems, almost half of which were classified as “complete” to qualify for Meaningful Use Stage 1 or Stage 2.
In spite of efforts to set standards for semantic interoperability of healthcare data, standards so far are only syntactic (based on HL7 and XML).
The alternative, to develop a common US-wide EHR system, has been accepted as being technically insurmountable – due to hurdles in specifying, developing, testing and deploying standardized tools, common architectures and vocabularies, within secure, real-time and scalable networks, and doing all this within the fast-changing world of information and communications technologies.
For proponents of a decentralized approach to EHR technology, in the US in particular, the sharp increase in offtake of EHR systems has shown that it has delivered – as far as healthcare IT objectives are concerned.
EHR faces teething problems
Still, teething troubles for EHRs also clearly remain.
In early September 2013, one of the leading EHR systems, from EPIC, crashed across seven major healthcare facilities of Sutter Health, a nearly 100 year-old healthcare provider in California. Some suspect the role of a routine upgrade a few days earlier in the EHR system, which was launched by Sutter at a cost of $1.2 billion in 2004, but has so far reached only a halfway mark.
EHR challenges for labs remain to be resolved
Such issues with the evolution of maturity of EHRs pose especially major problems for labs, who (as mentioned) have to develop and fund interfaces between their LISs and the EHRs of their client physicians but are also forced to cope with the lack of uniform EHR standards.
Some vendors have nevertheless sought to fill the gap.
A leading example is HDD Access, a joint initiative by the US Department of Defense, the Department of Veterans Affairs and 3M Health Information Systems to create a public use version of 3M’s Healthcare Data Dictionary (HDD). HDD Access consists of a relational database and Application Programming Interface (API) runtime services to which other applications can interface. The terminology is organized as a controlled medical vocabulary – a comprehensive set of clinical and other concepts used in healthcare.
HDD Access offers specific benefits for integrating LIS and EHR platforms. Independent of source system, it can track local fields and translate them into laboratory concepts. Nevertheless, HDD Access warns that it is “not a standard terminology and is not a replacement for standard terminologies.
In effect, in the US, clinical labs are likely to continue to face a host of technical challenges with respect to EHRs in the years to come.
EHR Big Bang fizzles in Europe
Unlike the US, Europe made a massive effort in 2004 to devise common semantic standards for EHR interoperability as part of its Single eHealth Area. The EU’s EHR objectives sought to integrate all patient information – from primary to tertiary settings, and include emergency and in-patient care. Also on the radar were ambitious plans to connect pharmacies as well as the web of disparate billing/reimbursement procedures, and do so across Europe.
In mid–2008, the EU Commission set 2015 as the target year for EHR interoperability, to ensure that key EHR datasets could cross European borders, and do so in conformity with medical rules and other relevant legal frameworks.
In January 2011, however, these ambitions were put on the backburner, after an official report criticized the effort as being both impractical and ‘grandiose’. The report found that a pan-EU EHR system would neither be technically feasible, cost-effective or even medically justified, and instead urged more emphasis on decentralized efforts – in other words, just like the US.
Technical challenges aside, massive differences in physician and medical cultures across Europe played a major role in derailing efforts toward a common EHR. Or, as EuroRec, an umbrella organization tasked with pan-EU EHR implementation, states: it was “widely recognized that social and organizational aspects are as likely to ruin an implementation process as technical factors are.”
European focus shifts to national efforts
The EHR focus in Europe has now totally shifted to national efforts. A new eHealth Governance Initiative (eHGI) encourages cooperation “between Member States” and “between national authorities and standardization bodies”, and seeks to “enable the recommendation of standards and (harmonized) profiles based on selected use cases.” On the technical side, compared to the Big Bang efforts of the Single eHealth Area, it also aims to “link and harmonize coding systems” and “facilitate access to existing standards and medical vocabularies.”
The second area for Europe’s EHR focus is a minimalistic intra-EU/regional approach embodied in a project called epSOS, which dates back to 2008, but was (temporarily) eclipsed by the ambitions of the Single eHealth Area. epSOS, which went live in April 2012, has the modest goal of connecting 20 EU nations (and 3 non-EU members) to a secure database, and sharing only Patient Summaries and ePrescription records via IHE X* profiles. Its target consists of Europeans holidaying overseas.
Today, EHR adoption varies considerably in Europe. The Nordic countries have been using the technology for over a decade and are fairly advanced as a result in EHR implementation.
However, adoption in France, Germany, Spain and the UK is ‘on course’ with the US.
Shift from Single eHealth Area encourages new EHR-directed lab applications
The shift away from forcing through a Single eHealth Area has also opened the way for innovative working approaches aimed at clinical labs. One good example of this is Valle de los Pedroches Hospital at Cordoba, Spain, which has designed and implemented a unified lab test request module for the Andalusian regional EHR.
In spite of some outstanding issues (such as rigidity in error solving, and the need to adapt to a new nomenclature), implementation of the laboratory module in the EHR improved the analytical process, with better patient safety and less programming or container errors and shorter response times. Clinical professionals gave a rating of 7.8 out of 10, positively highlighting the speed at which results are delivered and their integration in the EHR.
Such efforts are likely to grow with time.
Eco Series: The next generation freezers
, /in Featured Articles /by 3wmediaThink Coag – Think Tcoag
, /in Featured Articles /by 3wmediaStat Profile Prime
, /in Featured Articles /by 3wmediaCXCL13 and anti-Borrelia
, /in Featured Articles /by 3wmediaIMMUVIEW
, /in Featured Articles /by 3wmedia