Interviews

In addition to letting us post another one of her databases, Dr. Carmen Ricos agreed to answer a few questions about the work, the results, and the meaning of all this biologic variation.

Dr. Carmen Ricos on the Biologic Variation Databases

June 2009
Interview by Sten Westgard, MS

For many years, Westgard Web has had the honor of hosting the Biologic Variation database assembled by Dr. Carmen Ricos and her colleagues. This vast set of data has been updated about every two years by the Ricos group. They recently added a set of data that includes biologic variation of subjects with disease, which we are again lucky to be able to host. We took this opportunity to ask Dr. Ricos a few questions about why they've taken on such a vast task.

Can you give us an idea of how the database collection idea came about? How did you decide to begin collecting the information? Why did you do it?

Dr. Ricos: The idea came from evidence in 1996 that laboratories were calculating specifications for imprecision, bias, and total error from the bibliography they had found on within- and between-subject variation. Consequently, the specifications were dissimilar among laboratories.

Callun Fraser, Per Hyltoft Petersen, and I discussed this in depth during the 1996 IFCC congress in London. With their support, I put forth a suggestion to the SEQC Analytical Quality Committee to create a database that would include all the available information on the components of biological variation (BV). At that time, we already had a consolidated working group with extensive knowledge on BV, and we had the necessary time and resources to carry out this initiative.

The purpose was to provide laboratories with a single specification value for each analyte and analytical quality indicator.

How does the process work? During the two years between updates, what kind of work are you doing? How does the data arrive? How does the group perform research? How do you make decisions on the calculations, or on the inclusion or exclusion of an analyte or a study in the database?

Dr. Ricos: In the last months of 1996, all available papers on BV were collated, arranged alphabetically by the author’s name, and distributed to the group members (a number of papers for each 2 members). At the same time, a spreadsheet was created with the following headings: system (serum, whole blood, etc.), analyte (name), member of the group filling in data, within-subject (CV_I) and between-subject (CV_G) components of BV, analytical variation (CV_A), desirable goal for imprecision (I), bias (B), and total error (TE), individuality index (II), reference change value (RCV), fiduciability index (FI, calculated as CV_A/I_G) number of subjects studied and separated by sex, time span of the study (in days), number of samples per subject, mean value obtained and units, type of CV_A used in the experience (within batch, between batch), population studied (healthy or patients and pathology), author’s name, source (journal of publication, year, volume and pages).

Each pair of members read the papers and filled in the first draft spreadsheet. Various meetings were organized with the overall group to discuss any discrepancies occurring within each pair of members and to agree on the definitive values for each analyte and paper. After one year of work, the first database was prepared and presented to the Stockholm consensus conference.

Up to now, an extract of the database containing CV_I, CV_G, and the desirable , minimum and maximum quality specifications for imprecision, bias, and total error has been prepared every two years. The chair of the group retrieves papers (using PubMed) and proposes to include or not new values in the database. If they are accepted, she fills in the new values and prepares the updated extract, which is further revised by the group and sent for publication.

The decision to accept a value is made on the following basis: design of the study is directly focused on estimating BV components, analytical CV is available and reasonably low (FI>2), CV_I and CV_G have been calculated using ANOVA, and time length of the study higher than one day.

Do you get a lot of feedback from laboratories on the database? Are there more complaints than compliments?

Dr. Ricos: Yes, we have received a great deal of feedback, mainly from laboratory professionals who want to make sure they are using the data correctly. From these consultations, we have seen that the majority of labs use our database to evaluate their quality indicators, while others ask specific questions on the application in the internal QC. Sometimes they notice mistakes and we are very grateful for their informing us; in all cases, the corresponding amendments are made. Only very few complaints have been received, usually from colleagues who can’t reach the desirable goals, particularly for analytes with a very narrow CV_I (for example, sodium).

Do you have any sense of the impact this database has had on laboratory medicine? Do you think there are concrete examples of improvements in the laboratory due to the database?

Dr. Ricos: Effectively, we have seen a number of laboratories initiating corrective or preventive actions (by planning IQC, teaching technicians, rewriting SOPs, etc.) with the aim of reaching desirable imprecision, bias, and total error. Usually labs ask questions through the SEQC–EQAS organization. We have also been consulted by distributors of instruments and kits regarding the fundamentals of quality specifications derived form biology, so they can explain their use to their clients or help them to reach the desirable goals.

What do you think are the most important lessons to learn from this database?

Dr. Ricos: Some lessons are:

• The Stockholm conference conclusions (1999) have been widely accepted and are still valid today. Also its basic philosophy can be expanded to the laboratory non analytical processes.
• It is not necessary for each laboratory to make its own estimates of the components of BV
• The practical applications evidently used are: to plan internal QC (IQC), to review analytical quality indicators (imprecision, bias and total error or inaccuracy), to use the reference change value (RCV) as a delta check, to notify clinicians about changes in serial results (also applying the RCV concept.

Are there any findings that have surprised you?

Dr. Ricos: A couple of findings:

• Some discrepancies between authors for certain analytes, for example, testosterone, with 8% (myself, Ann Clin Biochem 1980;27:353-358) 17% (Valero, Clin Chem 1993;39:1723-1725) and 21% (Garde, Clin Chem 2000;46:551-559).
• The relatively small number of new studies on this subject (less than 10 per year); so, about half the analytes tested in medical laboratories still have no reliable estimates of the components of BV.

What do you think the future of the database will be?

Dr. Ricos: Examples of further studies on this topic could be: expanding estimations to include all the analytes used in laboratory medicine, assuring the reliability of the available information by scientific methods such as meta-analysis, routinely using the RCV in laboratory reports to notify clinicians about significant changes in patient status, investigating maximum time span between samplings in which the RCV is still valid, and exploring poorly used applications, such as the number of tests needed for a single analyte to establish its homeostatic set point (very necessary in clinical protocols and erroneously omitted up to now).

Biography: Carmen Ricós, Ph.D.

Dr. Ricós graduated in Pharmacy at the University of Barcelona in 1969 and earned her Doctorate in Pharmacy at the University of Barcelona in 1973.

She was awarded a four-year grant in a biochemistry research institution. In 1975 she joined the Catalan Health Institute as a pharmacist specialized in medical analyses in two Primary Care Laboratories.

In 1979 she moved to the Biochemistry Department of Vall d'Hebron General Hospital, where she gained the position of Quality Assurance Head of a clinical laboratory processing around 3.128.000 tests per year. From January 1980 to the present she has occupied this position.

Besides her normal tasks, she has been involved in establishing external quality assessment schemes organized by the Spanish Society of Clinical Biochemistry and Molecular Pathology since 1981 and has been chairwoman of the Analytical Quality Commission of this Society since 1990. She has contributed to several European working groups concerning external quality assessment, and now participates in Technical Committee 140 (Laboratory Medicine) of the European Committee for Normalization (CEN) and in Technical Committee 212 (Clinical Laboratory and in vitro laboratory tests) of the International Standardization Organization (ISO) working group on subjects related to External Quality Assessment and Analytical quality Goals. She is also a member of the Expert Advisory Panel on Health Laboratory Services, World Health Organization (WHO) for the period 1997-2001.

She has directed two doctoral theses, and has written and lectured on a number of works related with internal and external quality control, quality systems and quality goals. She regularly imparts classes on laboratory accreditation, in connection with the ENAC (Spanish Accreditation Body)