2000 - Hematological Health-related Intervals Estimated Using an Indirect Method in Order to Satisfy...

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Accred Qual Assur (2000) 5:367–370Q Springer-Verlag 2000 PRACTITIONER’S REPORT

Romolo M. Dorizzi

Michele SchinellaAntonella PupilloLuca Endrizzi

Hematological health-related intervals

estimated using an indirect method

in order to satisfy the accreditation

standards

Received: 15 April 2000Accepted: 20 April 2000

Presented at the 5th Conference onQuality (R)evolution in ClinicalLaboratories, 11–12 October, 1999,Antwerp, Belgium

R.M. Dorizzi (Y)Clinical Chemistry and HematologyLaboratory, Verona Hospital,Piazzale A. Stefani 1, 37126 Verona, Italye-mail: dorizzi6easynet.itTel: c39-045-8073248Fax: c39-045-8072156

M. Schinella 7 A. Pupillo 7 L. EndrizziClinical Chemistry and MicrobiologyLaboratory, Rovereto Hospital (TN),Italy

Abstract The estimation of refer-ence limits represents quite a tax-ing task for laboratories which fre-quently adopt the limits suggestedby manufacturers or those reportedin the literature. This practice doesnot meet the requirements of ac-creditation programs (i.e. EssentialCriteria, Clinical Pathology Accre-ditation) that require laboratoriesto produce or check all their refer-ence intervals. We collected 15 244hematological results from femalesaged 0–99 years obtained by theRovereto Hospital Laboratory andcalculated the reference intervals,or to be more precise the health-related intervals, using an indirectmethod (based on all the inpatientand outpatient results). All themeasurements were carried out us-ing an automatic Coulter STK Sanalyzer, and the results weretransferred to Verona by e-mail.The results for hemoglobin were:~1 year (np154)p90–171 g/l;

2–8 years (np619)p104–136 g/l;9–14 years (np322)p118–143 g/l;15–44 years (np6329)p106–144 g/l;45–75 years (np4893)p107–148 g/l;75–99 years (np2927)p90–153 g/l.The results appear different fromthe results currently used by Ro-vereto Hospital (120–160 g/l) butcomparable to those reported inthe literature with the exception of the subjects under 1 year and over75 years, probably due to the ex-cess of “diseased” subjects in theseclasses. The indirect method allowseven small laboratories to produceor check their reference intervalsfor all age groups, increasing theclinical effectiveness of laboratoryresults and satisfying the accredita-tion standards.

Key words Hematologicalquantities 7 Health-relatedintervals 7 Reference limits 7Accreditation program

Introduction

The recently published policy statement of the Interna-tional Federation of Clinical Chemistry and LaboratoryMedicine (IFCC) concerning the principles of clinicallaboratory accreditation covers the points of major in-terest in the field but not in detail. According to thedocument: “It is in the interests of patients, of societyand of governments that clinical laboratories operate athigh standards of professional and technical compe-

tence, since decisions about diagnosis, prognosis andtreatment are frequently based on the results and inter-pretations of laboratory tests.” [1] It is again stated thatquality documentation of policies and procedures mustcover the pre-analytical, analytical and post-analyticalphases of sample analysis. One of the most relevantpost-analytical phases is the production of referencevalues; the Essential Criteria (EC4) recommend thatthey must be checked [2] while Clinical Pathology Ac-creditation (CPA) stresses the necessity to indicatetheir origin [3]. In reality, the task of the laboratory be-


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Table 1 Health-related limits obtained in 15224 samples using an indirect method: RBC, erythrocytes; Hb, hemoglobin; MCV, meancorpuscular volume; WBC, leukocytes; PLT, platelets

Age (years) n RBC (*106/ml) Hb (g/l) MCV (fl) WBC (*103/ml) PLT (*103/ml)

0–1 154 3.12 5.38 8.7 17.1 76.5 108 7.0 15.3 114 5262–8 619 4.07 5.04 10.4 13.6 74.0 87 4.3 12.3 181 4399–14 322 4.10 5.00 11.8 14.3 76.0 90 3.6 9.1 155 33815–44 6329 3.46 4.72 10.6 14.4 83.4 95.1 4.1 10.7 143 29945–75 4893 3.56 4.87 10.7 14.8 83.3 95.1 3.7 8.9 138 31976–99 2927 2.98 4.83 9.0 15.3 83.9 95 4.0 9.8 106 301

comes much more taxing; analysts have to measurehundreds of analytes, changing analyzers frequently.The laboratory becomes entrapped between the ethical

pledge towards the patient to produce high quality re-sults, the strict requirements of accreditation and certi-fication programs, and the practicability of devotingsuch a large number of personnel, reagents and timeresources in producing reference intervals and decisionlimits.

The basic concept of reference values is to obtainvalues from subjects who must be studied in detail andwho are relevant controls for the patients. Usually, ref-erence intervals are established from a population of healthy, non-pregnant, non-obese individuals, whohave neither ingested drugs nor smoked prior to sam-ple collection. This a priori selection of qualified refer-ence individuals is a cumbersome task and can result inselecting a high percentage of too “healthy” subjects. Aclassical example is the collection of reference subjectsamong blood donors or laboratory staff. Since 1960, theproduction of “normal” intervals using routine labora-tory data has been advocated [4] but it has not beensuccessful, mainly because of the difficulty in manuallymanipulating many thousands of assay results in orderto calculate the reference values. The laboratory of Ve-rona Hospital is seeking renewal of CPA accreditationand Rovereto Hospital has requested to be accreditedby CALC (a professional peer-based Italian excellenceprogram). Therefore, we investigated the possibility of using an indirect method to estimate health-related in-tervals for hematological quantities using a commonhematology analyzer.

Methods

We collected 15244 hematological results from femalesaged 0–99 years obtained by the Rovereto Hospital La-boratory, and calculated the health-related intervals us-ing the indirect method proposed by Kairisto and Poola[5]. All the measurements were carried out using an au-tomatic analyzer (Coulter STK S, Coulter, Hileah, Fla.,USA) following the manufacturer’s recommendations.

The results were directly transmitted to the laboratory

information system (LIS) (Bull, France), transferred toan Excel spreadsheet (Microsoft) and then to Veronaby e-mail. In Verona the data were assessed using

GraphROC for Windows, a software program for clini-cal test evaluation, kindly provided by Dr. Kairisto[5].

Results and discussion

The results were divided into the following age groups:~1 year (np154); 2–8 years (np619); 9–14 years(np322); 15–44 years (np6329); 45–75 years(np4893); 76–99 years (np2927). The results relativeto erythrocytes (RBC), hemoglobin (Hb), leukocytes(WBC), platelets (PLT), mean corpuscular volume(MCV) are summarized in Table 1. Table 2 shows thereference intervals that the Rovereto Hospital Labora-tory was using before this study was complete.

In our opinion, the study confirms that the indirectmethod for the production of reference values is quitepromising. The most appealing aspect is that this toolemploys data that most laboratories have stored intheir LIS, which can be easily downloaded to a com-mercial spreadsheet. The data can be manipulated andanalyzed and, for example, any laboratory can partitionthe data and follow the eventual change of the intervalthrough the age decades which is virtually impossible(even for the largest laboratories) using the IFCC-rec-ommended method.

However it must be stressed that the indirect meth-od can only be used if: 1) a great number of subjects arecollected, 2) the health-related subdistribution forms amajor part of the total distribution and, 3) the total dis-tribution is unimodal. The rationale is that patients suf-fering from a disease affecting a particular analyte arein the minority and, therefore, by collecting a greatnumber of subjects the “diseased” subjects do not in-fluence the limits. In order to further stress the tech-nique (and further simplify it), we did not use any se-lection criteria in choosing the data: all the data storedin the database of the LIS were analyzed and we alsoskipped the common rule of this type of analysis; that

only the first result of a subject is considered. We con-


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Fig. 1 Erythrocyte (RBC) dis-tribution in the subject groups2–14 years (A), 15–44 years(B), 45–75 years (C) and

76–99 years (D). The asteriskin D indicates a probable sub-group of “diseased” subjectswhich affects the health-re-lated interval

Table 2 Reference intervals in use at the Rovereto Hospital

Laboratory

RBC(*106/ml)

Hb(g/l)

MCV(fl)

WBC(*103/ml)

PLT(*103/ml)

4.2–5.4 120–160 80–97 4–11 150–400

sidered health-related limits of the 5th and the 95thpercentile at 90% confidence interval.

Figure 1 shows that throughout the different agesgroups the Gaussian distribution of Hb results is quitegood, probably not worse than the distribution ob-

tained following IFCC recommendations. Even in thecase of the older age group (76–99 years), looking atthe distribution curve, it is possible to appreciate a sortof “hump” (indicated by the asterisk) that could becaused by an excess of diseased patients. In this case,the presence of many results of “diseased” people af-fects the calculation of the health-related interval. Onthe contrary, the indirect technique presents several ad-vantages. For example, it is almost inevitable that a la-boratory takes “special care” in producing the resultsnecessary to calculate reference limits according toIFCC recommendations compared to routine work. Byusing the indirect method, we can be sure that the ref-

erence limits have been obtained by processing thesamples in exactly the same way as patients’ results.Furthermore, the selection criteria are very explicit andeasily transferable from one hospital to another. Final-ly, since the number of collected samples is very high, itis possible to partition the data when necessary or ad-visable.

Conclusions

The results obtained in this study appear interestingfrom the speculative and practical point of view. Theindirect method appears to provide very interesting and

useful data which should be much more suitable forclinicians. The main advantage is that it is possible totailor reference values to different age groups; this as-pect has been disregarded until now, damaging, in ouropinion, patients and clinicians. For example, the refer-ence limits for Hb used until now by the Rovereto Hos-pital Laboratory were 120–160 g/l for all age groups, asrecommended in the literature [6, 7]. The results ob-tained by us using the indirect method are lower andare similar to those reported by Kouri et al. who usedan indirect method in hospitalized subjects aged20–65 years [8]. Really, the health-related limits calcu-lated in children under 1 year and in people older than


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75 years appear too low. In these cases the low numberof subjects (under 1 year) and the probable high per-centage of “diseased” subjects (as previously noted) af-

fected (lowering) the limits too much. It must be noted,however, that comparably low RBC, WBC and PLTcounts have been reported by Tietz [9] and by Faulknerand Meites [10].

A more recent investigation relative to 3654 subjectsaged 49–97 years excluded subjects with confoundingfactors such as smoking, high alcohol intake, medica-tion, chronic disease and high creatinine [11]. In this re-port the reference interval was 122–161 g/l but, in ouropinion, aspects such as the altitude where the selectedsubjects were living (700–1000 m) and the difference inthe composition of population (Australian vs Italian)and the different analyzer (H2, Bayer) used, make anyreliable comparison impossible. Also the platelet refer-ence limits are surprising, but it should be kept in mindthat other authors reported similar platelet counts: bothTietz [9] and Woo reported a low reference limit of 109109/l [12]. The WBC count supports the belief that theour selection was not particularly biased: the high countin children, especially in the first year of life, was con-firmed; all the other age groups showed limits lower

than those usually proposed but very similar to thoserecently reported using the same analyzer in a20–80 years Norwegian reference group following

IFCC recommendations [13].To conclude, the indirect method appears to be avery convenient way for laboratories of every size toproduce and/or validate their reference intervals for allage groups. Today, the financial limitations in healthsystems all around the world and the rapidity of analyz-er turnover, virtually precludes the majority of labora-tories from calculating reference limits for thehundreds of assayed analytes. Ferré-Masferrer et al.calculated indirect-reference limits for 14 biochemicalanalytes (albumin, bilirubin, calcium, creatinine, phos-phate, potassium, protein, sodium, urate, urea, alanineand aspartate aminotransferase, alkaline phosphateand glutamyltransferase) in serum using 3 different in-direct techniques and compared them to the referencelimits calculated following IFCC recommendations[14]. Their limits were reliable for most of the analytes,and we think that this is true also for hematologicalquantities. Imperfect reference limits are definitivelybetter than no or wrong reference limits.

References

1. http://194.79.144.120/EXEC/HDB9799/DiversDoc/accred9 poli-

cy.html (last accessed 21 November1999)

2. Jansen RTP, Blaton V, Burnett D,Huisman W, Queraltó JM, Zérah S,Allman B (1997) Eur J Clin ChemClin Biochem 35:121–32

3. Clinical pathology accreditation(1999). Accreditation handbook, ver-sion 7.0. Clinical Pathology Accredi-tation (UK) Ltd, Sheffield, UK

4. Pryce JD (1960) Lancet ii: 333–6

5. Kairisto V, Poola A (1995) Scand JLab Invest Suppl 55 222:43–60

6. Tietz NW (1997) Clinical guide to la-boratory tests. 3rd Edition. Philadel-phia: Saunders

7. Thomas L (1998) Clinical LaboratoryDiagnostics. Frankfurt: TH-Books

8. Kouri T, Kairisto V, Virtanen A, Uu-sipaikka E, Rajamäki A, FinnemanH, Juva K, Koivula T, Nänto V(1994) Clin Chem 40:2209–15

9. Tietz NW, Shuey DF, Wekstein DR(1992) Clin Chem 38:1167–85

10. Faulkner WR, Meites S (1994) Ger-iatric Clinical Chemistry. Referencevalues; Washington: AACC

11. Tsang CW, Lazarus R, Smith W, Mit-chell P, Koutts J, Burnett L (1998)

Clin Chem 44:96–10112. Woo J, Arumanayagam M, Ho S,

Swaminathan R (1989) Pathology21:31–4

13. Bäck SE, Nilsson JE, Fex G, JeppsonJO, Rosén U, Tryding N, vonSchenck H, Norlund L (1999) ClinChem Lab Med 37:573–93

14. Ferré-Masferrer M, Fuentes-ArderiuX, Puchal-Ané R (1999) Clin ChimActa 279:97–105

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