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    CAP Laboratory Improvement Programs The Origin of Reference Intervals A College of American Pathologists Q-Probes Study of “Normal Ranges” Used in 163 Clinical Laboratories Richard C. Friedberg, MD, PhD; Rhona Souers, MS; Elizabeth A. Wagar, MD; Ana K. Stankovic, MD, PhD, MPH; Paul N. Valenstein, MD Context.—Standards have been developed for establish- ing reference intervals, but little is known about how tervals are determined in practice, interlaboratory vari tion in intervals, or errors that occur while setting refer- tence intervals. Objectives—To determine (1) methods used by clinical laboratories to establish reference intervals for 7 common analytes, 2) variation in intervals, and (3) factors that con- tribute to establishment of “out ervals. Design—One hundred sixty-three clinical laboratories provided information about their reference intervals for Potassium, calcium, magnesium, thyroid-stimulating hor- ‘mone, hemoglobin, platelet count, and activated partial thromboplastin time. Results—Approximately half the laboratories reported ‘conducting an internal study of healthy individuals to va idate reference intervals for adults. Most laboratories relied ‘on external sources to establish reference intervals for pe- [tert sts te commonly compare to erence interval before caregivers make physiological assessments, medical diagnoses, or management det The importance of reference intervals is underscored by Us "regulation: the ‘Clinical Laboratory. Improvement Amendments of 1988 require that Iaboratories that into- duce an unmodified, US Food and Drug Administaton Cleared or approved nonwaived test system “verify that the manufacturers reference intervals (normal values) are Appropriate forthe laboratory's patent population" Labs sratorkes that modify US Food and Drug Administration - Spproved tests or develop thir wn assays are required WO establish ther owen relerence intervals for thir assays, ‘Accepted for publication Sepiember 8, 2008 From the Department of Pathology, BayState Medical Cente, Sping Fld, Mas (Dr Fiedbeugy, the Depart wsis, College of Anetiran Paholgise, Norivikl ll (Me Souersy the Departs of Pathology, The David Geflen School of Medicine a UCLA, Lox Angeles, Clif (DF Wagar) Preanalytical ‘Systems, BD Diagnoses, Fanklin Likes, NJ (Dr Stankovi), and Department of Pathology, t Joseph Mer (6) Hospital, Ann Arbor Mich (DF Valente) tutors have nw telean ruarrsalameses she pwd ‘companies described in this article Reprints: Paul N Valenstein, MD, Department of Pathology St Joseph Mercy Hospital, Ann Arbor, MA 48106-0995 (e-mail paul valentin, om 248 Arch Patol Lab Med Vol 121, March 2007 diatric patients. There was slight variation in intervals used by the central 80% of study laboratories, but some labo- ratories outside the central 80% had surprisingly low and tervals. In some cases the hhad no overlap. For ex- ample, one laboratory considered a hemoglobin of 13.8 g/dL ina woman to be “low” while another considered the same value to be “high.” Three percent of reference inter- vals contained a limit that qualified as an “outlier” using standard statistical tests; we could not identify any practice Conclusions-—Many laboratories adopt reference inter- vals from manufacturers without on-site testing of healthy validated with on-site studies. (Arch Pathol Lab Med. 2007;131:348-357) Regulations also specity that reference intervals be includ- tin laboratory ports or made available upon request to individuals who order test, pos Reference intervals are of 2 types? The most common type has been termed feassothted and is derived fon 2 Feference sample of persons who ate in good health For example, the reference interval normally reported for Serum potasslum is health-associated. The cental 93% of the healthy adult population tested by many laboratories has serum potassium levels between 33 and 5.1 mEq/L, and these Hts define the serum potasium reference in: terval The other type of reference interval has been termed decsion-hnef and defines specific medical decision limits that clinicians use to diagnose or manage patients For example, a serum total cholesterol of more than 200 mg/L. defines the level at which diet and exerse are ist recommended by most authorities fo lower cholesterol in otherwise healthy adults Smilary the International Nor malized Ratio range of 2.0 40 30 defines what some au- thors consider appropriate long-term anticoagulation in gate thot a itn risa who have Elude Medical bileaet prosthetic aortic valves” Refer: ence intervals that incorporate medical decision limits are Sten defined with cinal trials and adopted by labora tories from the medical iterstur. In ths study Wwe inves tigated the process clinical laboratories use to establish helti-asoctated reference intervals. These intervals are Reference Intervals—Fredberg etal also popularly known as reference ranges, normal values, no ina res, blogic! reeence intersected Tees, Health-associated reference intervals vary from labora- tory to laboratory. For example, ina survey of 525 clinical laboratories the lower limit of the laboratory's total serum calcium reference interval ranged from 8.3 0 88 mg/dL (th and 90th percentile of laboratories) and the upper limit from 10.2 to 10.7 mg/dL. Some of this variation may have been due to differences among laboratorics in clinical service needs, analytic platforms, populations of healthy individuals, or analytic imprecision that was present when reference intervals were determined. Yet some of the var- iation may have resulted from different approaches labo- ratories used to establish their reference intervals, as the [process for establishing health-associated reference inter ‘als has historically been poorly defined. No single authoritative Source specifies the process that clinical laboratories should use to establish health-associ- ated reference intervals. The document that most closely approaches an authoritative source is the Clinical and Lab- ‘oratory Standards Institute (CLSI; formerly NCCLS) doc- uument C28-A2. The CLSI document is based on the sem- inal work of Solberg and colleagues;~ who served in the 19805 on the Expert Panel on Theory of Reference Values of the International Federation of Clinical Chemistry and the Standing Committee on Reference Values of the Inter- national Cotineil for Standardization in Haematology. This CLSI standard recommends one approach for es tablishing reference intervals of a newly developed or modified analytical test system andl a second, abbreviated, 20-specimen approach for validating the transfer of refer ance intervals among, comparable analytical plaorms, The more involved approach is applicable to instrument manufacturers first determining reference intervals for their test systems or to laboratories that develop their own assays of modify commercially available assays. The less involved appro allows linia Iaboatores using modified US Food and Drug Administration-approved as- says to validate reference intervals supplied By the man- ufacturers of their analytic instruments. The current version of the Centers for Medicare and Medicaid Services (CMS) Suraey Procedures and Interpretive Guidelines for Laboratories and Laboratory Seroices indicates a “Maboratory must evaluate an appropriate number of spec- imens to verity the manufacturers claims for normal val tes of, a8 applicable, the published reference ranges.” The CMS provides no guidance about what constitutes an “appropriate” number of specimens, when age-specil and secspecificinterals need to be establishes, of how data from tested healthy individuals are to be used to verify a manufacturer’ claims. The CMS agents make judgmental determinations about each facility’ efforts to Yalidate reference intervals on a case-by-case basis during the course of laboratory inspections. Lite is known about how laboratories establish health- associated reference intervals in practice. During 2004, 1.3% of laboratories enrolled in the College of American Pathologists (CAP) Laboratory Accreditation Program ‘were cited by inspectors for failing to validate reference intervals properly, but the specific types of omissions were rot documented and it snot clear whether inspectors ape proached this problem in a consistent manner A survey {f 500 laboratdries conducted by the CAP in 2001 found that 390 (78% of laboratories) adopted manufacturers’ published values for their reference’ intervals Appro ‘Ach Pathol Lab Med—Vol 131, March 2007 mately one fifth of laboratories reported receiving, hel from manufacturers in validating 2 manufacturers refer cence interval either inthe form of stalstcal consultation, test materials, or procedures. The survey did not collect information about the proportion of laboratories. that adopted manufacturers’ felerence intervals without test- ing any healthy individuals. The aims of the present study were to (1) describe meth- ‘ods actually used ‘by clinical laboratories to establish ref- ference inteFvals for common analytes, (2) document inter laboratory variation inthe reference intervals used in prac- tice, and (3) identify institutional factors and practices that influenced the reference intervals a laboratory adopted. We considered the aims of this study to be important for two reasons: Fist, the validation of reference intervals can consume considerable laboratory time and resources. Methods for validating reference intervals that require less effort but that still produce reliable intervals may be at- tractive to clinical laboratories operating with tightly con- strained resources. Second, we were concerned that some laboratories may have adopted unusual reference intervals that posed patient safety risks, because of some sort of ‘oversight or conceptual ezzoe. We wished to examine how often “outlier” reference intervals (defined in the “Mate- als and Methods”) were found in laboratories, and ‘whether any’ particular laboratory practices predisposed to the adoption of outlier interval MATERIALS AND METHODS Study Design The study was conducted according tothe Q-Probes study for ‘mat previously described, which reli on a convenience sample ‘of clinical laboratories that subscribe to the CAP Q.Prabes bench- ‘marking program: After refinement of a standardized data cok Tection instrament, CAP Q-Prabes subscribers were male data collection instructions in Tate 2005, Participants wore asked to provide thei laboratories’ lw and high vals for referonce intervals fr 7 analytes: potassium, total calcium, magnesium, thyrotd-stimulating hormone (TSH), be- moglobin,phtelet count, and activated. partial Uuromboplastin time (aPTH}. Adult values (assuming a 32-year-old male inpae tient) and pediatric values suming an S-yearold male inpa- tient) were collected. In addition, hemoglobin reference intervals were collected for female adult 3nd pediaeic inpatients, Fr each analyte, the fllowing additonal information was col lected unit of measure, primary specimen type, ana¥tc instruc rent manufacturer year the reference interval was orginally es tablished, year of the most recent revalidation of the relerence interval, and year the primary instrument was placed nto ser vice: The methods the laboratory used to determine reference Intervals for each analyte were also ascertained. Participants were ssked whether they festod "healthy individuals” as part of the process they used to determine reference intervals, ut no wxplict {Sefiition of» healthy individual was provided. Reference intervals for pointo-care instruments and capillary (fngestick oF earlobe) blood collections were exchided. In ad shtion, intervals that were in the process of being reviewed were ‘aclu, a were intervals for secondary laboratory testing sites Sand analyzers (Gf more than one testing site or analyzer was in tse and reference intervals ifered between site or analyzers). Participants vere also queried about several institutional char- acteristics occupied bed siz, teaching satu, pathology resident training status, government afation, institution location, istic tution type, CAP inspection statu, and inspection status by the Joint Commission om Accreditation of Healthcare Organizations. Laboratory Characteristics Participants from a total of 163 institutions submitted data, Most of the institutions (27%) were located in the United States Reference Intervals—Friedberg et al 249 ‘with the remaining located in Canada (2), Australia (1), Lebanon (), and South Korea (1). Approximately 31% of participating in- stitutions were teaching hospitals and 15% had 8 pathology re=- idency program. Within the past 2 years the CAP inspected 78° ‘of the study laboratories. Hospital or laboratory inspections were conducted by the Joint Commission on Accreditation of Health- ‘are Organizations at 66% of participating institutions. Table 1 displays characteristics of participating institutions. For chemistry assays the majority of institutions reported that they most commonly tested serum, rather than plasma. Ninety- ‘one institutions (56.5%) most commonly tested for potassium us- ing serum 94 (59.1%) used serum for cakium; 92 (579%) used serum for magnesium; and 120 (78.9%) used serum to test for TSH. Statistical Analysis Where required, calcium and magnesium reference interval data were standardized to milligrams per deciliter (if they had bbeen reported in millimoles pet liter or millequivalents per lite). Prior to performing statistical tests fr association, values were screened for outliers, Several participating institutions did not fnswer all of the questions on the questionnaire about demo- ‘graphic characteristics, institutional practices, or reference inter- ‘als for particular analytes or age groups. These institutions were excluded only from tabulations and analyses that required the Imissing data elements All statistical analysis were performed using SAS v9.1 (SAS Institute Inc, Cary, NC). The low and high values for the reference intervals were tested for associations with the institutions” demographic and practice variable information in Tables 1 and 2, as well as the analytic platform used by the laboratory. Individual associations were First tested using the nonparametric Kruskal-Wallis test. Variables ‘with significant associations (P ~- 10) were then inclided ina Forward selection regression model. All remaining variables were significantly associated atthe .05 significance level ‘We used multivariate analysis of variance to perform a joint analysis ofthe dependent variables: low and high adult reference intervals and low and high pediatric reference intervals. This ap- ‘proach simultaneously tests whether the mean low /high vectors re statistically different for the analytespecific predictor vari fables. Since the cell counts for the predictor variables were not ‘equal, the significance level was set at OL ‘We investigated outliers/atypical reference intervals using sev- ral techniques. First, we screened reference interval limits for ‘outliers using 2 tests, the Tukey procedure (in which an outlier is defined as any value less than the first quartile — 15 > Inter- quartile Range or greater than the third quartile 1.5 X Inter- ‘uartle Range) and a 2-pass/3 SD procedure (in which an outlier iS defined as any value tha fell more than 3 standard deviations from the mean, either during a first pass with al data included ‘or during a second pass in which outliers identified during the first pass were excluded). We also used a logit regression model to examine whether unusual reference interval lmits—thove in the upper or lower decile—wvere associated with any of the de- ‘mognaphic and practice variables listed in Tables Land 2. For the logit regression, the significance level was set at 05 RESULTS When Are Reference Intervals Established? A number of institutions reported that they did not know the year that their original reference inierval had been established or the date of their most recent reference interval revalidation. Nine participants (5.5%) could not provide the year of their most recent revalidation of aPTT reference iniervals, while 30 participants (18.4%) did not know the most recent year that potassium reference inter- vals were revalidated. Among laboratories that reported the year of their most recent revalidation, most had reval- idated reference intervals within the past 5 years. Exclud- ing aPTT, approximately two thirds reported that they re- 350 Arch Pathol Lab Med—Vol 191, March 2007, Table 1. Characteristics of Participating Laboratories” Tnstiatons Characteristic Non % Trattaion pe vivate, sone 8 State, county or ity hospital 18 University hospital 6 Governmental federal 5 Independent lab 5 Other 8 Occupied beds 0-150 st aa 151-300 a as 301-450 % asa 451-600 10 ‘600 3 os Institution location ity 63 ara Suburban ” 28 Rural =u 2 Federal installation lab 2 15 Goverrmentalalliaio Nongovernmental 104 800 NNonfederal governmental 2 162 Federal governmental 3 va ‘writen policy for establishing, revising, or updating intervals Yes Nz 73.6 No a 268 Unique intervals fr distinct populations by patient age Yes 40 870 No Fy) 10 Unique intervals fr distinct populations by patient location Yes 4 25 No 1s? os Unique intervals fr distinct provider or practice group Yes 2 12 No 159 ow Unique intervals fr distinct populations based on disease type Yes 6 3a No 153 962 Unique intervals fr distinct populations by patient ethnicity Yes 7 44 No 153 956 Reference intervals validated inthe same year as new instrument acquisition Potassium 6 63. Calcium 6 a7 Magnesium 8 ora TSH 6 0 Hemoglobin (male) 8 63. Hemoglobin (lemale) fs 596 Platelet count 6 ont apr 2 295, TSH indicates thyroid Simulating hormone! APT, activated partial thromboplastin time. validated their intervals in the same year that a new an- alyzer was purchased (Table 1). Nevertheless, in some lab- oratories and for some analytes the most recent revalidation of a reference interval had not occurred for more than 10 years, and one participant indicated the lab- ‘oratory had last revalidated several reference intervals in Reference Intervals—Fredberg etal Table 2. Source of Reference Intervals" Tnatons, Nox Hah Hab Potassium — Calcium Magnesium TSH (Male) (Female) Platelets PTT "a Inwemal study of heathy individuals 701443) 701438) 701886) 751484) 851535) 836525) 81.613) 130082. Manufacturer's ecommendations! inserts 55048) 56050) 570363) 460297) 17007) 1HL4 19020 1207.6) Published literature textbooks, 1912.0) 17408 16402) 27) 42070) BA72 Ore 60.) ‘Other laboratories ladopted with intemal validation) 860 966 861) 1065) 860 861) GN) 502) Nonlaboratony medical stat recommendations 20a) 405 203) 426 30% 309 349 203) ‘ther laboratories ladopted with- out internal validation) 0 = 00) += =~ 203) 108 §=—106 = 10H =~ 203) Other 425) 425 405) 6G9 203 20a) 24a) 108) Peciaie Inwemal study of heathy individuals 350252) 44241) 36259) 210157) 5238 3420 we28 45.620) Manufacturer's ecommendations! inserts 45024) 2098) 45024 S940) 1368 1405) 15105) 11.1) Published literature textbooks, 42002) 44012) 2.009 16 75610 756607) sur) 26078 ‘Other laboratories ladopted with intemal validation) 760 867 643) 762) 74H 864) 866 5.0.7) Nonlaboratony medical stat recommendations 302) 505 322) 507 407 4en 42H 205) ‘ther laboratories ladopted with- out internal validation) 107) 204 107) 46.0 1068 1068 96a) 40.0) Other 64a 64) 586 587 320 320 505) 400) TSH indicates thyroid stimulating hormone; Hgb, hemoglobin and aPTT, awated pavial twomboplastin time 1983, more than 22 years before the study was conducted and more than 8 years before the laboratory's current an- alytic instrument was placed in service. Methods Used to Establish Reference Intervals roximately half the participants reported that they conte a internal stu of healthy individuals to help establish chemistry and hematology reference intervals fOr adults, and half relied exclusively upon external sources (manufacturers’ inserts, published literature, intervals used at other laboratories, or medical staff recommenda- tions), For aPTT, 130 facilities (823%) reported conducting fn internal study of healthy individuals to establish ref ference intervals. These data are shown in Table 2. Most laboratories relied on external sources to establish reference intervals for pediatric patients (Table 2). Ap- proximately one fourth of participants indicated they per- formed an internal study on healthy individuals to estab- lish chemistry reference intervals for pediatric patients, da spproutately 10's of focitescondocted ntemal Studies to establish hematology and aPTT pediatric ref erence intervals. ‘One hundred thirty-six (84%) of 162 laboratories re- ported that they received some assistance from instrument manufacturers in establishing, reference intervals. Of lab- ‘oratories that received assistance from manufacturers, 111 (62%) reported receiving statistical support, 91. (67%) re- Ceived consultative support, 35 40%) followed 2 i dlr for establishing reference intervals that had been pro- vvided by the manufacturer, and 27 (20%) received speci mens for testing from the manufacturer. ‘Ach Patho Lab Med—Vol 131, March 2007 We sh pts sve deal ution abet tne proses they ud oe potas reference ters for adults. OF the respondents that indicted they had conducted an intemal reference interval study of healthy individuals, half (65 laboratories) indicated that they ad tested_specimens from between 21" and 50 I nda and ene unter (2 abortr in dicated they had tested more than 10) specimens. OF the Sites that feted heathy individuals to help establish ret tence intervals, 56 sites (9%) set thei reference intervals ting the mean ofthe tested reference population plus or minus 2 standard deviations, while the remainder of re Spondents (73 sites; 37%) used test resulls 0 “verify” an tktemal reference interval obtained from the manufactur: lished textbook, or some other source. These data Ste shown in Table 3 Laboratories that set their reference intervals from the results of intemal testing (mean = 2 $1) did not fend fo fest more healthy patients than labo ratoies that used internal testing 10 "erly" at external interval (Table 4 chisquare = 257; P = 33) Interlaboratory Variation in Reference Intervals There was slight variation in reference intervals among the central 80% of study laboratories (Table 5). Upper lim= its of reference intervals tended to vary slightly more from laboratory to laboratory than lower limits did. There was rno dramatic difference between the amount of interlabo- ratory variation in adult reference intervals and pediatric reference intervals, even though adult reference intervals ‘were more often validated by testing specimens from healthy individuals and pediatric reference intervals were Reference Intervals—Friedberg et al 351 Table 3._ Methods Used to Establish Potassium Reference Interval Twatatons ota evel ran on Which specimen type Both plasma and serum 100 ou Plasma 2 154 Serum ” 228 1 potassium levels run om both plasma and serum, laboratory “Converts” a result from one specimen type to the equivalent level fom the other type 28 622 Esablishes and reports? diferent reference intervals base on specimen type 0 7. If an intemal reference interval study was performed for potassium values, how many healthy individuals were studied? 20 4 aa 21-50 6 soa 51-100 2 217 100. 2 28 If an intemal reference interval study was performed for potassium values, how did laboratory’ set the reference interval? Satstcal analysis of collected data (eg, mean * 2 SD) 56 Ba ‘Manufacturers recommendation after comparing to collected data fom an interal reference interval ‘tu 55 126 Texthook data after comparing to collected data from an internal reference interval study 0 78 Another laboratory's reference intenal after comparing to collected dat rom an internal reference in tensa study 23 other 5 Yo most often obtained from external sources. Reference in- Institutional Factors and Practices Associated With tervals forthe 7 study analytes showed similar levels of interlaboratory variation Outside of the central 80% of laboratories there was more substantial variation in reference intervals. A Tew laboratories had surprisingly low and high limits for their reference intervals. For example, ae laboratory reported that its reference interval for adult polasium extended down to'3.0 mmol/L, while another feported thatthe up- per limit of is potassium reerence interval extended up {0 57 mmol/L In some cass the reference intervals used by 2 laboratories did not overlap, and the upper lint of che laboratory’ reference interval was lower than the lov- er limit of another’. For example, one laboratory consil- ted an aPTT of 30 seconde to be “low” while another considered an aPTT of 30 seconds tobe “high.” Using the Tukey procedure, 40 (3.1%) of 1271 adult reference inter vals contained at least 1 limit that was an outer. The 2- pass/3 SD procedure idenified the same total number of Sule. There were no significant differences in the fac- tin of outlier reference interval limits among the analytes wwe studied, Reference Intervals, We examined all ofthe institutional factors and practic: es in Tables Tand 2 to elucidate variables that Were as Soviated with reference intervals. For several analytes, par fcular instrument manufacturers were associated with higher of lower reference intervals, Tables 6 and 7 iis: trate this relationship, showing statistically significant as Soriatons between instrument manufacturer and the me- dian value ofthe upper and lower limits of adult reference interval, respectively: Tables 8 and 9 show the same Te lationship forthe upper and lower limits of pediatic re thence iMerals: Investing, specimen Spe dil not af fect the potassium reference intervals used by partic pants even though the potassium concentration i plasma {lower than in serum™® The method used to establish a reference interval (adoption from manufacturer versus on- site testing of a healthy population) was not sssocated with the interval in se. We examined whether any ofthe characteristics in Ta- bles and were associated With the use of aberrant adult Table 4. Number of Healthy tadivi als Tested for Potassium and Method Used to Establish Reference Intervals® Interval Calalated Using Statistical Taboratoris Determining Reference Tnteral Adopted From Manufacturer, No.of Healthy ‘Analysis of Tested Reslls Alter Comparison to Total Individuals Tested “ean 28D) Internal Tested Results Laboratories, No.) 50 w a a a) 51-100 a 15 28.23) “100 16 2 28.23) Total Laboratories 56 (46) 6754) 123.100), No association was detected between The number of ested individuals and the method used to tern the a2 Poa 352. Arch Pathol Lab Med—Vol 121, March 2007 france terval, aque Reference Intervals—Fredberg etal Table 5. Variation in Reference Intervals of Selected Analyles Among 163 Laboratories ‘All stution Percents Analyte, 50m Population, and Litt Minimum 100h——25th_—_(Medlan)—_75th_—_—_90th Maximum Pousiom, mmol ‘Adult, low 12 3033358 ‘Adal, igh 1 45 50 0ST 3208357 Pediatric ow wa 30003303535 Pediatric, high 41 50 OST 5205456 (Calcium toa, mgt ‘Adult, low 12 7683S 8S 8D ‘Adal, high tol 96 101 tT tS Sta Pediatric ow 576 84 BABS 8B 8G Pediatric, high 439% T2007 tS Magnesium, mgd ‘Adult, low 7 13S ‘Adal, igh 37200222322 Pediatric, low wa 121566 we Pediatric, high wa 200212 od ‘Thyroid stimulating hormone, LL ‘Adult, low 154 010030034035 0447050 ‘Adal, igh 155 300420468494 5.50, 5.60.00 Pediatric low 133 010-030-034 03504050 0.70 Pediatric, high 136 400440475 5.00 5.50 5.90 8.00 Hemoglobin (male), g/l. ‘dul, low i 115 OOH ttt ‘Adal, igh tel 15016517075 ttt Pediatric ow Me '8S 03 OS? So Pediatric, high 8027137118200 Hemoglobin (female, pL ‘Adal, low 39° 14ST OO tO ‘Adal, high 139135150155 te0 tet tO Pediatric ow 9001055130 Pediatric, high 8 7174S DSTO TBO Platelets, x10" ‘dul, low 1200030 thigh tor 316 400-400, 4004050500 Pediatric, low 146 100130015050 Pediatric, high 1332532 4004005050539 ‘Activated partial thromboplastin time, s ‘Adult, low 13617 2 2 2B 25 2% oR ‘Adal, igh 15928 32 33 35 a BG Pediatric low 350 2 2 2 25 % Pediatric, high 13828 2 33 35 a BG ~ Taw indicates the Tower Tit ofthe reference inten high the upper Tint ofthe relerence interval sfc nal ins i he upper or er dei) I~ Some of th borne th st Hey als cate Stitutions that established their felerence intervals before their own reference intervals from their findings, but most 2001 were 3.1 times more likely to have aberrant high use inlaboratory testing to “validate” reference intervals PTT limits than were institutions that established their supplied by manufacturers. intervals during 2001 to 2005 (P — 02) Institutions that Although different approaches were used to establish placed test instruments in service before 2002 were 13 reference intervals, no particular approach was associated fimes more likely to have aberrant low TSH limits than with the reference interval that laboratories ultimately es- were institutions that placed instruments in service in tablished. In other words, there was no discernable differ 2002 to 2005 (P= 01)" No other factor was statically ence between the relerence intervals of laboratories that ‘ssociated with aberrant reference interval limit. adopted manufacturers’ reference intervals without fur- ther testing, laboratories that tested healthy subjects to COMMENT validate manufacturer supplied intervals, and laboratories To our knowledge, this is the frst large survey describ- that tested healthy subjects to caleulate their own rete ing how reference intervals are_actualy established by ence intervals clinical laboratories “in the field” We found that approx: Since the approach laboratories used to determine ref- imately haf of all laboratories test healthy adults toestab- erence intervals did not appear to influence the interval lish reference intervals, but few test healthy children. that was ultimately established, we question the conver ‘Ach Pathol Lab Med—Vol 131, March 2007 Reference IntervalsFriedberg et al 353 TSH indicates thyroid stimuating hormane; APT, activated paral thromboplastin time tional wisdom that itis always necessary for laboratories to validate manufacturers’ intervals with on-site testing before adopting the interval locally. I'a manufacturer ad quately describes the process it used to establish a hhealth-associated reference interval, and the laboratory is using the manufacturer's analytic platform in accordance ‘with the manufacturer's instructions and is testing a sim- ilar population, validation of a manufacturer's interval might consist of nothing more than the laboratory medical director making a professional determination that the sup- plied interval is appropriate for the local laboratory. This Approach is contemplated in the CLSI standard,” but not in the current version of the CMS survey procedures." Klein and Junge! sound a note of caution about adopt- ing manufacturers’ reference intervals without local on- site testing of healthy individuals; the authors have con- cers that preanalytic procedures used by manufacturers (uch as specimen collection and storage procedures) may not be adequately duplicated by every laboratory, creating the need for local testing of healthy patients to ensure that manufacturers’ intervals are locally applicable. While rec- ‘ognizing that the adoption of maniufacturers’ reference in- tervals without on-site validation poses some risk, our study suggests these risks are already being assumed by most laboratories that report pediatric reference intervals, since little testing of healthy children is taking place in laboratories even though specimen collection procedures for pediatric patients show a great deal of variability from institution 40 institution. ‘The establishment of reference intervals for “special fluids” poses problems similar to those sen in pediatrics, a8 spetal ld samples are rarely 354 Arch Pathol Lab Med—Vol 121, March 2007 Table & Relationships Between Inorument Table 7, Relationships Between notameat Manuel Ada efrence tral Upper Manure at Adare Ira Lower Te Ti ‘it ‘i tetence tetence Ante, ince nay ‘nc ni a are neat ‘Upper uni ae, woot owe porte vsti ‘Ei sn anaere instal Naan, mga (= OO) TH aU P= 900 Mies 4230 toche now Dae Bring ey fochet lich Hest Poe aOR Bettina Recess 3 tbe Balkan Sychron a i Baan Bon foc haat ae) Be Bo Ons foche Bho vio bow TSH, mitt. (P= 001) ‘Abibor 8 048 te no 420 srr s 000) fiche tachi Se Biotrun Pati Boon hen ete bade etn 8 i B Ci ma Festi arts BOS Dae Bring bin Das Being Actin st BO Poe ub Bagosterdasmarrra te BRL Aces B38 Rohruriemelonce syahasi._— 1825 ares P= 001 Ta nts Hon snag Homnone APT TST Pa Dade Behring Actin FS 10 33 "hrombeplastin time Botte Pain SR Dade Beg tn FS es HeneiterlinceSynias, 183 collected from healthy patients without ciical suspicion iagnosica Sago STA-PTT A 8 36 i Blames Sage f 8 of disease and reference intervals tend tobe adopted from extemal sources without on-site validation.» Reference in tervals for children and special Muids can beset by mul- tiple cooperating laboratories but diferences between test systems make this approach somewhat dificult to m= lement." PaWhile we do not believe local testing of healthy patients is required before adopting a well-documented reference interval from a manufacturer there s nothing wrong with 2 loca laboratory performing on-site testing of Healthy ne dividuals using te abbreviated 20specinen CLSI proce: dure to validate a manufacturers reference interval Ir no facility performs omsite validation of manufactures rel ftence interval the entire laboratory community will be relying on manufacturers and their regulators fo ensure that intial reference interval studies are performed cor realy: We must also point out that a dection by 2 labo- talory ditector to forgo on-site testing of healthy individ tals forthe purpose of establishing a reference interval does not relleve the laboratory ofits obligation fo ade- Guately calibrate a new instrument and test the instru thent®s analytic accuracy and precision before placing it into service We found that for most institutions, interlaboratory var iabilty inthe reference interval values for our study an- alytes was fairly low. The type of test instument in use was the main source of reference interval variability that wwe could identify explaining much of the variation in el ‘rence intervals, Varatoninfeference intervals among = alytic platforms is probably appropriate given that major instrument platforms show analytic bia relative 0 one another Were the reference intervals used by most study partic: ipanis accurate? Without acces fo the patient populations tring tested by each of our study laboratories, we cannot answer this question diectly. However, we collected ine direct evidence that the potassium reference interval used Reference Intervals—Fredberg etal ‘ales (approximately 03 mmol/L, depending on the an Biylc test System). Only 28 sites “converted” results for 1 Specimen type tothe equivalent level from the other type before reporting, and only 17 sites established diferent tec ners fr ea

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