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Limitations and opportunities of whole blood bilirubin measurements by GEM premier 4000® Wang, Li; Albert, Arianne Y K; Jung, Benjamin; Hadad, Keyvan; Lyon, Martha E; Basso, Melanie Mar 29, 2017

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RESEARCH ARTICLELimitations and opportunivaBackground unconjugated bilirubin crosses the blood-brain barriern of BINDr risk factors,d early treat-e transfusionbilirubinemiaSB) or trans-Wang et al. BMC Pediatrics  (2017) 17:92 DOI 10.1186/s12887-017-0842-8determining risk for kernicterus since the publication ofVancouver, BC, CanadaFull list of author information is available at the end of the articlecutaneous bilirubin (TcB) has been adopted by manycountries [3]. TSB has been the clinical standard for1BC Children’s & Women’s Hospital, University of British Columbia, 4500 OakStreet, Room 2J9, Vancouver, BC V6H 3 N1, Canada6BC Children’s Hospital Research Institute, University of British Columbia,medical attention in newborns. Although it is benignand transient in most cases, some neonates with severehyperbilirubinemia are at risk for bilirubin-inducedneurologic dysfunction (BIND), which occurs whendamage if left untreated [1]. Preventiorequires appropriate clinical assessment fotimely measurement of bilirubin levels anment with either phototherapy or exchang[2]. Universal screening for newborn hyperby measuring either total serum bilirubin (T* Correspondence: li.wang@cw.bc.caJaundice is the most common condition that requires and binds to brain tissue causing irreversible neurologicAbstractBackground: Neonatal hyperbilirubinemia has traditionally been screened by either total serum bilirubin ortranscutaneous bilirubin. Whole blood bilirubin (TwB) by the GEM Premier 4000® blood gas analyzer (GEM) is arelatively new technology and it provides fast bilirubin results with a small sample volume and can measure co-oximetry and other analytes. Our clinical study was to evaluate the reliability of TwB measured by the GEM and identifyanalytical and clinical factors that may contribute to possible bias.Methods: 440 consecutive healthy newborn samples that had plasma bilirubin ordered for neonatal hyperbilirubinemiascreening were included. TwB was first measured using the GEM, after which the remainder of the blood was spun andplasma neonatal bilirubin was measured using the VITROS 5600® (VITROS).Results: 62 samples (14%) were excluded from analysis due to failure in obtaining GEM results. Passing-Bablok regressionsuggested that the GEM results were negatively biased at low concentrations of bilirubin and positively biased at higherconcentrations relative to the VITROS results (y= 1.43x-61.13). Bland-Altman plots showed an overall negative bias of theGEM bilirubin with a wide range of differences compared to VITROS. Both hemoglobin concentration and hemolysisaffected the accuracy of the GEM results. Clinically, male infants had higher mean bilirubin levels, and infants delivered bycaesarean section had lower hemoglobin levels. When comparing the number of results below the 40th percentile andabove the 95th percentile cut-offs in the Bhutani nomogram which would trigger discharge or treatment, GEM bilirubinexhibited poor sensitivity and poor specificity in contrast to VITROS bilirubin.Conclusions: An imperfect correlation was observed between whole blood bilirubin measured on the GEM4000® andplasma bilirubin on the VITROS 5600®. The contributors to the observed differences between the two instruments werespecimen hemolysis and the accuracy of hemoglobin measurements, the latter of which affects the calculation ofplasma-equivalent bilirubin. Additionally, the lack of standardization of total bilirubin calibration particularly in newbornspecimens, may also account for some of the disagreement in results.Keywords: Neonatal, Hyperbilirubinemia, Screening, Whole blood bilirubinblood bilirubin measurempremier 4000®Li Wang1,6* , Arianne Y. K. Albert2, Benjamin Jung1,6, Key© The Author(s). 2017 Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zeOpen Accessties of wholeents by GEMn Hadad3, Martha E. Lyon4 and Melanie Basso5,6le is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.Wang et al. BMC Pediatrics  (2017) 17:92 Page 2 of 7Bhutani (1999) [4]. TcB is known to be less accurate athigh bilirubin levels and may be affected by skinpigmentation (although improved with newer models)and skin thickening, making it unsuitable for olderneonates [5, 6]. Most importantly, TcB is a physiolo-gically different parameter than TSB because TcB as-sesses mainly extravascular bilirubin whereas TSBreflects the intravascular bilirubin concentration [6].Whole blood bilirubin (TwB) analyzed on a blood gasinstrument is a new and promising alternate method forneonatal hyperbilirubinemia screening. Compared toTSB it requires a smaller sample volume, has a fasterturnaround time, and offers concurrent measurement ofa full range of analytes (blood gas, electrolytes, glucose,lactate and co-oximetry), which allows for an efficientand comprehensive assessment of newborn status espe-cially in critically ill neonates. Given these potentialadvantages of TwB, we conducted a prospective clinicalstudy to compare TwB to TSB in the laboratory. Ourobjectives were to compare TwB results on the GEMPremier 4000® blood gas analyzer (InstrumentationLaboratory, Bedford, MA) (GEM) against plasma neo-natal bilirubin results on the VITROS 5600® (OrthoClinical Diagnostics, Rochester, NY) (VITROS) and toexamine whether bilirubin measurement is influenced byvarious pre-analytical, analytical or clinical factors.MethodsPatientsThree hundred and thirty-one newborns for whom bili-rubin testing was clinically required were enrolledbetween May and August 2014 (total of 440 samples assome neonates had multiple samples). The inclusion cri-teria were for the neonates to be <14 days postnatal ageand that sufficient blood volume was collected to enablemeasurement of both whole blood and plasma bilirubin.Capillary whole blood samples were collected into plainheparinized microtainers. TwB was measured using theGEM after which the remainder of the specimen wascentrifuged and the clinically required plasma neonatalbilirubin was measured using the unconjugated and con-jugated bilirubin (BuBc) slide on the VITROS. Clinicaldata such as gestational age, gender, birth weight, post-natal age, Apgar score and delivery methods (caesareansection (CS) vs vaginal delivery) were extracted fromchart reviews. This study was approved by the ResearchEthics Committee of the University of British Columbia(H13-02615). Consent was not required as this was aquality assessment project in the lab and no additionalblood was drawn.Laboratory analysis principlesTwB measured by the GEM is a point-of-care test thatwas approved by the Federal Drug Administration in2010. The blood gas analyzer measures total bilirubinalong with the hemoglobin (Hb) fractions in hemolyzedwhole blood samples by direct spectrophotometry in theco-oximetry module. In order to distinguish each com-ponent, multi-wavelengths are used and multi-variateregression algorithms established in a spectral library arecompared when measuring a whole blood sample.Plasma equivalent bilirubin results are then reportedusing a formula [Bili plasma = bili whole blood/(1-hematocrit)], and hematocrit (Hct) is calculated as[Hct = 0.03x Hb]. The constant 0.03 represents the aver-age concentration of hemoglobin (g/dL) within the redblood cells. GEM bilirubin is calibrated based on totalbilirubin spectrum made of known levels of conjugatedand unconjugated bilirubin. Since the GEM uses a directspectrophotometric assay, it cannot distinguish differentfractions of bilirubin.Neonatal bilirubin concentrations in heparinized plasmawere measured using the multi-layered slide technique byreflectance spectrophotometry on a VITROS 5600®analyzer. In the BuBc slide, plasma distributes and reactswith reagents while Hb and other interfering compoundsare trapped and masked from being measured. Bu and Bcare measured simultaneously. The VITROS calibrator iscomposed of high grades of Bu that is traceable to NIST916a and the synthetic ditaurobilirubin disodium salt forBc. The Hemolysis index (H index) is a quantitative esti-mate of Hb that can be measured spectrophotometricallyusing the VITROS and was used to assess the effect ofhemolysis on the measurement of whole blood bilirubinby the GEM.Statistical analysisThe study population was characterized by descriptivestatistics. Passing-Bablok regression, Bland-Altman plots[7], and paired sample t-tests were used to examine thedifferences between the whole blood bilirubin (GEM)and BuBc measurements (VITROS). To determine therelationship between the difference in measurements bythe GEM and the VITROS and clinical factors such asgestational age, gender, birth weight, Apgar score anddelivery mode, we used Welch’s t-tests for comparisonsbetween two groups, ANOVA for comparisons amongmore than two groups, and linear regression for relation-ships with continuous variables. Apgar scores weredichotomized into <7 and ≥7 groups for comparison. Allcomparisons of the above clinical variables were con-ducted on the first sample from each neonate.We used generalized additive modeling to describethe association between the difference in methods andHb concentration (as the relationship was clearly non-linear) and linear modeling to describe the associationbetween the difference in methods and hemolysis (Hindex) on all samples, including the repeat samples onsome neonates.Finally, we assessed the predictive value of the GEMwhole blood bilirubin results by applying the Bhutaninomogram [4] to classify them into the different riskcategories. We also classified the VITROS values againstthe nomogram and used the numbers in each of the riskcategories as the standard against which to compare theGEM results. We calculated sensitivity, specificity,negative predictive value (NPV), and positive predictivevalue (PPV) for risk cutoffs at the <40th percentile and>95th percentile, which would trigger discharge andtreatment, respectively. Analyses were carried out usingR version 3.2.4.(from 331 newborns) collected during the study period.There was a significant underestimation of bilirubinconcentration with the GEM method at low bilirubinconcentrations, whereas at bilirubin concentrationsgreater than 142 umol/L, the GEM method tended tooverestimate bilirubin concentrations relative to theVITROS method. The regression equation was: y = 1.43x-61.13 (95% CI: 1.36 to 1.50 for the slope, and −73.8umol/L to −50.5 umol/L for the y-intercept).Bland-Altman plotThe Bland-Altman analysis estimated a mean bias of −0.14umol/L (95% Limits of agreement = −81.6 umol/L to 81.3umol/L) over the range of bilirubin concentrations tested.The minimum bilirubin was 25 umol/L, and the maximumbilirubin was 361 umol/L (Fig. 2). Although the meandifference (bias) is near zero, the GEM values underesti-mate at low concentrations of bilirubin and overestimate atfit to the data compared to a linear model (F test onEMWang et al. BMC Pediatrics  (2017) 17:92 Page 3 of 7Table 1 Demographic and clinical variables of the 318 uniqueneonatesVariableGestational age (weeks), mean (SD) 38.8 (2.0)Postnatal age (hours), median (IQR)a 48 (24–72)Male gender 167 [53%]Mode of deliveryCS 112 [41%]Vaginal 158 [59%]APGAR at 1 min <7 21 [8%]median (IQR) 9 (8–9)APGAR at 5 min <7 10 [4%]Three hundred and seventy eight samples (86%) were in-cluded in the analysis while 62 samples (14%) were ex-cluded because the instrument reported whole bloodbilirubin and/or co-oximetry results as incalculable.Among these 378 samples (from 318 neonates), 60neonates had multiple bilirubin samples collected. Themean gestational age was 38.8 weeks and median post-natal age was 48 h. In total, 41% of neonates were deliv-ered by CS while 59% were vaginal deliveries. Fifty-threepercent of the study population was male.Passing-bablok regressionThe Passing-Bablok linear regression estimated the sys-tematic difference (intercept) and proportional differ-ence (slope) between the GEM and the VITROS (Fig. 1).ResultsDemographicTable 1 shows the demographic and clinical variables ofthe study population. There were a total of 440 samplesmedian (IQR) 9 (9–9)aFor all samples0 100 200 300 400 5000100VITROS bilirubin ( mol/L)GFig. 1 Comparison of results by Passing-Bablok regression. The solidline indicates the unbiased estimates of the intercept and slope fromchange in deviance, p < 0.001) with an estimated numberof degrees of freedom = 2.8 (p < 0.001). The model fit200300400500 bilirubin (mol/L)Intercept = -61.13 [-73.75 : -50.45]Slope = 1.426 [1.361 :   1.5]higher concentrations, as revealed by the Passing-Bablokregression above.Hemoglobin effects/hemolysis effectsThe total Hb concentration in the study populationranged between 122 g/L to 230 g/L with a mean concen-tration of 195 g/L. No difference was detected in Hbconcentrations between male (Mean: 195.8 g/L, SD =19.8) and female infants (Mean = 195.3 g/L, SD = 18.3).Fig. 3a demonstrates the effect of Hb concentration onthe measurement of whole blood bilirubin using theGEM method. The GEM bilirubin method tended tooverestimate bilirubin when Hb was relatively low andunderestimate it when Hb concentrations were high.The generalized additive model provided a much betterthe regression. The grey indicates the 95%CI around those estimates.The dashed line shows the 1:1 line120 140 160 180 200 220-150-100Coox hemoglobin (g/L)GEM bi50 100 150 200-150-100-50050100150H index (VITROS)GEM bilirubin - VITROS bilirubin (mol/L)bFig. 3 a The hemoglobin effect on the difference between GEMand VITROS: relationship between hemoglobin and the difference inWang et al. BMC Pediatrics  (2017) 17:92 Page 4 of 7suggested that GEM tended to overestimate bilirubinconcentration at Hb concentrations up to 200 g/L atwhich point it begins to strongly underestimate the bili-rubin concentration. Fig. 3b demonstrates the effect ofhemolysis on the measurement of whole blood bilirubinwith the GEM method. Similar to Hb concentration,specimens with more hemolysis demonstrated a greaterunderestimation of bilirubin with the GEM methodologycompared to the VITROS BuBc (slope = −0.4, p < 0.001).Clinical factors contributing to the differences in bilirubinmeasurement between the GEM and VITROS methodsA statistically significant difference in bilirubin levelswas detected between male and female infants. Whenplasma bilirubin was measured using the BuBc slide,male infants had higher levels with an average concen-0 100 200 300 400-200-1000100200GEM bilirubin - VITROS bilirubin (mol/L)GEM bilirubin + VITROS bilirubin2 81.3-0.14-81.6Fig. 2 Bland-Altman plot. The solid line indicates the estimated biasand the dashed lines indicate the 95% limits of agreementtration of 163.5 umol/L and standard deviation of 58.2umol/L than female infants with an average of 143.4umol/L and a standard deviation of 52.1 umol/L(Welch’s t = −3.2, df = 313, p = 0.001). A significant dif-ference in whole blood bilirubin levels between maleand female infants (Welch’s t = −3.2, df = 312.9, p =0.002) was also detected when measured with the GEMmethodology. Similar to the BuBc slide, male infants hadhigher whole blood bilirubin concentrations when com-pared to female infants (162.9 umol/L for male; 136.1umol/L for female) when measured with the GEMmethod. Although method differences were observed ingender specific bilirubin levels, these differences werenot statistically significant.Similarly, we found that there were no significant ef-fects of mode of delivery, gestational age, birth weightand Apgar scores on the difference between the twomethods (data not shown). However, we found thatthere was a significant difference in the mean Hbconcentrations in neonates delivered by CS in comparison-50050100150lirubin - VITROS bilirubin (mol/L)ato those delivered vaginally (Welch's t = −2.86, df = 230.1,p = 0.005). Babies born via CS had lower hemoglobinlevels on average (190.8 g/L vs 197.7 g/L).Sensitivity, specificity, and predictive values for VITROSnomogram vs GEM nomogramWe examined the potential impact on clinical interpret-ation by comparing bilirubin results produced by theGEM versus the VITROS against the Bhutani nomo-gram. Five results from the dataset had to be excludedfrom this analysis because the time of collection was notknown. For comparisons at the >95th percentile level,which would trigger treatment, the sensitivity (truebilirubin estimated by the two methods. The solid line indicates theadditive model fit, and the dashed lines indicate the 95% confidenceintervals. b. The hemolysis effect on the difference between GEMand VITROS: relationship between hemolysis (H index) and thedifference in bilirubin estimated by the two methods. The solidline indicates the linear model fit, and the dashed lines indicatethe 95% confidence intervalspositive rate) was 65%, specificity (true negative rate)was 84%, positive predictive value (PPV) was 46%, andthe negative predictive value (NPV) was 92% (Table 2);while for comparisons at the <40th percentile whichwould trigger discharge, the sensitivity was 78%, specifi-rate would be problematic for a diagnostic device beingconsidered as a screening tool. We also found thathemolysis can affect the difference between the GEMand the VITROS. Since all whole blood samples have tobe hemolyzed before co-oximetry analysis, it is puzzlingmS reeWang et al. BMC Pediatrics  (2017) 17:92 Page 5 of 7city was 79%, PPV was 61%, and NPV was 90%(Table 3).DiscussionThis clinical study compared the bilirubin measurementsbetween the whole blood GEM methodology and theplasma VITROS BuBc slide methodology in healthynewborns with capillary samples. We found an imperfectcorrelation between TwB and neonatal bilirubin suchthat bilirubin levels were underestimated at low concen-trations by the GEM method while at concentrationsgreater than 142 umol/L, the GEM method tended tooverestimate relative to the VITROS method. Whenclassifying the risks for neonatal hyperbilirubinemiabased on the Bhutani nomogram with these twomethods, GEM exhibited low sensitivity and low positivepredictive value in comparison to VITROS. Many factorsincluding pre-analytical, analytical and clinical may havecontributed to the observed differences between themethods.First, although TwB is measured, the instrument re-ports plasma equivalent bilirubin using a calculation thatrelies on the measurement of Hb. While this conversionfacilitates comparison with the Bhutani nomogram forrisk stratification, inaccurate Hb leads to inaccurateplasma equivalent bilirubin results. Additionally, TwBwas unreportable in 14% of samples because Hb wasoutside of the manufacturer’s claimed measurable range(30 g/L - 230 g/L). This observation could be related tothe methodology used by the GEM to measure Hb orpre-analytical factors such as microclot formation due topoor sample mixing which may have affected the accur-acy of the co-oximetry with falsely high Hb results.Interestingly, we did find that healthy term newbornswithin the first 2 days of life have higher normal Hblevels up to 239 g/L [8]. Neonatal Hb levels may be evenhigher due to polycythemia or other conditions and thiswill definitely challenge the analytical range of Hb by theGEM methodology (upper analytical range is 230 g/L).Specimens with Hb exceeding the 230 g/L will lead to afailure in generating a bilirubin result and a high failureTable 2 GEM results of >95th percentile on the Bhutani nomograVITROPositivGEM results Positive (treatment) 42 (truNegative (no treatment) 23 (false65why hemolysis can affect accuracy. Based on the similartrends observed for both hemoglobin effect and hemolysiseffect, we postulate this is just another reflection that highHb concentration in the hemolyzed specimen can affectaccuracy.Second, the difference between results by the twomethods might be related to differences in calibration.The GEM bilirubin is calibrated to total bilirubin,whereas the BuBc slides on the VITROS is calibrated tothe respective fractions. Two tests are available fromOrtho Diagnostics: neonatal bilirubin (BuBc) and totalbilirubin (TBIL) [9], with BuBc being recommended fortesting in neonates under 2 weeks of age and TBIL forpatients 15 days old and above by the manufacturer [9].The sum of Bu and Bc is not the same as total bilirubinbecause the latter contains not only Bu and Bc, but alsodelta bilirubin which is a bilirubin covalently boundedwith albumin. Due to the lack of interference by Hb[10], the simultaneous measurement of Bu and Bc, andthe absence of a clinically significant difference betweenBuBc and total bilirubin measurements in newborns (ne-onates have <2% delta bilirubin) [11, 12], we only offerBuBc in our hospital to avoid clinician confusion. Com-mercial calibrators used by field methods are known toaffect the accuracy of bilirubin measurements on chem-istry analyzers [13] and the clinical impact by differentcalibrators has been published recently. Kuzniewicz et al.[14] reported that the recalibration of the BuBc methodby the manufacturer in 2012 led to a 39% relative reduc-tion in infants with a TSB level of 257 umol/L and morethan 50% reduction in both birth hospital phototherapyand readmissions for phototherapy. Similarly, the imple-mentation of a new formulation of total bilirubin byanother manufacturer (Roche diagnostics) also affectedneonatal phototherapy rates even compared to its previ-ous formulation [15]. Our comparison of GEM total bili-rubin to BuBc instead of TBIL would add anotherchallenge for the comparison with the whole blood bili-rubin method by GEM. Standardization is needed for allbilirubin methods, which would improve the care forneonatal hyperbilirubinemia and allow for neonates tocompared to VITROS results of >95th percentileesults Totals(treatment) Negative (no treatment)positives) 50 (false positives) 92negatives) 258 (true negatives) 281308mS rveuelseWang et al. BMC Pediatrics  (2017) 17:92 Page 6 of 7be monitored using different methods during the courseof their disease.We also analyzed possible contributing clinical factorsto the observed differences in the methods and found asignificant difference between methods for male andfemale infants. Additionally, we found that male infantshad higher bilirubin levels than female infants in ourpatient population, which supports a previous reportthat male gender is associated with a higher risk ofdeveloping hyperbilirubinemia [16]. This suggests thatthe relationship between the difference in the methodsand infant sex was at least partially driven by the rela-tionship between average bilirubin levels and infant sex.For comparisons at the >95th percentile level whichwould trigger treatment, sensitivity and PPV were 65and 46%, respectively. These results suggest that hadGEM bilirubin been used as the screening tool for riskstratification based on the Bhutani nomogram, 35% ofneonates that would have been treated by VITROS re-sults would not have been treated by the GEM results.Similarly, for low risk neonates (<40th percentile), whocan be safely discharged, the sensitivity and PPV were 78and 61%, respectively. This suggests that only 61% ofthose low-risk levels by GEM would be classified as low-risk by VITROS. These results support the conclusionthat GEM bilirubin is neither sensitive nor specificenough to screen for neonatal hyperbilirubinemia.Finally, we found that neonates delivered by CS hadlower Hb concentrations than neonates delivered vagi-nally. This is consistent with the previous finding thatneonates post vaginal deliveries have higher hemoglobinlevels which could be due to the recommendation of de-layed cord clamping which increases placental-fetaltransfusion [17], whereas the duration of placental trans-fusion in CS tends to be shorter since an immediatecord clamping is often performed to avoid maternalTable 3 GEM results of <40th percentile on the Bhutani nomograVITROPositiGEM results Positive (discharge) 87 (trNegative (no discharge) 24 (fa111bleeding, infections or other surgery-related complica-tions [18]. A systematic review and meta-analysis studyalso indicated that CS compared with vaginal delivery,was associated with an increased placental residualblood volume which would cause a decreased level ofhematological indices including hemoglobins in the neo-nates [19]. These interesting findings could be achieved inthis study because of the availability of Hb measurementsby whole blood gas analyzers. This is extremely usefulwhen caring for babies with hyperbilirubinemia due tohemolytic causes as simultaneous availability of wholeblood bilirubin and Hb results would reduce the totalblood volume and time needed for both tests in the lab.ConclusionsThis study suggests that TwB by the GEM is not yet readyfor neonatal hyperbilirubinemia screening. Handling thedifficult matrix of whole blood samples from newbornsrequires technological improvements to control pre-analytical and analytical variables. Ultimately, improvementof total bilirubin calibration with standardization and theaccuracy of Hb measurements will help TwB becomeutilized clinically. With technical improvement, we believewhole blood bilirubin has the potential to become a validscreening tool considering the benefits of having additionalanalytes especially hemoglobin.AbbreviationsBc: Conjugated bilirubin; Bu: Unconjugated bilirubin; CS: Caesarean section;GEM: GEM Premier 4000® blood gas analyzer; Hb: Hemoglobin; Hct: Hematocrit;TSB: Total serum bilirubin; TwB: Whole blood bilirubin; VITROS: VITROS 5600®AcknowledgementsWe gratefully acknowledge the mentorship of Dr. Cathy Halstead and thekeen assistance of the medical laboratory technologists and assistants of thechemistry lab, especially Ms. Leslie Trowski. We also thank Michelle Dittrickfor REB application and two nursing students: Abraham Cabaccang & AnitaWong for collecting demographic data of the study.FundingNo internal or external funding for this manuscript.Availability of data and materialsThe datasets used and/or analysed during the current study available fromthe corresponding author on reasonable request.Authors’ contributionsLW conceptualized and designed the study, drafted the initial manuscript, andapproved the final manuscript as submitted; AA carried out the initial analyses,reviewed and revised the manuscript, and approved the final manuscript assubmitted; BJ, KH and ML were involved in the interpretation of data, revisingthe manuscript and approved the final manuscript as submitted; MB designedcompared to VITROS results of >95th percentileesults Totals(discharge) Negative (no discharge)positives) 55 (false positives) 142negatives) 207 (true negatives) 231262the data collection sheets, coordinated and supervised data collection, criticallyreviewed the manuscript, and approved the final manuscript as submitted.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateThis study was approved by the Research Ethics Committee of the Universityof British Columbia (H13-02615). Consent was not required as this was aquality assessment project in the lab and no additional blood was drawn.TechDocSearch.aspx?tID=0&culture=en-ca. Accessed 4 Nov 2016.•  We accept pre-submission inquiries Submit your next manuscript to BioMed Central and we will help you at every step:Wang et al. BMC Pediatrics  (2017) 17:92 Page 7 of 710. Lo SF, Jendrzejczak B, Doumas BT. Total or neonatal bilirubin assays in theVitros 5,1 FS: hemoglobin interference, hemolysis, icterus index. Clin Chem.2007;53(4):799–800.11. Langbaum ME, Farber SJ, Rosenthal P. Automated total and neonatalbilirubin values in newborns: is a distinction clinically relevant? Clin Chem.1992;38(9):1690–3.12. Brett EM, Hicks JM, Powers DM, Rand RN. Delta bilirubin in serum of pediatricpatients: correlations with age and disease. Clin Chem. 1984;30(9):1561–4.13. Lo SF, Doumas BT. The status of bilirubin measurements in U.S. laboratories:why is accuracy elusive? Semin Perinatol. 2011;35(3):141–7.14. Kuzniewicz MW, Greene DN, Walsh EM, McCulloch CE, Newman TB.Association between laboratory calibration of a serum bilirubin assay,neonatal bilirubin levels, and phototherapy use. JAMA Pediatr.2016;170(6):557–61.15. Lyon ME, Baerg KL, Olson TN, Agnew BL, Smith-Fehr JC, Lyon AW. Theclinical impact of implementing the Roche® bilirubin total Gen.3 method onneonate phototherapy. Clin Biochem. 2015;48(16–17):1171–3.16. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and preventionof extreme neonatal hyperbilirubinemia in a mature health maintenanceorganization. Arch Pediatr Adolesc Med. 2000;154(11):1140–7.17. World Health Organization. WHO recommendations for the prevention andPublisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1BC Children’s & Women’s Hospital, University of British Columbia, 4500 OakStreet, Room 2J9, Vancouver, BC V6H 3 N1, Canada. 2Women’s HealthResearch Institute, Children’s and Women’s Health Centre of BritishColumbia, University of British Columbia, Vancouver, Canada. 3Department ofPediatrics, Children’s and Women’s Health Centre of British Columbia,University of British Columbia, Vancouver, Canada. 4Department of Pathologyand Laboratory Medicine, Royal University Hospital, Saskatoon Health Region,University of Saskatchewan, Saskatoon, Canada. 5Perinatal Health Program,Department of Obstetrics and Gynecology, Children’s and Women’s HealthCentre of British Columbia, University of British Columbia, Vancouver, Canada.6BC Children’s Hospital Research Institute, University of British Columbia,Vancouver, BC, Canada.Received: 7 November 2016 Accepted: 21 March 2017References1. 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Limitations and opportunities of transcutaneous bilirubinmeasurements. Pediatrics. 2012;129(4):689–94.7. Bland JM, Altman DG. Statistical methods for assessing agreement betweentwo methods of clinical measurement. Lancet. 1986;1(8476):307–10.8. Cousineau J, Anctil S, Carceller A, Gonthier M, Delvin EE. Neonate capillaryblood gas reference values. Clin Biochem. 2005;38(10):905–7.9. VITROS Chemistry Products BuBc Slides, TBIL Slides and BilirubinSupplement [Package inserts]. http://techdocs.orthoclinical.com/TechDocs/treatment of postpartum haemorrhage. http://apps.who.int/iris/bitstream/10665/75411/1/9789241548502_eng.pdf. Accessed 4 Nov 2016.•  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services 18. Shirvani F, Radfar M, Hashemieh M, Soltanzadeh MH, Khaledi H, MogadamMA. Effect of timing of umbilical cord clamp on newborns’ iron status andits relation to delivery type. Arch Iran Med. 2010;13(5):420–5.19. Zhou YB, Li HT, Zhu LP, Liu JM. Impact of cesarean section on placentaltransfusion and iron-related hematological indices in term neonates asystemic review and meta-analysis. Placenta. 2014;35(1):1–8.•  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submit


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