Research

Original Investigation

Association Between Laboratory Calibration

of a Serum Bilirubin Assay, Neonatal Bilirubin Levels,
and Phototherapy Use
Michael W. Kuzniewicz, MD, MPH; Dina N. Greene, PhD; Eileen M. Walsh, RN, MPH;
Charles E. McCulloch, PhD; Thomas B. Newman, MD, MPH

Editorial page 529

IMPORTANCE The American Academy of Pediatrics treatment recommendations for neonatal Journal Club Slides at
jaundice are based on age-specific total serum bilirubin (TSB) levels. In May 2012, Ortho jamapediatrics.com
Clinical Diagnostics adjusted the calibrator values for Vitros Chemistry Products BuBc Slides
CME Quiz at
(Ortho Clinical Diagnostics), a widely used method to quantify TSB, after concerns of
jamanetworkcme.com and
positively biased results. CME Questions page 627

OBJECTIVE To investigate the association between recalibration of a reflectance

spectrophotometry serum bilirubin assay and TSB levels and phototherapy use among
newborns.

DESIGN, SETTING, AND PARTICIPANTS Descriptive study comparing TSB levels and
phototherapy use before and after recalibration at Kaiser Permanente Northern California,
a large, integrated health care delivery system. The study evaluated live births at or after 35
weeks’ gestation at 12 facilities that used universal serum bilirubin screening before (January
1, 2010, through April 30, 2012; n = 61 677) and after (July 1, 2012, through December 31,
2013; n = 42 571) recalibration. The analysis took place in December 2015.

INTERVENTION Recalibration of bilirubin testing instruments.

MAIN OUTCOMES AND MEASURES Proportions of newborns with (1) at least 1 TSB value at or
above 15 mg/dL; (2) at least 1 TSB level exceeding the American Academy of Pediatrics
phototherapy threshold; (3) phototherapy during the birth hospitalization; and (4) at least
1 readmission for phototherapy.

RESULTS In 104 420 infants (61 677 in the prerecalibration period and 42 511 in the
postrecalibration period), a TSB was obtained in 99.2% of infants during birth and in 99.5%
of infants within the first 30 days after birth. The postrecalibration period was associated
with a 1.25 mg/dL (95% CI, 1.19-1.31; P < .001) decrease in mean maximum TSB, which led to
a 39% relative reduction (from 20.4% to 12.4%) in infants with a TSB level of 15 mg/dL or
more and a 51% relative reduction (from 9.3% to 4.5%) in infants with a TSB level that was
Author Affiliations: Division of
at or above the American Academy of Pediatrics phototherapy threshold. Phototherapy Research, Kaiser Permanente
during birth hospitalizations was reduced by 59% (absolute risk reduction, 5.5%; 95% CI, Northern California, Oakland
4.7%-6.1%) and readmissions for phototherapy by 53% (absolute risk reduction, 1.8%; (Kuzniewicz, Walsh, Newman);
Division of Neonatology, Kaiser
95% CI, 1.4%-2.3%). Permanente Northern California,
Oakland, California (Kuzniewicz);
CONCLUSIONS AND RELEVANCE Modest recalibration-induced reductions in mean TSB Department of Pediatrics, University
of California, San Francisco
concentrations was associated with a significant reduction in the percentage of infants
(Kuzniewicz, Newman); Department
with clinically significant hyperbilirubinemia. Current laboratory accuracy standards are of Laboratory Medicine, University of
insufficient to detect biases that can have significant clinical effect. These data underline the Washington, Seattle (Greene);
need for increased integration of laboratory expertise into clinical guidelines and to support Department of Epidemiology and
Biostatistics, University of California,
international initiatives to standardize laboratory measurements.
San Francisco (McCulloch, Newman).
Corresponding Author: Michael W.
Kuzniewicz, MD, MPH, Division of
Research, Kaiser Permanente
Northern California, 2000 Broadway
JAMA Pediatr. 2016;170(6):557-561. doi:10.1001/jamapediatrics.2015.4944 Ave, Oakland, CA 94612
Published online April 11, 2016. (michael.w.kuzniewicz@kp.org).

(Reprinted) 557

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 Research Original Investigation
T
he American Academy of Pediatrics (AAP) treatment rec-
ommendations for neonatal jaundice are based on age-
specific total serum bilirubin (TSB) levels.1 In the 1960s,
variability in TSB concentrations across methods led to the for-
mation of a joint committee between the AAP, the College of
American Pathologists, the American Association for Clinical
Chemistry, and the National Institutes of Health to develop rec-
ommendations for a uniform bilirubin standard.2-5 A stan-
dard reference material, 916 bilirubin, was developed by the
National Institute of Standards and Technology in the 1970s,
and a reference method for the determination of TSB was pub-
lished in 1985.6-8
The Vitros BuBc Neonatal Bilirubin assay (Ortho Clinical
Diagnostics) is one of only a few commercially available re-
flectance spectrophotometry assays for measuring serum bil-
irubin in the clinical laboratory.9,10 The instrument provides
2 measured and 1 calculated result per sample: unconjugated
bilirubin, conjugated bilirubin, and the sum of the 1 (uncon-
jugated bilirubin + conjugated bilirubin = TSB). On May 21,
2012, Ortho Clinical Diagnostics notified customers that it had
“received customer complaints of positively biased results
using Vitros … BuBc Slides for CAP [College of American Pa-
thologists] proficiency testing.” Based on customer input and
an internal investigation, Ortho Clinical Diagnostics re-
sponded by adjusting the calibrator values for Vitros BuBc
Slides. The company predicted an average reduction in un-
conjugated bilirubin values of 0.1 to 2.16 mg/dL (to convert to
micromoles per liter, multiply by 17.104), depending on the con-
centration range of the unconjugated bilirubin.
The objective of this study was to investigate the clinical
effect of this recalibration on maximum TSB levels and pho-
totherapy use in Kaiser Permanente Northern California
(KPNC), a large, integrated health care delivery system.
Methods
This was a descriptive study of all live births at or after 35 weeks’
gestation between January 2010 and December 2013 at 12 KPNC
facilities that used universal bilirubin screening with a TSB prior
to discharge.11 The analysis took place in December 2015.
From existing KPNC databases, we obtained all TSB values
from each infant’s first month after birth by using previously de-
scribed methods.11,12 We used each infant's maximum TSB value
and also compared each TSB value with the 2004 AAP photo-
therapy guideline, based on hour-specific TSB value, gestational
age, and direct antiglobulin test result13,14 and used each infant’s
highest TSB value in relation to the guideline. The KPNC insti-
tutional review board and the University of California, San Fran-
cisco Committee on Human Research approved this study.
Informed consent was waived because this study had no direct
patient contact and minimal risk to the patients.
Phototherapy was defined by a birth hospitalization or re-
admission with either an International Classification of Diseases,
Ninth Revision code for phototherapy (99.83) and an order for
phototherapy in the electronic medical record or an electronic
medical record flowsheet entry for phototherapy. Total serum
bilirubin (unconjugated bilirubin + conjugated bilirubin) was
558 JAMA Pediatrics June 2016 Volume 170, Number 6 (Reprinted)
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Effect of Laboratory Calibration of Neonatal Bilirubin
Key Points
Question How did recalibration of a bilirubin assay affect total
serum bilirubin levels and phototherapy use?
Findings In this large, descriptive study, recalibration resulted in
a signification reduction in percentage of infants with a total serum
bilirubin level of 15 mg/dL or higher or a total serum bilirubin
value at or above the American Academy of Pediatrics
phototherapy threshold. Both birth hospital phototherapy and
readmissions for phototherapy were reduced by more than 50%.
Meaning Calibration shifts in laboratory assays can have
important clinical implications, illustrating the need for increased
integration of laboratory expertise into clinical guidelines and
supporting international initiatives to standardize laboratory
measurements.
quantified using either the Vitros Fusion 5.1 or Vitros 250 accord-
ing to manufacturer instructions using the BuBc slide. Testing
was performed across 21 hospital laboratories using 42 individual
instruments. The hospital laboratories implemented the
manufacturer-adjusted calibrators between May 24, 2012, and
June 13, 2012. We defined the prerecalibration cohort as births
from January 1, 2010, through April 30, 2012, and the postreca-
libration cohort as births from July 1, 2012, through December
31, 2013. One facility transitioned to a different method of mea-
suring TSB on November 19, 2013. Thus, we excluded infants born
at this facility after the change. The outcomes compared between
the cohorts were (1) the percentage of infants with at least 1 TSB
value above 15 mg/dL; (2) the percentage of infants with at least
1 TSB level at or above the AAP phototherapy threshold; (3) the
percentage of infants receiving phototherapy during the birth
hospitalization; and (4) the percentage of infants readmitted for
phototherapy.
We compared basic demographics between the 2 cohorts
using the χ2 test and mean maximum TSB values using the
t test. We compared outcomes between the 2 cohorts using an
autoregressive integrated moving average time-series model
with Stata version 14 (StataCorp). The autoregressive inte-
grated moving average command fits linear regression mod-
els that can accommodate correlated error terms. We fit sepa-
rate models for each of the dependent variables (monthly
percentage of TSB levels ≥15 mg/dL, a TSB level ≥AAP photo-
therapy threshold, phototherapy during the birth hospitaliza-
tion, and readmission for phototherapy) with an indepen-
dent variable of prerecalibration vs postrecalibration. In
sensitivity analyses, we explored the effect of increasing the
autoregressive lag in the autoregressive integrated moving av-
erage model up to order 4 and the effect of including a secu-
lar trend modeled using restricted cubic splines. Addition-
ally, we investigated including May 2012 and June 2012 and
setting the recalibration date as June 1, 2012.
Results
The cohort consisted of 104 428 infants born at or after 35
weeks’ gestation: 61 677 in the prerecalibration period and
jamapediatrics.com
 Effect of Laboratory Calibration of Neonatal Bilirubin
Table 1. Characteristics of Cohort
Prerecalibration Postrecalibration
Characteristic (n = 61 677) (n = 42 571)
Male, No. (%) 31 377 (50.9) 21 724 (51.1)
Race/ethnicity, No. (%)
Asian 12 341 (20.0)
Black 4294 (6.9)
Hispanic 13 625 (22.1)
White 26 012 (42.2) 17 630 (41.4)
Other 5405 (8.7)
Birth weight, mean (SD), g 3397 (500)
SGA (<5th percentile), No. (%) 1099 (1.8)
LGA (>95th percentile), No. (%) 2379 (3.9)
Gestational age, mean (SD), wk 39.4 (1.3)
Preterm (<37 wk), No. (%) 3402 (5.5)
DAT positive, No. (%)a 2151 (5.5)
42 571 in the postrecalibration period. Infants in the 2 periods
were similar in terms of birth weight and percentage born be-
fore 37 weeks’ gestation. In the postrecalibration cohort, there
were more Asian infants and infants of “other” race/
ethnicity. In addition, a lower percentage of infants who were
tested were direct antiglobulin test–positive in the postreca-
libration cohort (Table 1). A TSB was obtained in 99.2% of in-
fants during birth hospitalization and in 99.5% of infants within
the first 30 days after birth. The mean (SD) maximum TSB was
10.1 (4.9) mg/dL in the prerecalibration period and 8.8 (4.5)
mg/dL in the postrecalibration period (absolute difference, 1.25
mg/dL; 95% CI, 1.19-1.31; P < .001).
Monthly rates of phototherapy administration and hyper-
bilirubinemia are shown in the Figure. Hyperbilirubinemia de-
fined by either a maximum TSB level of 15 mg/dL or higher or
1 TSB value at or above AAP phototherapy thresholds dropped
dramatically after recalibration in June 2012. Similarly, both
the monthly rates of phototherapy administration during the
birth hospitalization and readmissions for phototherapy
dropped precipitously in June 2012 and remained lower. Table 2
shows the TSB values and rates of phototherapy before and af-
ter recalibration. With recalibration, phototherapy use dur-
ing the birth hospitalization and readmissions for photo-
therapy dropped by more than 50%.
In the autoregressive integrated moving average models,
the postrecalibration period was associated with an 8.0% (95%
CI, 7.1%-8.8%) absolute reduction in infants with a TSB level
at or above 15 mg/dL, a 4.8% (95% CI, 4.1%-5.4%) absolute re-
duction in infants with a TSB level at or above the AAP pho-
totherapy threshold, a 5.5% (95% CI, 5.1%-6.0%) absolute re-
duction in infants receiving phototherapy during the birth
hospitalization, and a 2.0% (95% CI, 1.7%-2.3%) absolute re-
duction in phototherapy readmissions. Sensitivity analyses did
not give appreciably different results.
Adjusting for delivery mode, the postrecalibration pe-
riod was associated with a small but significant reduction in
overall length of stay by 0.08 days during the birth hospital-
ization (95% CI, 0.05-0.1 days). However, in both periods, pho-
totherapy during the birth hospitalization increased length of
stay by more than 2 days (prerecalibration, 2.2 days; 95% CI,
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Original Investigation Research
P Value
.62
8741 (20.6) <.001
2997 (7.0) NA
8614 (20.2) NA
NA
4589 (10.8) NA
3402 (499) .09
693 (1.6) .07
1752 (4.1) .04 Abbreviations: DAT, direct
39.3 (1.3) <.001 antiglobulin test; LGA, large for
gestational age; NA, not applicable;
2479 (5.8) .03
SGA, small for gestational age.
1305 (5.9) .03 a
Among infants who were tested.
2.1-2.3 days vs postrecalibration, 2.5 days; 95% CI, 2.4-2.7 days).
Phototherapy readmission lengths of stay were approxi-
mately 1 day (prerecalibration, 1.30 days; 95% CI, 1.26-1.33 days
vs postrecalibration, 1.17 days; 95% CI, 1.11-1.24 days). The num-
ber of TSB tests sent per patient dropped from 2.65 tests/
infant to 2.20 tests/infant, a difference of 0.45 tests/infant (95%
CI, 0.43-0.48).
Discussion
We observed a large-scale clinical effect of the Vitros BuBc Neo-
natal Bilirubin assay recalibration. Ortho Clinical Diagnostics
predicted an average drop in unconjugated bilirubin values of
approximately 0.1 to 2.16 mg/dL. Our data confirmed that the
mean maximum TSB concentration decreased by 1.25 mg/dL.
We hypothesized that the effect of this decrease on photo-
therapy rates would be clinically significant because many in-
fants have TSB concentrations near the AAP thresholds for
treatment. In the prerecalibration period, 7.3% of infants had
1 or more TSB levels of 0 to 2 mg/dL above the AAP photo-
therapy threshold. Indeed, the use of phototherapy in birth
hospitalizations dropped 59% and readmissions for photo-
therapy dropped 53%. These data demonstrate that seem-
ingly modest systematic reductions in TSB concentrations re-
sulted in a major reduction in the percentage of infants with
clinically significant hyperbilirubinemia. The infants in the 2
times differed slightly, with more Asian infants and infants of
“other” race/ethnicity in the postrecalibration cohort and a
lower percentage of infants with a positive direct antiglobu-
lin test result. Because these race/ethnicity categories were risk
factors for hyperbilirubinemia, this would only serve to at-
tenuate our results. The difference in DAT positivity percent-
age was small.
Recalibration led to a significant reduction in use. We es-
timate for every 10 000 deliveries, recalibration resulted in a
reduction of 1300 patient-days/year (1100 days during the birth
hospitalization and 200 phototherapy readmission days) and
4500 fewer TSB tests/year. Although costs are specific to each
hospital, estimating an inpatient hospitalization day at $1000
(Reprinted) JAMA Pediatrics June 2016 Volume 170, Number 6 559
 Research Original Investigation Effect of Laboratory Calibration of Neonatal Bilirubin

Figure. Monthly Rates of Phototherapy Administration and Hyperbilirubinemia

A Phototherapy during birth hospitalization B Phototherapy readmissions

12 5

10
4
Recalibration
8
Recalibration
3
Infants, %

Infants, %
6

2
4

1
2

0 0
Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan
2010 2011 2012 2013 2014 2010 2011 2012 2013 2014
Year Year
C Total serum bilirubin ≥15 mg/dL D Total serum bilirubin ≥ American Academy of Pediatrics phototherapy threshold

25 15

20 Recalibration

10
15
Infants, %

Infants, %

Recalibration

10
5

0 0
Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan
2010 2011 2012 2013 2014 2010 2011 2012 2013 2014
Year Year

In June 2012, monthly rates of phototherapy administration during the birth hospitalization and readmissions for phototherapy dropped precipitously along with
the percentage of infants with hyperbilirubinemia. To convert bilirubin to micromoles per liter, multiply by 17.104.

Table 2. TSB Levels and Phototherapy Rates

Recalibration Change
Before After
(n = 61 945) (n = 42 665) Absolute Relative P Value
TSB ≥15 mg/dL, No. (%) 12 551 (20.4) 5283(12.4) −8.0 −39 <.001
TSB ≥AAP PT threshold, No. (%)a 5719 (9.3) 1914 (4.5) −4.8 −51 <.001
Birth hospital phototherapy, No. (%) 5823 (9.4) 1663 (3.9) −5.5 −59 <.001
Phototherapy readmissions, No. (%) 2335 (3.8) 762 (1.8) −2.0 −53 <.001
a
Abbreviations: AAP, American Academy of Pediatrics; PT, phototherapy; TSB, American Academy of Pediatrics phototherapy threshold (based on AAP risk
total serum bilirubin. group defined be gestational age and direct antiglobulin testing result).
SI conversion factor: to convert total serum bilirubin to micromoles per liter,
multiply by 17.104.

and the cost of a TSB test and blood draw at $30, recalibration
saved $1.4 million for every 10 000 deliveries. Thus, from Janu-
ary 2010 to April 2012, the excess cost for KPNC was more than
$8 million. At the time of recalibration, approximately 380 labo-
ratories across the United States were enrolled in College of
American Pathologists proficiency testing for neonatal total bil-
irubin using the Vitros assay; our hospital laboratories repre-
sented about 6% of those enrolled. Thus, the overall health care
resources lost to analytical inaccuracy far exceed what was cal-
culated for our health care system. Beyond cost, photo-
therapy often means separating the mother and infant. This
can interfere with breastfeeding and bonding and cause pa-
rental anxiety.15-18
Calibration shifts in laboratory assays can have major clini-
cal implications. While theoretical models can predict these
effects, it is rare to capture the consequential extent of the

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 Effect of Laboratory Calibration of Neonatal Bilirubin Original Investigation Research

changes. This study provides a powerful example of how small
changes in measurement methods can lead to large changes
in diagnosis and treatment. These data highlight 2 main limi-
tations. First, when there is significant interinstrument vari-
ability, guidelines should specify the analytical assays that were
used to determine treatment thresholds. Second, current labo-
ratory accuracy standards (proficiency testing and quality con-
trol monitoring) are insufficient to detect biases that can have
significant clinical effect. The positive bias imposed by the
Vitros BuBc assay was ultimately identified by comparing neo-
natal bilirubin proficiency testing peer group means with those
of other instrument/assays, but the problem was undetected
and under investigation for at least 2 years (Figure) before the
recalibration was implemented.
Conclusions
The data from the Vitros BuBc assay recalibration underline
the need for increased integration of laboratory expertise into
clinical guidelines and to support international initiatives to
standardize laboratory measurements.19

ARTICLE INFORMATION
Accepted for Publication: December 22, 2015.
Published Online: April 11, 2016.
doi:10.1001/jamapediatrics.2015.4944.
Author Contributions: Dr Kuzniewicz had full
access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Kuzniewicz, Newman.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Kuzniewicz.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Kuzniewicz, McCulloch,
Newman.
Obtained funding: Kuzniewicz, Newman.
Administrative, technical, or material support:
Kuzneiwicz, Greene, Walsh.
Study supervision: Kuzniewicz.
Conflict of Interest Disclosures: None reported.
Funding/Support: This project was supported by
grant R01HS020618 from the Agency for
Healthcare Research and Quality.
Role of the Funder/Sponsor: The funding source
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: The content is solely the responsibility
of the authors and does not necessarily represent
the official views of the Agency for Healthcare
Research and Quality.
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