Early Diagnosis of Extrahepatic Biliary Atresia in an
Open-Access Medical System
Justin Hollon1,2*, Matilda Eide1, Gregory Gorman1,3
1Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America, 2Division of Pediatric Gastroenterology
and Nutrition, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 3Department of Pediatrics, Walter Reed National Military
Medical Center, Bethesda, Maryland, United States of America
Introduction: Biliary atresia (BA) is the most common cause of cholestatic jaundice in infancy. Early diagnosis and surgical
management, ideally before 60 days of age, result in improved outcomes. We aimed to determine the age at diagnosis of
BA in the Military Health System (MHS) and to compare the age at diagnosis by access to care models. We hypothesized that
children with BA receiving primary care in military facilities have an earlier age at diagnosis due to decreased economic and
Methods: Data for all Tricare enrollees born in fiscal years 2004–2008 with a diagnosis of BA were extracted from MHS
databases. Non-parametric tests, Kaplan-Meier curves and log rank tests compared differences in age at diagnosis by type of
primary care facility, gender, prematurity and presence of additional anomalies.
Results: 64 subjects were identified within the five year period. Median age at diagnosis was 40 days [range 1–189], with
67% diagnosed by 60 days and 80% by 90 days. 45 (70%) received civilian primary care within the MHS. There was no
difference in the median age at diagnosis between subjects in the MHS with civilian primary care vs. military primary care
(37 days [1–188] vs. 46 days [1–189]; p=0.58).
Conclusion: In the MHS, two-thirds of infants with biliary atresia are diagnosed prior to 60 days of life. Gender, prematurity
or presence of additional anomalies do not affect the timing of diagnosis. Civilian and military primary care models within
the MHS make timely diagnoses of biliary atresia at equivalent rates.
Citation: Hollon J, Eide M, Gorman G (2012) Early Diagnosis of Extrahepatic Biliary Atresia in an Open-Access Medical System. PLoS ONE 7(11): e49643.
Editor: John E. Mendelson, California Pacific Medical Center Research Institute, United States of America
Received June 18, 2012; Accepted October 16, 2012; Published November 20, 2012
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: These authors have no support or funding to report.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Cholestatic jaundice in the newborn period is a marker of
hepatobiliary dysfunction that necessitates a timely work-up and
diagnosis. The most common cause of cholestatic jaundice in the
first months of life, and the major indication for pediatric liver
transplantation, is biliary atresia (BA), a condition characterized by
an inflammatory obliteration of the extrahepatic biliary system.
The incidence of BA in the US is 1 in 12,000–14,000 live births
[1,2]. Infants may appear healthy with normal birthweight and
appropriate weight gain until this sclerosing process eventually
leads to signs of progressive disease, such as hepatomegaly, ascites,
wasting and coagulopathy. Early diagnosis is essential in order to
maximize the survival of the infant’s native liver . Early
detection of BA permits surgical repair by the Kasai portoenter-
ostomy, which can restore bile flow, prevent further biliary
cirrhosis and worsening liver disease and prevent or at least delay
liver transplantation . It has been well established that the
earlier the Kasai procedure is performed, the better the outcome,
with the goal to perform this surgical procedure before 45 to 60
days of age [5–7].
Access to medical care before this 45–60 day mark is critical to
making the diagnosis of biliary atresia. However, the relationship
between the timing of BA diagnosis and access to medical care has
not been studied. This may be particularly important in the U.S.
where the routine pediatric well-baby schedule does not include a
scheduled visit between 2 and 8 weeks of age. Economics and
overall access may play a significant role in influencing whether
parents seek care between these standard scheduled visits.
The U.S. Military Health System provides an open access
medical system to all of its active duty members and their family
members free of charge at its Military Treatment Facilities (MTF).
MTFs are typically located on or near a military base and
capabilities range from acute care clinics to tertiary care medical
centers. Beneficiaries may also opt into several health plans
administered by the MHS that allow them to receive care at
civilian facilities at a small financial cost, for instance through a
managed care plan that requires copayments for each visit. With
over 9.3 million beneficiaries in a system that theoretically
eliminates economic barriers to access, the MHS has served as
the study population in several studies evaluating how ready access
to healthcare affects the prevalence, stage at diagnosis and
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predictive survival of specific diseases [8–10]. However, none have
looked at diseases affecting infants. In this study, we aim to see if
those patients with a diagnosis of biliary atresia who receive care at
military treatment facilities have a younger age of diagnosis than
those who receive their primary care at civilian facilities.
This was a minimal risk retrospective study approved by the
Uniformed Services University Institutional Review Board. Data
were analyzed anonymously using a pre-existing database of
clinical, financial and beneficiary information for MHS opera-
tions. Included subjects were identified using the Standard
Ambulatory Data Record (SADR), Standard Inpatient Data
Record (SIDR) and outpatient and inpatient purchased care
claims databases. These databases, collectively called the M2
Database, contain health care data, such as diagnostic coding, for
all military beneficiaries worldwide and include data from both
military and civilian treatment facilities. Using the International
Classification of Diseases, 9th Revision (ICD-9) code for BA
(751.61), all subjects born in fiscal years (FY) 2004–2008 who had
BA diagnosis prior to 30 May 2009 were included. All military and
civilian facility visits for these subjects were extracted from the M2
database from FY 2004 to 30 May 2009. In order to capture only
those patients born within the MHS, only those seen within the
MHS prior to 21 days of life for any reason were included. To
adjust for so-called ‘rule-out coding’, in which patients are coded
at an outpatient visit with the possible or suspected diagnosis,
rather than the symptom for which further testing or consultation
was ordered (e.g. cholestasis), subjects needed at least one inpatient
admission or two outpatient visits coded for BA to be considered to
carry a diagnosis of BA and remain within the study. This
inclusion criteria is identical to that used by the Department of
Defense Birth and Infant Health Registry in the 2008 Congenital
Malformation Surveillance Report , and recognizes that, as a
chronic condition, true BA patients continue to necessitate follow-
up care and monitoring irrespective of surgical repair. The age at
first diagnosis was defined as the earliest occurrence of an inpatient
or outpatient encounter coded as BA. Any subjects with an age of
first diagnosis greater than 365 days of life were excluded as
presumed misdiagnoses or as subjects with missing data.
Subjects’ place of primary care was classified as military or
civilian by the type of facility providing the majority of primary
care visits prior to BA diagnosis. Subjects were classified as
premature if they were diagnosed with ICD-9 codes 765.21–
765.28 (,37 weeks of gestation). Additional congenital anomalies
were assessed by searching subjects’ records for ICD-9 codes
740.0–759.9. As the ductus arteriosus may physiologically be open
at birth and, furthermore, some mild persistent patency may be
associated with immaturity at birth, patent ductus arteriosus (ICD-
9 747.0) was not included as a congenital anomaly for purposes of
comparison. Non-parametric tests, Kaplan-Meier curves and log
rank tests compared differences in the ages at diagnosis by type of
primary care facility, as well as by gender, gestational age, and
presence of additional anomalies. As race data were not available
for the majority of subjects it was not included as data for
Multivariate proportional hazards modeling was performed to
determine the effect of confounding variables. Tests of propor-
tional-hazards assumptions were performed using Schoenfeld
residuals. Post-hoc power analysis to determine the minimum
detectable difference was performed to gauge the chance of a type
II error using a power of 0.8. Significance was defined as p-
values,0.05. All analyses were conducted with Stata Intercooled
10 (Statacorp, College Station, TX).
134 children with ICD-9 code 751.61 for BA were born in the
five-year study period of FY 2004–2008. Of these, 64 subjects met
the inclusion criteria. Details of the exclusion process are shown in
Figure 1. Table 1 shows the characteristics of included subjects
and their distribution by FY. Of the 64 subjects, 17 (27%) were
identified as having additional congenital anomalies. Table 2
shows the occurrence of additional anomalies, with the majority
(14 of the 17; 82%) having non-PDA congenital heart disease. The
most prevalent BA-associated congenital heart defect in this
population was a secundum ASD, with 11 of the 14 (79%) having
this diagnosis. Just over half (9 of the 17) of these subjects had non-
BA gastrointestinal disease, such as small intestinal atresia. One
subject had spina bifida and one subject had trisomy 13.
The median age of diagnosis of BA in the MHS was 40 days
(range of 1–189), with 67% of subjects diagnosed by 60 days of age
and 80% diagnosed by 90 days of age (Figure 2). There was no
significant difference in median age at diagnosis between those
with civilian primary care and those followed at military treatment
facilities (37 days [1–188] vs. 46 days [1–189]; p=0.58). Likewise,
there were no differences in median age at diagnosis when
examining other comparison groups. The median age at diagnosis
for males vs. females was 30 days [1–188] vs. 49 days [1–189];
p=0.075. Premature infants were diagnosed at a median age of 37
days [1–128] compared to term infants who had a median age of
diagnosis of 41 days [1–189]; p=1. Subjects who had congenital
anomalies in addition to BA had a median age of diagnosis of 30
days [1–189] compared to 43 days [1–188] for those with biliary
atresia alone (p=0.57). Median age of diagnosis by FY was 43 [1–
188] for 2004, 50 [2–126] for 2005, 23 [1–189] for 2006, 31 [2–
128] for 2007 and 29 [1–123] for 2008 (p=0.67).
Post-hoc power analysis determined that the minimum detect-
able hazard ratio for the sample was 0.5.
Log-rank tests of cumulative time to diagnosis showed no
significant difference by type of primary care facility (p=0.12)
(Figure 3), gender (p=0.19), prematurity (p=0.95), or presence of
additional anomalies (p=0.86).
In multivariate proportional hazards modeling of the effect of
the primary care model adjusted for prematurity, gender, and the
presence of additional congenital anomalies, there was no
significance in earlier diagnosis in care provided by civilian vs.
military providers (HR 1.45 [95%CI 0.81–2.6; p=0.21]).
Likewise, there was no significant difference in time to diagnosis
by gender or the presence of anomalies in multivariate models.
Hazard ratio estimates of the model are shown in Table 3.
Early detection of BA permits surgical repair by the Kasai
portoenterostomy. In the industrial world, the median age at Kasai
operation is between 54 and 69 days of age . Unfortunately,
even with a successful Kasai, more than 70% of children
eventually develop cirrhosis and require liver transplantation prior
to adulthood, but much of this depends on age of surgery . In
a retrospective analysis of 349 Canadian patients treated with the
Kasai procedure, those who had surgery at,than 30 days of age
had a 52% survival of the native liver vs. a 21% survival rate for
those who underwent surgery at.90 days of age .
For the primary care clinician, improving the age of diagnosis is
akin to improving the prognosis of the Kasai. To this aim, parent
education on the signs and symptoms of BA, particularly acholic
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stools, has been a major focus in many countries [14,15]. In
Taiwan, an infant stool color card is sent home with every neonate
to educate parents on the importance of acholic stools and increase
the rate of early self-referral. A recent study credits this card
program for increasing the rate of detection before 60 days of age
to 72.5% in 2004 (start of program) and 97.1% in 2005, with
subsequent age at Kasai before 60 days of age improving from
23.3% (1976–1989 historical data) to 60% in 2004 and 74.3% in
2005 . What’s not mentioned in this study is Taiwan’s
establishment of National Health Insurance (NHI) in 1995, prior
to which 41% of the population was uninsured . With a
concomitant dramatic increase in childhood immunizations since
NHI implementation , one must wonder if greater access to
care in this population has also strongly contributed to the
increased rate of BA detection from pre to post–NHI years.
In the MHS, where all active duty members and their families
have access to medical care, two-thirds of infants with biliary
atresia were diagnosed prior to 60 days of life. Despite the
economic differences in receiving primary care at a civilian facility
versus a military treatment facility, there was no difference in
median age at BA diagnosis by access to care models, with timely
diagnoses of biliary atresia made at equivalent rates. The median
age of diagnosis of BA in the MHS was 40 days of age, ranging
from 1 to 189 days, with no significant change in age of diagnosis
Figure 1. Exclusion algorithm for identification of biliary atresia patients in the MHS. MHS=Military Health System; BA=Biliary Atresia.
Table 1. Demographics and distribution by fiscal year (FY) of
all 64 biliary atresia born in the military health system FY
Civilian primary care45 (70)
Male 38 (59)
Additional anomalies17 (27)
Born in FY:
2004 21 (33)
2005 13 (20)
2007 8 (13)
2008 7 (11)
Table 2. Occurrence of additional congenital anomalies
among the 64 biliary atresia patients.
n (% of total study
Additional congenital anomalies17 (27)
Non-PDA congenital heart disease14 (22)
Secundum ASD 11 (17)
Tetralogy of Fallot1 (2)
Coarctation of aorta1 (2)
Anomalous pulmonary artery1 (2)
Ebstein’s anomaly1 (2)
Non-BA Gastrointestinal Disease9 (14)
Small intestinal atresia4 (6)
Abdominal wall defect1 (2)
Pyloric stenosis1 (2)
PDA=Patent Ductus Arteriosus; ASD=Atrial Septal Defect; BA=Biliary Atresia.
Biliary Atresia in an Open-Access Medical System
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from 2004 to 2008. Comparing this age of diagnosis to data from
the US purchased care system may help uncover any influence
healthcare access has on age of diagnosis within this country.
Median age at diagnosis has been recently reported for the 55
patients who underwent a Kasai Procedure for BA at the St Louis
Children’s Hospital from 1990–2004 . The overall median age
at diagnosis was 60 days, with the breakdown by 5-year time
period demonstrating a worsening trend toward increasing age.
Median age at diagnosis from 1990 to 1994 was 48.5 days,
increasing to 60 days from 1995 to 19999 and 69 days from 2000
to 2004. The difference in median age was significant (p,0.1)
comparing those diagnosed from the 1990–1994 period to the
more recent 2000–2004 subjects. In 2006, The Biliary Atresia
Research Consortium (BARC) studied 104 infants who underwent
Figure 2. Cumulative prevalence of documented biliary atresia within the Military Health System by age at diagnosis.
Figure 3. Cumulative prevalence of documented biliary atresia within the Military Health System by primary care model.
Biliary Atresia in an Open-Access Medical System
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Kasai Procedure between 1997 and 2000 at 9 clinical centers and
demonstrated a mean age at initial evaluation of 53 days, with
mean age at surgery of 61 days .
Comparing our data to that from within the U.S. purchased
care system implies that BA is diagnosed at an earlier age in the
MHS. However, there are a number of differences between these
studies that make a direct comparison difficult. For example, the St
Louis study defines age at diagnosis as the age that subjects
underwent Kasai. In our study, age at diagnosis was set as the first
date that an inpatient or outpatient encounter was coded as BA,
allowing for the possibility of BA diagnosis before Kasai Procedure
(if performed). This may lead to a comparative earlier median age
in our study when compared to the St Louis study. On the other
hand, both the St Louis study and BARC study looked only at that
subset of patients who underwent Kasai. Not all patients with BA
get this procedure, particularly those who are diagnosed at an
advanced age. As our study includes all patients, regardless of
Kasai Procedure, the median age could easily be advanced when
compared to studies that exclude non-Kasai patients.
There were several limitations to our study. We relied on health
claims data and not direct chart review to identify infants with
biliary atresia. We minimized ascertainment bias by using a
validated algorithm for the identification of infants with congenital
conditions in these health claims data. Despite the relative large
size of the identified sample compared with other studies of biliary
atresia, the sample size was limited to only detect a significant
determinant of an early diagnosis of biliary atresia if the effect size
was twice or one-half of the comparison group. There is the
possibility that primary care model and the other factors
considered in our analysis did significantly impact diagnosis at a
level less than the minimum detectable difference.
As the importance of early age at Kasai Procedure has been
well-established, age at Kasai Procedure was not the focus of this
study. However, a limitation of our study is that the M2 database
inpatient procedure codes were significantly lacking, making
further analysis of our data by presence or absence of Kasai
Procedure not possible. There were other limitations secondary to
the M2 database data-mining process. Whereas the BARC study
found differences in age at Kasai by race and ethnicity, with non-
Hispanic whites being more likely to undergo Kasai by 60 days of
life , the significant absence of race data in our subject
population precluded comparison of age at diagnosis by this
Gender, prematurity or presence of additional anomalies did
not affect the timing of BA diagnosis in the MHS. In the BARC
study, 26 of the total 104 patients (25%) had additional congenital
anomalies identified, 11 of which were identified as having Biliary
Atresia Splenic Malformation Syndrome (BASM) . Those with
BASM were found to undergo evaluation and Kasai at an earlier
age, although the great majority of them had a poor outcome.
None of our patients had ICD-9 diagnostic codes for spleen
anomalies (i.e. polysplenia or other splenic malformations),
implying that there were no cases of BASM in our study
population; however this could be the result of incomplete coding.
We did not examine mortality data and cannot establish whether
or not patients with additional anomalies have a worse prognosis
than those without.
We were unable to reliably determine the total number of births
within the MHS during our study period, making any attempt at
annual incidence or overall incidence inaccurate. The Department
of Defense Birth and Infant Health Registry  published their
total five year rate of BA for 2001–2005 as 1.37 per 10,000, with a
total of 65 BA patients over this five year period. Unfortunately,
there is no distribution by year in this report. Our data is drawn
from FY 2004–2008, with a total of 64 BA subjects. Examining the
distribution by FY in Table 2, there is a decreasing number of BA
diagnoses with subsequent years, yet we cannot determine if this is
a change in overall incidence or a reflection of decreased total
births during this time period.
Our study design was not able to make causal inferences about
the effect of the determinants considered on timely BA diagnosis.
Primary care systems in the U.S. are complex systems with
national, family, and individual patient level contributors to
outcomes. As such, our study was designed to detect associations
only to provide insight into possible causal determinants.
The strengths of this study derive from the large study
population in an open access health care system that minimizes
economic health care disparities. The population also has the
option of having their medical care in 2 parallel systems – one
provided by civilian providers and one provided by military
providers – that allows additional comparisons by type of access
Timely diagnoses of biliary atresia (BA) are made in an open
access medical system with a fully insured population. The
majority of infants with biliary atresia are diagnosed prior to 60
days of age, when the success of a Kasai procedure is highest.
Military and civilian primary care providers make timely BA
diagnoses at equivalent rates within the same open-access system.
Presence of prematurity, co-existent congenital anomalies, and
gender do not influence the timing of BA diagnoses. Fully insured
infants in open-access health care systems appear to be diagnosed
approximately 2 weeks earlier than in traditional health care
systems. Nevertheless, a sizeable portion of our study population
(20%) had diagnosis beyond 90 days of age. Efforts must continue
to be made to eliminate delayed diagnosis in order to improve
success of Kasai and reduce the necessity of liver transplantation.
Further studies directly comparing infants in competing health-
care delivery systems should be conducted and efforts made to
identify factors that may be contributing to delayed diagnosis in
subjects with advanced age at BA diagnosis.
The views expressed in this manuscript are those of the authors and do not
necessarily reflect the official policy or position of the Department of the
Table 3. Hazard ratios of time to diagnosis of biliary atresia
by type of primary care model within the Military Health
HR (95% CI)p-value
Civilian vs. Military PC1.48 [0.83–2.63] 0.19
Civilian vs. Military PC 1.46 [0.81–2.57] 0.21
Male vs. Female 1.45 [0.85–2.50] 0.18
Test of proportional hazards assumption p-value=0.78.
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