ORIGINAL ARTICLE: HEPATOLOGY AND NUTRITION
Derivation of a Clinical Prediction Rule for the
Noninvasive Diagnosis of Varices in Children


Juan Cristobal Gana, yDan Turner, zEve A. Roberts, and
Simon C. Ling
ABSTRACT
Background and Objectives: Identification of children who are at high risk
for having varices using noninvasive tests would enable the selection of
children for future studies of primary prophylaxis of variceal hemorrhage,
but this has been inadequately studied. The objective of the study was to
derive a noninvasive clinical prediction rule that is able to identify children
with esophageal varices.
Methods: Fifty-one consecutive children with liver disease or portal
hypertension who underwent endoscopy were included in the present
retrospective study. At endoscopy, variceal size was graded on a 4-point
Likert scale. Results of physical examination, blood tests, and abdominal
ultrasound scan (USS) were recorded. Spleen length on USS was expressed
as a standard deviation score (z score). A descriptive univariate analysis was
performed on variables that were potentially associated with esophageal
varices and multivariate logistic regression was then modeled to derive a
clinical prediction rule.
Results: Esophageal varices were found in 17 of the 51 children (33%).
Variables found to differ significantly between children with and without
varices included platelet/spleen-length z score ratio (P < 0.001), platelet
count (P < 0.001), international normalized ratio (P 0.001), aspartate
aminotransferase/alanine aminotransferase ratio (P 0.002), and albumin
(P 0.003). Using multivariate logistic regression, a model with platelet
count, spleen length z score, and albumin as the independent variables had
the best fit. Area under the receiver operating characteristic curve for this
clinical prediction rule was 0.93 (95% confidence interval 0.850.99),
sensitivity 94%, specificity 81%, positive predictive value 0.83, negative
predictive value 0.94, positive likelihood ratio 5, and negative likelihood
ratio 0.06.
Conclusions: This clinical prediction rule is a simple noninvasive measure
that may identify children at high risk for esophageal varices. A prospective
validation study is in progress.
Key Words: clinical predictor rule, esophageal varices, portal hypertension
(JPGN 2010;50: 188193)
Received May 11, 2009; accepted June 18, 2009.


From the Division of Gastroenterology, Hepatology & Nutrition, the
yPediatric Gastroenterology Unit, Shaare Zedek Medical Center, Hebrew
University of Jerusalem, Israel, and the zGenetics and Genome Biology
Program, Hospital for Sick Children Research Institute, Toronto,
Canada.
Address correspondence and reprint requests to Juan Cristobal Gana,
Department of Pediatrics, School of Medicine, Pontificia Universidad
Catolica de Chile, Lira 85, Santiago, Chile (e-mail: jcgana@gmail.
com).
The study was funded by the Canadian Association for the Study of the
Liver.
The authors report no conflicts of interest.
Copyright # 2010 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3181b64437
188
Copyright 2010 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
V ariceal bleeding is among the most serious consequences of
chronic liver disease or portal vein obstruction in children and
is associated with a high risk of death (18). Management of
children at risk for variceal bleeding differs considerably among
pediatric hepatologists, largely because of a lack of pediatric
research studies that examine approaches to screening for varices
and treatment to prevent hemorrhage (9).
To improve the management of children at risk for bleeding
from esophageal varices, it is first necessary to identify affected
children who can be included in pediatric studies of primary
prophylaxis. Esophagogastroduodenoscopy (EGD) is the present
reference standard diagnostic test, but it is invasive, time consum-
ing, expensive, and associated with risk. There is therefore a
pressing need for a noninvasive test that reliably enables targeting
of EGD to those children with the highest risk of varices, and
avoidance of EGD in children without varices.
The aim of the present study was to derive a noninvasive
clinical prediction rule capable of identifying children with eso-
phageal varices, in line with 1 of the research priorities of the
American Association for the Study of Liver Disease and the
American College of Gastroenterology (10).
METHODS
Setting and Eligibility
In the present retrospective study, consecutive children
younger than 18 years of age who underwent EGD between
2000 and 2007 at the Hospital for Sick Children, Toronto, were
included if they had liver disease or portal vein thrombosis. The
hospital specializes in the delivery of secondary and tertiary level
care to the children of the greater Toronto area and provides the
largest pediatric liver transplant program in Canada. Endoscopies
were undertaken to screen for either esophageal varices or gas-
trointestinal symptoms. We excluded children with history of use
of b-blockers, previous portal-systemic shunt surgery or transju-
gular-intrahepatic-portal-systemic shunt, endoscopic ligation, or
sclerotherapy of varices or upper gastrointestinal bleeding before
the EGD. Children with malignancy or who had undergone organ
transplantation before the EGD were also excluded. The study was
approved by the institutional research ethics board.
Data Collection
Data were collected by review of the health record and
included demographic details, primary diagnoses, comorbidities,
and medications. Clinical, imaging, and laboratory test parameters
were recorded, including those that may provide evidence of the
severity of portal hypertension. Bloodwork and abdominal ultra-
sound scan (USS) results were obtained from the test performed
closest in time to the EGD and always within a maximum of
6 months. All of the endoscopies were performed by 1 of 3
experienced physicians who used the same Paquet classification
JPGN  Volume 50, Number 2, February 2010
 JPGN  Volume 50, Number 2, February 2010 Noninvasive Diagnosis of Varices in Children

system for gradation of esophageal variceal size. In this system,
varix size is graded on a 4-point Likert scale: grade 1 varices are
small and flattened by insufflation of air, grade 2 are slightly larger
and do not flatten, grade 3 are larger but do not touch in the middle
of the lumen, and grade 4 varices are large and touch each other in
the middle of the lumen (11). Routine practice at our institution is to
measure spleen length during abdominal USS. These measurements
were expressed as standard deviation scores (z scores) relative to
previously established reference standards of spleen length for
different ages (12).
Statistical Analysis
First, a descriptive univariate analysis was performed on
variables that were determined subjectively by the investigators to
be potentially associated with esophageal varices. Categorical
variables (eg, existence of collaterals on Doppler ultrasound exami-
nation) are presented as proportions and compared using x2 or
Fisher exact tests. Continuous variables (eg, platelet count, albumin
concentration, international normalized ratio [INR], spleen length)
are presented as mean  standard deviation (SD) or median inter-
quartile range and compared using unpaired Student t test or
Wilcoxon rank-sum test as appropriate for the normal distribution.
Univariate logistic regression was used to obtain the corresponding
odds ratio (OR) and 95% confidence interval (CI) for each pre-
dictive variable. A correction factor of 0.5 was added to cells that
contained 0 within the data tables.
Multivariate logistic regression was then modeled to asso-
ciate predictors with esophageal varices. Screening of variables for
the multivariable predictive rules using univariate statistical sig-
nificance levels involves multiple comparison problems and is
known to produce unreliable models (1317). Therefore, we fol-
lowed the strong recommendation to set possible predictors a priori
based on extensive literature review and expert opinion (16,18).
Fine-tuning of the initial limited list of possible predictive variables
may be aided by fitting a few models while trying to maximize the c
statistic of the binary model. Calibration of the prediction rule was
assessed using the Hosmer and Lemeshow goodness-of-fit test. The
small sample size in the present study limited the number of
independent variables to be included. We selected a priori 2 sets
of variables that were consistently reproduced in the adult literature
(1927); albumin or INR to be the first variable (reflecting the
severity of liver disease) and platelet count or platelet/spleen z score
to be the second variable (reflecting severity of portal hyperten-
sion). To avoid negative z scores, a factor of 5 was added to all of the
spleen length z scores. The choice of either variable in each set
(albumin or INR) depended on optimizing the model by maximiz-
ing the c statistic and minimizing 2 log-likelihood after fitting all
of the possible models. The b-estimates of the predictors retained in
the best model were used to guide the weights of the variables in the
clinical prediction rule, after multiplication by 10 and rounding to
the nearest 0.5.
The best cutoff point of the resulting clinical prediction
rule to differentiate children with and without varices was deter-
mined to be the point where the second diagonal crossed the
receiver operating characteristic (ROC) curve. However, other
cutoffs to maximize sensitivity or specificity were also explored.
An area under the ROC curve (95% CI) of more than 0.7 was
considered a fair prediction rule, 0.8 good, and more than 0.9 excel-
lent. Sensitivity, specificity, negative and positive predictive
values, and likelihood ratios were calculated for different cutoff
points. Ninety-five percent CI were calculated for all of the point
estimates.
All of the comparisons were made using 2-sided significance
levels of P < 0.05. Statistical analyses were performed using SAS
version 9.1 (SAS, Cary, NC) and SPSS version 15.0 (SPSS Inc,
Chicago, IL).
RESULTS
Of the 87 children with liver disease or portal vein throm-
bosis who underwent EGD during the study period, 51 met the
eligibility criteria and were included in the present study (mean age
11 years, range 2 months17 years, 25 males) (Table 1). The
common reason for exclusion was a previous episode of bleeding

TABLE 1. Baseline characteristics of 51 patients included

Variable EV () (n 17) EV () (n 34) P

Diagnosis
Primary sclerosing cholangitis 2 (12%) 13 (38%)
Autoimmune hepatitis 3 (18%) 4 (12%)
Overlap syndrome 3 (18%) 4 (12%)
Portal vein thrombosis 4 (24%) 1 (3%)
Congenital hepatic fibrosis 2 (12%) 1 (3%)
Others
3 (18%) 11 (32%)
Male sex 6 (35%) 19 (56%) 0.17
Mean age 11  3.5 11.9  4.2 0.44
No. <2 y old 0 (0%) 1 (3%)
No. 210 y old 6 (35%) 5 (15%)
No. >10 y old 11 (65%) 28 (82%)
Child-Pugh (A/B/C) 14/3/0 29/4/0
Mean Child-Pugh 5.65  1.06 5.36  0.68 0.27
No. with splenomegaly 13/4 2/31 <0.001
EV esophageal varices.


Others include biliary atresia (1), Caroli syndrome (1), hepatitis B (2), hepatitis C (1), Budd-Chiari syndrome (1), nonalcoholic fatty liver disease (1)
glycogen storage disease (1), focal nodular hyperplasia (1), drug-related liver disease (1) parenteral nutrition cholestasis (1), hemochromatosis (1), a-1
antitrypsin deficiency (1), and cryptogenic liver disease (1).

www.jpgn.org 189

Copyright 2010 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
 Gana et al JPGN  Volume 50, Number 2, February 2010

TABLE 2. Univariate analysis of potential predictors of esophageal varices

Variable Varices (n 17) Nonvarices (n 34) OR 95% CI P

Spleen length and markers of

hypersplenism
Splenomegaly on PE 13 (76%) 2 (6%) 0.026 0.003, 0.24 <0.001
SAZ 7.14 (3.78) 1.48 (3.86) 1.94 1.32, 2.86 <0.001
Platelets, 109/L 123 (104) 336 (129) 0.47
0.32, 0.70 <0.001
Platelets/SAZ 13.7 (18.7) 57.2 (33.6) 0.81y 0.67, 0.996 <0.001
White blood count, 109/L 4.91 (1.95) 9.16 (4.13) 0.56 0.39, 0.79 <0.001
Hemoglobin, g/L 123 (16.2) 127 (17.9) 0.99 0.95, 1.02 0.48
Other USS variables
Collaterals 9 (60%) 0 (0%) 60.5 3.2, >1000 <0.001
Ascites 6 (38%) 3 (13%) 13.3 2.3, 90.5 0.002
Liver synthetic function
Albumin, g/L 37.7 (5.6) 43 (4.9) 0.83 0.72, 0.95 0.003
INR 1.21 (0.26) 1.02 (0.08) 3.14z 1.43, 6.90 0.001
Other tests and ratios
Bilirubin conjugated, mmol/L 7.68 (19.3) 11.48 (49.6) 0.997 0.98, 1.01 0.666
AST 112 (127) 140 (228) 0.999 0.996, 1.003 0.9
ALT 73.8 (81.6) 156 (208) 0.996 0.99, 1.001 0.119
AST/ALT ratio 2.04 (1.53) 1.02 (0.49) 4.68 1.34, 16.0 0.003
AST/platelets ratio 1.25 (1.66) 0.51 (1.27) 1.64 0.92, 2.92 <0.001
GGT 148 (201) 205 (350) 1.64 0.92, 2.92 0.439
Alkaline phosphatase 410 (373) 345 (404) 0.999 0.998, 1.002 0.623
Creatinine, mmol/L 43.1 (10.4) 71.1 (94.2) 0.94 0.89, 0.995 0.017
Numbers in parenthesis represent % or SD as appropriate.
ALT alanine aminotransferase; AST aspartate aminotransferase; CI confidence interval; GGT g-glutamyltransferase; INR international normal-
ized ratio; OR odds ratio; PE physical examination; SAZ spleen length for age z score; USS ultrasound scan.


For a 50-unit change in platelets/spleen.
y
For a 100-unit change in platelets/spleen.
z
For a 0.1-unit change in INR.

(n 17). Ninety-two percent of all of the data fielded were complete
for the 51 eligible children. Forty patients were taking medications,
the most frequent was ursodeoxycholic acid (n 25), but none were
receiving b-blockers. Basic characteristics did not differ between
the patients with or without esophageal varices, including age, sex,
Child-Pugh Score, and Pediatric End-Stage Liver Disease (PELD)
or Model for End-Stage Liver Disease (MELD) scores. There were
no patients with evidence of encephalopathy.
EGD identified esophageal varices in 17 of the 51 children
(33%), 9 of whom had large varices (grade 2 or more than 18% of
the total, 53% of the varices group). Eight patients had portal
hypertensive gastropathy and 3 patients with large esophageal
varices also had gastric varices.
Variables found to differ significantly between children with
and without varices included splenomegaly on physical examin-
ation, spleen length z score measured by USS, presence of collat-
erals on USS, platelet/spleen length z score ratio, platelet count,
white blood cell count, aspartate aminotransferase/platelet ratio,
INR, aspartate aminotransferase/alanine aminotransferase ratio,
albumin, and creatinine (Table 2).
Derivation of the Noninvasive
Prediction Rule
Multivariate logistic regression was modeled to associate
predictors with esophageal varices. A model with platelets, spleen
length z score, and albumin as the independent variables had the
best fit among all of the models, with the smallest 2 log-likelihood
and highest c statistic (Table 3). After adjusting the b-coefficient as
described, the resulting clinical prediction rule was:
 
0:75  Platelets
2:5  Albumin
SAZ 5
where platelet count is measured in units  109/L, SAZ is the
spleen length z score, and albumin is measured in grams per liter.
Smaller values are associated with a higher likelihood of varices,
with the best cutoff value of 130 chosen to maximize sensitivity and
negative predictive value as required for a screening test (Fig. 1,
Table 4). The model was well calibrated as evident from the Hosmer
and Lemeshow goodness-of-fit test (P 0.81). The area under the
ROC curve of this clinical rule to predict esophageal varices was
0.93 (0.850.99), implying excellent discriminant ability. Other
cutoff values maximizing specificity are also presented (Table 4).
DISCUSSION
We report the derivation of a predictive model that has a high
sensitivity and negative predictive value for the identification of
children with esophageal varices. The rule could be used to identify
children most likely to have varices, thereby avoiding EGD in
children who do not have varices. We considered only simple,
commonly available, reproducible variables because we believe
that the other previously reported noninvasive predictors of eso-
phageal varices were less reproducible in clinical practice (28) and

190 www.jpgn.org

Copyright 2010 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
 JPGN  Volume 50, Number 2, February 2010 Noninvasive Diagnosis of Varices in Children

TABLE 3. Summary of the 4 contending logistic regression models

b-coefficient OR (95% CI) P c Statistic 2LL

Model 1
PLT/spleen 0.074 0.93 (0.880.98) 0.007 0.93 23.346
Alb 0.247 0.78 (0.620.98) 0.039
Model 2
PLT/spleen 0.063 0.94 (0.890.99) 0.019 0.91 28.697
INR 4.056 57.7 (0.01>100) 0.362
Model 3
PLT 0.016 0.98 (0.970.99) 0.002 0.88 25.09
Alb 0.313 0.73 (0.570.94) 0.016
Model 4
PLT 0.012 0.98 (0.970.99) 0.006 0.90 33.08
INR 4.373 79.3 (0.02>100) 0.298
Alb albumin; CI confidence interval; INR international normalized ratio; 2LL 2 log-likelihood; PLT platelets.

were subject to interobserver variability (29). We measured spleen
length using ultrasonography which is an easily obtainable, non-
invasive, and reproducible test (30,31). The expression of SAZ
enables appropriate comparison among children of different ages.
The platelet count/spleen diameter ratio has been previously shown
to accurately identify varices in adults with cirrhosis and has a
logical pathophysiological basis in children with portal hyperten-
sion. The increase in spleen length in patients with chronic liver
disease almost always reflects the increased portal pressure (32,33),
and thrombocytopenia may be the result of splenic pooling of
platelets because of portal hypertension, immune-mediated mech-
anisms, or lower thrombopoietin synthesis (3436).
Endoscopic screening is recommended for adults with cir-
rhosis to identify those with varices who may benefit from pro-
phylactic treatment, because there is evidence that prophylactic
therapy with b-blockers or endoscopic variceal ligation is effective
in reducing the incidence of variceal bleeding (10). However, EGD
is invasive and unpleasant and will find no varices in up to 50% of
adults with cirrhosis (10,37). There is, therefore, a strong interest in
identifying a noninvasive test that can either replace screening EGD
FIGURE 1. The prediction rule in patients with and without
varices.
or select patients for EGD who have a greater likelihood of
having varices.
Data to support the noninvasive identification of varices in
children are sparse. In a recent study of children with portal
hypertension, children having cirrhosis with splenomegaly were
14.6-fold more likely to have esophageal varices compared with
children having cirrhosis without splenomegaly. Hypoalbuminemia
increased the likelihood of varices (OR 4.17 [95%] CI 1.4312.18),
whereas the significance of thrombocytopenia in the univariate
analysis did not hold in the multivariable modeling (38). Fifteen
children with portal vein cavernoma and esophageal varices were
evaluated in another pediatric study that analyzed ultrasound
markers for esophageal varices. Abdominal USS revealed an
increased lesser omentum/aorta diameter ratio in children with
portal hypertension, compared with controls (P < 0.001) (39).
Several studies in adults with cirrhosis have demonstrated the
potential for noninvasive tests to identify esophageal varices (20
24,26,27,4050). The ratio between spleen diameter and platelet
count has repeatedly shown high diagnostic accuracy in these adult
studies, ranging from 0.86 to 1 (24,25,4042). The optimal cutoff
value for this ratio has yet to be determined and depends in part
upon the severity of disease in the patient population under con-
sideration. Interestingly, patients identified by the ratio as false-
positives were more likely to have esophageal varices at follow-up
compared with the patients with true-negative results (25).
The limitations of the present study include its retrospective
design and small sample size. Screening EGD for esophageal
varices in children was not routinely performed in our center
and the study population is therefore also composed of children
undergoing endoscopy for investigations of gastrointestinal symp-
toms. For this reason, younger children with biliary atresia are
poorly represented, and there is an excess of older children with
primary sclerosing cholangitis who underwent endoscopy as a part
of their assessment for inflammatory bowel disease. Blinding of
endoscopists to the presence and degree of splenomegaly and
thrombocytopenia cannot be guaranteed in retrospect. The inclusion
of children with portal vein thrombosis as well as intrahepatic
disease may make the clinical prediction rule more widely
applicable to different patient groups, although validation studies
will be required in each group. The number of patients in the present
study did not allow for reliable subgroup analysis to compare
children with prehepatic and hepatic portal hypertension. None-
theless, EGD was performed in children with various severities of
liver disease in the same center and using a single classification

www.jpgn.org 191

Copyright 2010 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
 Gana et al
TABLE 4. Performance characteristics of the clinical prediction rule at different cutoff values
Cutoff value Sensitivity (%) Specificity (%) PPV
116 81 91 0.82
130 94 81 0.83
145 100 67 0.61
AUROC area under receiver operating characteristic curve; LR positive likelihood ratio; LR negative likelihood ratio; NPV negative predictive
value; PPV positive predictive value.
system. We focused on the presence of esophageal varices of any
size, rather than on the presence of large esophageal varices,
because this is the first step in the diagnostic workup at which
point decisions regarding follow-up and treatment are made.
Although our clinical prediction rule was the most accu-
rate test of those we studied, other simple tests such as spleno-
megaly and platelet count also showed a high degree of diagnostic
accuracy. A previous study suggested that splenomegaly detected
on physical examination has a high sensitivity and specificity
for the diagnosis of esophageal varices (38). These simple tests
would be more practical to use on a daily basis. Nevertheless, the
clinical prediction rule standardizes subjective assessments of
physicians and we therefore speculate that the reliability of our
clinical prediction rule will prove to be higher when measured
in validation studies. The clinical prediction rule uses variables
that are commonly measured in routine clinical care of children
with liver disease or portal vein thrombosis, thus reducing the
potential cost of the present approach to the identification of
varices.
CONCLUSIONS
In summary, we found that variables linked to portal hyper-
tension (platelet count, spleen length) as well as those linked to the
severity of liver dysfunction (albumin, INR) are associated with the
presence of esophageal varices. We have derived a clinical pre-
diction rule that uses simple noninvasive tests and shows accuracy
for the identification of children who require EGD to characterize
their esophageal varices. We are now undertaking a prospective
study to validate these encouraging results in an additional cohort
of children.
REFERENCES
1. Lykavieris P, Gauthier F, Hadchouel P, et al. Risk of gastrointestinal
bleeding during adolescence and early adulthood in children with portal
vein obstruction. J Pediatr 2000;136:8058.
2. Goncalves ME, Cardoso SR, Maksoud JG. Prophylactic sclerotherapy
in children with esophageal varices: long-term results of a controlled
prospective randomized trial. J Pediatr Surg 2000;35:4015.
3. Miga D, Sokol RJ, Mackenzie T, et al. Survival after first esophageal
variceal hemorrhage in patients with biliary atresia. J Pediatr 2001;
139:2916.
4. van Heurn LW, Saing H, Tam PK. Portoenterostomy for biliary atresia:
Long-term survival and prognosis after esophageal variceal bleeding.
J Pediatr Surg 2004;39:69.
5. Kobayashi A, Itabashi F, Ohbe Y. Long-term prognosis in biliary atresia
after hepatic portoenterostomy: analysis of 35 patients who survived
beyond 5 years of age. J Pediatr 1984;105:2436.
6. Toyosaka A, Okamoto E, Okasora T, et al. Outcome of 21 patients with
biliary atresia living more than 10 years. J Pediatr Surg 1993;28:1498
501.
7. Mitra SK, Kumar V, Datta DV, et al. Extrahepatic portal hypertension:
A review of 70 cases. J Pediatr Surg 1978;13:517.
8. Webb LJ, Sherlock S. The aetiology, presentation and natural history of
extra-hepatic portal venous obstruction. Q J Med 1979;48:62739.
192
Copyright 2010 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
JPGN  Volume 50, Number 2, February 2010
 
0:75  Platelets 2:5  Albumin
SAZ 5
NPV LR LR AUROC P
0.91 9.3 0.19 0.93 <0.001
0.94 5 0.06 0.93 <0.001
1 3.09 0 0.93 <0.001
9. Shneider BL. Approaches to the management of pediatric portal hyper-
tension: results of an informal survey. In: Groszmann RJ, Bosch J, eds.
Portal Hypertension in the 21st Century. Dordrecht, the Netherlands:
Kluwer Academic Publishers; 2004, pp 16772.
10. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management
of gastroesophageal varices and variceal hemorrhage in cirrhosis.
Hepatology 2007;46:92238.
11. Paquet KJ. Prophylactic endoscopic sclerosing treatment of the eso-
phageal wall in varices a prospective controlled randomized trial.
Endoscopy 1982;14:45.
12. Megremis SD, Vlachonikolis IG, Tsilimigaki AM. Spleen length in
childhood with US: normal values based on age, sex, and somatometric
parameters. Radiology 2004;231:12934.
13. Harrell FE Jr, Lee KL, Califf RM, et al. Regression modelling strategies
for improved prognostic prediction. Stat Med 1984;3:14352.
14. Harrell FE Jr, Lee KL, Matchar DB, et al. Regression models for
prognostic prediction: advantages, problems, and suggested solutions.
Cancer Treat Rep 1985;69:10717.
15. Harrell F. Regression coefficients and scoring rules. J Clin Epidemiol
1996;49:819.
16. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models:
issues in developing models, evaluating assumptions and adequacy, and
measuring and reducing errors. Stat Med 1996;15:36187.
17. Austin PC, Tu JV. Automated variable selection methods for logistic
regression produced unstable models for predicting acute myocardial
infarction mortality. J Clin Epidemiol 2004;57:113846.
18. Laupacis A, Sekar N, Stiell IG. Clinical prediction rules. A review and
suggested modifications of methodological standards. JAMA 1997;
277:48894.
19. Sanyal AJ, Fontana RJ, Di Bisceglie AM, et al. The prevalence and risk
factors associated with esophageal varices in subjects with hepatitis C
and advanced fibrosis. Gastrointest Endosc 2006;64:85564.
20. Zaman A, Hapke R, Flora K, et al. Factors predicting the presence of
esophageal or gastric varices in patients with advanced liver disease. Am
J Gastroenterol 1999;94:32926.
21. Ng FH, Wong SY, Loo CK, et al. Prediction of oesophagogastric varices
in patients with liver cirrhosis. J Gastroenterol Hepatol 1999;14:785
90.
22. Pilette C, Oberti F, Aube C, et al. Non-invasive diagnosis of esophageal
varices in chronic liver diseases. J Hepatol 1999;31:86773.
23. Madhotra R, Mulcahy HE, Willner I, et al. Prediction of esophageal
varices in patients with cirrhosis. J Clin Gastroenterol 2002;34:815.
24. Giannini E, Botta F, Borro P, et al. Platelet count/spleen diameter ratio:
proposal and validation of a non-invasive parameter to predict the
presence of oesophageal varices in patients with liver cirrhosis. Gut
2003;52:12005.
25. Giannini EG, Botta F, Borro P, et al. Application of the platelet count/
spleen diameter ratio to rule out the presence of oesophageal varices in
patients with cirrhosis: a validation study based on follow-up. Dig Liver
Dis 2005;37:77985.
26. Chalasani N, Imperiale TF, Ismail A, et al. Predictors of large esophageal
varices in patients with cirrhosis. Am J Gastroenterol 1999;94:328591.
27. Zein CO, Lindor KD, Angulo P. Prevalence and predictors of esophageal
varices in patients with primary sclerosing cholangitis. Hepatology
2004;39:20410.
28. Valletta EA, Loreti S, Cipolli M, et al. Portal hypertension and eso-
phageal varices in cystic fibrosis. Unreliability of echo-Doppler flow-
metry. Scand J Gastroenterol 1993;28:10426.
www.jpgn.org
 JPGN  Volume 50, Number 2, February 2010
29. Tamayo SG, Rickman LS, Mathews WC, et al. Examiner dependence
on physical diagnostic tests for the detection of splenomegaly: a
prospective study with multiple observers. J Gen Intern Med 1993;8:
6975.
30. Winkfield B, Aube C, Burtin P, et al. Inter-observer and intra-observer
variability in hepatology. Eur J Gastroenterol Hepatol 2003;15:959
66.
31. ODonohue J, Ng C, Catnach S, et al. Diagnostic value of Doppler
assessment of the hepatic and portal vessels and ultrasound of the
spleen in liver disease. Eur J Gastroenterol Hepatol 2004;16:147
55.
32. Liangpunsakul S, Ulmer BJ, Chalasani N. Predictors and implications of
severe hypersplenism in patients with cirrhosis. Am J Med Sci 2003;326:
1116.
33. Pockros PJ, Duchini A, McMillan R, et al. Immune thrombocytopenic
purpura in patients with chronic hepatitis C virus infection. Am J
Gastroenterol 2002;97:20405.
34. Peck-Radosavljevic M. Thrombocytopenia in liver disease. Can J
Gastroenterol 2000;14 (Suppl D):60D6D.
35. Peck-Radosavljevic M. Review article: coagulation disorders in
chronic liver disease. Aliment Pharmacol Ther 2007;26 (Suppl 1):
218.
36. Giannini E, Botta F, Borro P, et al. Relationship between thrombopoietin
serum levels and liver function in patients with chronic liver disease
related to hepatitis C virus infection. Am J Gastroenterol 2003;98:
251620.
37. de Franchis R, Primignani M. Natural history of portal hypertension in
patients with cirrhosis. Clin Liver Dis 2001;5:64563.
38. Fagundes ED, Ferreira AR, Roquete ML, et al. Clinical and laboratory
predictors of esophageal varices in children and adolescents with portal
hypertension syndrome. J Pediatr Gastroenterol Nutr 2008;46:178
83.
39. Moreno E, Torres P, Trejo C, et al. Predictive value of ultrasonography in
portal hypertension. G E N 1991;45:1014.
www.jpgn.org
Copyright 2010 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
Noninvasive Diagnosis of Varices in Children
40. Giannini EG, Zaman A, Kreil A, et al. Platelet count/spleen diameter
ratio for the noninvasive diagnosis of esophageal varices: results of
a multicenter, prospective, validation study. Am J Gastroenterol 2006;
101:25119.
41. Sethar GH, Ahmed R, Rathi SK, et al. Platelet count/splenic size ratio:
a parameter to predict the presence of esophageal varices in cirrhotics.
J Coll Physicians Surg Pak 2006;16:1836.
42. Zimbwa TA, Blanshard C, Subramaniam A. Platelet count/spleen
diameter ratio as a predictor of oesophageal varices in alcoholic
cirrhosis. Gut 2004;53:1055.
43. Schepis F, Camma C, Niceforo D, et al. Which patients with cirrhosis
should undergo endoscopic screening for esophageal varices detection?
Hepatology 2001;33:3338.
44. Thomopoulos KC, Labropoulou-Karatza C, Mimidis KP, et al. Non-
invasive predictors of the presence of large oesophageal varices in
patients with cirrhosis. Dig Liver Dis 2003;35:4738.
45. Thabut D, Trabut JB, Massard J, et al. Non-invasive diagnosis of large
oesophageal varices with FibroTest in patients with cirrhosis: a pre-
liminary retrospective study. Liver Int 2006;26:2718.
46. Kazemi F, Kettaneh A, Nkontchou G, et al. Liver stiffness measurement
selects patients with cirrhosis at risk of bearing large oesophageal
varices. J Hepatol 2006;45:2305.
47. Cottone M, DAmico G, Maringhini A, et al. Predictive value of
ultrasonography in the screening of non-ascitic cirrhotic patients with
large varices. J Ultrasound Med 1986;5:18992.
48. Zaman A, Becker T, Lapidus J, et al. Risk factors for the presence of
varices in cirrhotic patients without a history of variceal hemorrhage.
Arch Intern Med 2001;161:256470.
49. Vanbiervliet G, Barjoan-Marine E, Anty R, et al. Serum fibrosis markers
can detect large oesophageal varices with a high accuracy. Eur J
Gastroenterol Hepatol 2005;17:3338.
50. Sethar GH, Ahmed R, Rathi SK, et al. Platelet count/splenic size ratio:
a parameter to predict the presence of esophageal varices in cirrhotics.
J Coll Physicians Surg Pak 2006;16:1836.
193