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Pediatric Surgery International (2022) 38:1377–1383
https://doi.org/10.1007/s00383-022-05180-5
ORIGINAL ARTICLE
Comparison ofthree risk stratification scores ingastroschisis neonates:
gastroschisis prognostic score, gastroschisis risk stratification index
andcomplex gastroschisis
AstaTauriainen1,2· ArimatiasRaitio2· TuomasTauriainen3· KariVanamo1· UllaSankilampi4,5· IlkkaHelenius6·
AnnaHyvärinen7
Accepted: 6 July 2022 / Published online: 26 July 2022
© The Author(s) 2022
Abstract
Purpose The aim of the study was to compare and evaluate the utility of three different risk stratification scores for gastro-
schisis neonates; simple/complex gastroschisis, gastroschisis prognostic score and risk stratification index.
Methods Data of neonates born with gastroschisis between the years 1993 and 2015 were collected. The national registers
and patient records of four Finnish University Hospitals were retrospectively reviewed. Logistic and linear regression analy-
sis were performed to identify independent predictors for adverse outcomes. The efficacy of these prognostic methods was
further assessed using ROC-curves and DeLong (1988) test.
Results Gastroschisis risk stratification index was an acceptable predictor of in-hospital mortality, AUC 0.70, 95% CI
0.48–0.91, p = 0.049. Complex gastroschisis and gastroschisis prognostic score were able to predict short bowel syndrome,
AUC 0.80, 95% CI 0.58–1.00, p = 0.012 and AUC 0.80, 95% CI 0.59–1.00, p = 0.012, respectively.
Conclusion There are three easily obtainable risk stratification scores for outcome prediction in gastroschisis patients,
however, their predictive ability did not have a statistical difference in the present study. The Gastroschisis risk stratification
index seemed to perform moderately well in mortality prediction.
Keywords Gastroschisis· Risk stratification· Complex gastroschisis· Score· Level of evidence: Level III
Introduction
Gastroschisis is a congenital defect of the anterior abdomi-
nal wall, characterized by prolapse of intestine and other
abdominal organs outside the abdominal cavity. Surgical
correction is required soon after delivery. The prevalence
of gastroschisis is increasing worldwide and has been
reported to be 1 to 5 in 10000 live births. [1–3]. Survival
* Asta Tauriainen
asta.tauriainen@fimnet.fi
Arimatias Raitio
arimatias.raitio@fimnet.fi
Tuomas Tauriainen
tuomas.ttau@gmail.com
Kari Vanamo
kari.vanamo@fimnet.fi
Ulla Sankilampi
ulla.sankilampi@kuh.fi
Ilkka Helenius
ilkka.helenius@hus.fi
Anna Hyvärinen
anna.hyvarinen@tuni.fi
1 Department ofPediatric Surgery, University ofEastern
Finland andKuopio University Hospital, Puijonlaaksontie 2,
70210Kuopio, Finland
2 Department ofPediatric Surgery, University ofTurku
andTurku University Hospital, Turku, Finland
3 Department ofSurgery, Oulu University Hospital, Oulu,
Finland
4 Department ofPediatrics, Kuopio University Hospital,
Kuopio, Finland
5 Department ofPediatrics, School ofMedicine, University
ofEastern Finland, Kuopio, Finland
6 Department ofOrthopedics andTraumatology, University
ofHelsinki andHelsinki University Hospital, Helsinki,
Finland
7 Department ofPediatric Surgery, University ofTampere
andTampere University Hospital, Tampere, Finland
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1378 Pediatric Surgery International (2022) 38:1377–1383
1 3
rates have been published to be greater than 90% [2, 4, 5].
The negative impact of additional intestinal anomalies or
bowel compromise have described in the literature and
division to simple and complex gastroschisis (complicated
by atresia, perforation, necrosis and/or volvulus) is the
most common categorization method [6, 7]. Cowan and
colleagues introduced a Gastroschisis Prognostic Score
(GPS) in 2012, which is a risk stratification method based
on visual assessment of bowel appearance after delivery.
It includes the following variables: matting, necrosis, atre-
sia and perforation. [8]. Elevated scores have been shown
to associate with increased length of stay, increased total
time of parenteral nutrition, increased time to enteral feeds
and mortality [8] in addition to complications [9]. Another
risk score for gastroschisis is the Gastroschisis Risk Strati-
fication Index (GRSI), which includes intestinal atresia,
necrotizing enterocolitis, rare cardiac anomalies and lung
hypoplasia to identify patients at greatest risk for mortal-
ity. This method was shown to successfully identify infants
at a high risk for death. [10]. To our knowledge, studies
comparing multiple risk assessment modalities for gastro-
schisis are scarce in the current literature. These scoring
systems could provide valuable information to both clini-
cians and researchers.
The aim of the study was to compare and evaluate the
utility of three different risk stratification scores for gas-
troschisis neonates; simple/complex gastroschisis, GPS and
GRSI.
Materials andmethods
Patients
We conducted a retrospective study of neonates born with
gastroschisis and treated at the Pediatric Surgery Depart-
ments of four University hospitals, Tampere, Turku, Kuopio
and Oulu, in Finland from 1993 to 2015. Unfortunately, we
do not have data from the fifth university hospital Helsinki,
which would have made the database nationwide. Gastro-
schisis patients were identified from the hospital registers
based on the diagnoses according to International Clas-
sification of Diseases (ICD-9 code 756.73, after the year
1994 Q79.3 ICD-10 code). Data regarding maternal factors,
prenatal observations, initial presentation at birth, surgi-
cal treatment, post-operative treatment, complications and
short-term outcomes were collected from the patient files at
each hospital, the Finnish Medical Birth Register and the
Finnish Register of Congenital Malformations maintained by
the Finnish Institution for Health and Welfare. The mean fol-
low-up time of this database was 11years. The institutional
review boards of the participating hospitals and the Finnish
Institution for Health and Welfare accepted the study. The
need for patients’ written consent was waived.
Definitions
The birth weight z score was obtained using the contempo-
rary Finnish Birth size reference [11]. Small for Gestational
Age (SGA) was defined as birth weight below – 2 Standard
deviation. Organ prolapse was defined as any intra-abdom-
inal organ fully or partially protruding trough the fascial
defect at birth, excluding small and large intestine. Patients
with associated bowel atresia, bowel perforation, bowel
necrosis or volvulus were defined to have a complex gastro-
schisis, as suggested by Molik and Abdullah [6, 12]. GRSI
includes a scoring system for intestinal atresia, necrotizing
enterocolitis, rare cardiac anomalies and pulmonary hypo-
plasia with range of 0–10 points. Atresia gives 1, NEC 2,
rare cardiac anomalies 3 and pulmonary hypoplasia 4 points
[10]. Rare cardiac anomalies were selected according to
Arnold etal. Points of GPS range from 0 to 12 and vari-
ables are matting, atresia, perforation and necrosis [8, 9].
Descriptions of bowel injury were based on the study and
instructions for use by Cowan etal. [13]. Points of matting
are 0 for none, 1 for mild and 4 for severe. Absent atresia,
perforation or necrosis values 0, suspected atresia 1, present
atresia or perforation 2 and present necrosis 4.
Outcome endpoints
The primary endpoints of the present study were to compare
and evaluate the function of three different risk stratification
scores for gastroschisis neonates in Finland; simple/complex
gastroschisis, GPS and GRSI. Our outcomes of interest were
in-hospital mortality, short bowel syndrome, positive blood
culture, intravenous nutrition time, in-hospital stay in days
and a re-laparotomy for any of the following—perforation,
ischemia or necrosis of the bowel.
Statistical analysis
Statistical analysis was performed using SPSS software (ver-
sion 25.0, IBM Corporation, New York, USA). No attempt
to replace missing values was made. Categorical variables
are reported as counts and percentages. Continuous variables
are reported as means and standard deviations. Logistic and
linear regression analysis were performed to identify inde-
pendent predictors for adverse outcomes. The following var-
iables were included in the multivariate models: gestational
age, birth weight, Apgar score at 5min of age, gender, hos-
pital transfer after delivery, prenatal diagnose known, any
organ prolapse other than bowel and twin status in addition
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1379Pediatric Surgery International (2022) 38:1377–1383
1 3
to each risk stratification method individually. Receiver
operating characteristic curves (ROC) were used to assess
the discriminatory power of GPS, GRSI and simple/complex
gastroschisis. ROC is a quantitative measure of the ability
of a diagnostic tool to differentiate between dichotomous
events. Area under the curve (AUC) values were calculated
to compare these models in a free web-based application
[14] with DeLong (1988) test [15]. All statistical tests were
performed as two-tailed and a p value ≤ 0.05 represented
statistical significance. AUC values depicting the accuracy
of risk stratification were classified as fail (0.50–0.59), poor
(0.60–0.69), moderate (0.70–0.79), good (0.80–0.89) and
excellent (0.90–1.00).
Results
A total of 156 newborns with gastroschisis were born
between January 1993 and December 2015. Thirteen neo-
nates were excluded, one who received most of the treat-
ment in a non-participating center, one with missing patient
records and 11 not having all variables needed to measure
the scores. Altogether 143 neonates were included in the
study. Perinatal characteristics are summarized in Table1.
There were 79 male (55.2%) and 64 female infants. Gastro-
schisis was prenatally diagnosed in 123 cases (86.0%). Ten
patients (7.0%) were born in a central hospital and required
transfer to a University Hospital postnatally. The average
birth weight and gestational age were 2530 ± 564g and
36.7 ± 1.8weeks, respectively. Vaginal delivery rate was
31.5 percent. Nine infants died before discharge from hos-
pital (6.3%). Re-laparotomy for bowel perforation, ischemia
or necrosis was performed for seven infants (4.9%). Short
bowel syndrome was diagnosed in6 cases (4.2%) and 21
infants had a positive blood culture (14.7%). The mean
duration of parenteral nutrition and hospital stay were
55.3 ± 198.4 and 39.2 ± 50.0days, respectively.
Numbers of infants classified into each risk prediction
model are presented in Table2. Comparison of risk predic-
tion models in patients with gastroschisis are presented in
Tables3 and 4. ROC-curves were drawn for dichotomized
variables. GPS was found to reliably predict short bowel syn-
drome, AUC 0.80, 95% CI 0.59–1.00, p = 0.012, as was also
classification to complex gastroschisis, AUC 0.80, 95% CI
0.58–1.00, p = 0.012. GRSI was a moderate predictor of in-
hospital mortality, AUC 0.70, 95% CI 0.48–0.91, p = 0.049.
Furthermore, we conducted multivariate models adjusted for
relevant perinatal variables and beforementioned risk scores.
Gastroschisis prognostic score was found to be an independ-
ent predictor for short bowel syndrome, OR 1.63, 95% CI
1.07–2.50, p = 0.023. Gastroschisis risk stratification index
was an independent predictor for re-laparotomy for perfora-
tion, ischemia, necrosis and also for in-hospital death, OR
4.27, 95% CI 1.40–13.07, p = 0.011 and OR 6.38 95% CI
Table 1 Overall demographic data
Nominal variables are presented as counts and percentages, continu-
ous variables as a mean and standard deviation
SGA small for gestational age
Variable Overall series n = 143
Gestational age in weeks 36.7 ± 1.8
Weight in grams 2530.0 ± 563.6
Weight < 2500g 77 (53.8%)
SGA 53 (37.1%)
Prematurity < 37weeks 77 (53.8%)
Male 79 (55.2%)
Twin 6 (4.2%)
Vaginal birth 45 (31.5%)
Hospital transfer at birth 10 (7.0%)
Organ prolapse other than bowel 71 (49.7%)
Apgar score at 5min age 7.9 ± 1.8
Table 2 Numbers of infants classified into each risk prediction mod-
els
Gastroschisis prognostic score (GPS) ranges between 0 and 12. The
degree of intestinal matting, atresia, perforation and necrosis are
assessed in GPS. Points for matting are 0 for none, 1 for mild and 4
for severe. Absent atresia, perforation or necrosis gives a value of 0,
suspected atresia 1, present atresia or perforation 2 and present necro-
sis 4 points. Gastroschisis risk stratification index (GRSI) includes
a scoring system assessing intestinal atresia, necrotizing enterocol-
itis (NEC), rare cardiac anomalies and pulmonary hypoplasia with a
range of 0–10 points. Atresia gives 1, NEC 2, rare cardiac anomalies
3 and pulmonary hypoplasia 4 points. In complex (1) versus simple
(0) gastroschisis, patients with associated bowel atresia, bowel perfo-
ration, bowel necrosis or volvulus were defined as having a complex
gastroschisis. Nominal variables are presented as counts and percent-
ages
GPS gastroschisis prognostic score, GRSI gastroschisis risk stratifica-
tion index
Score points GPS GRSI Complex gastroschisis
0 67 (46.9%) 129 (90.2%) 123 (86.0%)
1 37 (25.9%) 10 (7.0%) 20 (14.0%)
2 3 (2.1%) 2 (1.4%)
3 3 (2.1%) 1 (0.7%)
4 20 (14.0%) 1 (0.7%)
5 3 (2.1%) 0 (0%)
6 5 (3.5%) 0 (0%)
7 0 (0%) 0 (0%)
8 2 (1.4%) 0 (0%)
9 1 (0.7%) 0 (0%)
10 2 (1.4%) 0 (0%)
11 0 (0%)
12 0 (0%)
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1380 Pediatric Surgery International (2022) 38:1377–1383
1 3
Table 3 The numbers of outcomes between gastroschisis prognostic score, Gastroschisis risk stratification index and complex gastroschisis scoring systems
Gastroschisis prognostic score (GPS) ranges between 0 and 12. The degree of intestinal matting, atresia, perforation and necrosis are assessed in GPS. Points for matting are 0 for none, 1 for
mild and 4 for severe. Absent atresia, perforation or necrosis gives a value of 0, suspected atresia 1, present atresia or perforation 2 and present necrosis 4 points. Gastroschisis risk stratification
index (GRSI) includes a scoring system assessing intestinal atresia, necrotizing enterocolitis (NEC), rare cardiac anomalies and pulmonary hypoplasia with a range of 0–10 points. Atresia gives
1, NEC 2, rare cardiac anomalies 3 and pulmonary hypoplasia 4 points. In complex (1) versus simple (0) gastroschisis, patients with associated bowel atresia, bowel perforation, bowel necrosis
or volvulus were defined as having a complex gastroschisis. Nominal variables are presented as counts and percentages, continuous variables as a mean and standard deviation
N/A not available
Score points 0 1 2 3 4 5 6 7 8 9 10 11 12
Gastroschisis prognostic score (0–12)
In-hospital mortality 4 (6.0) 2 (5.4) 1 (33.3) 0 0 1 (33.3) 0 0 1 (50.0) 0 0 0 0
Re-laparotomy for perforation/
necrosis
3 (4.5) 1 (2.7) 0 1 (33.3) 0 1 (33.3) 0 0 1 (50.0) 0 0 0 0
Re-laparotomy for occlusion 1 (1.5) 5 (13.5) 0 1 (33.3) 0 0 2 (40.0) 0 2)100.0) 1 (100.0) 2 (100.0)
Short bowel syndrome 1 (1.5) 0 0 1 (33.3) 1 (5.0) 0 1 (20.0) 0 1 (50.0) 0 1 (50.0) 0 0
Positive blood culture 11 (17.7) 6 (16.7) 0 2 (66.7) 1 (5.3) 0 0 0 1 (100.0) 0 0 0 0
Parenteral nutrition time in days 55.1 ± 249.4 24.6 ± 17.4 41.0 ± 9.5 193.0 ± 210.7 23.5 ± 12.4 14.3 ± 12.1 243.2 ± 417.5 N/A 322.5 ± 447.6 N/A N/A N/A N/A
In-hospital stay in days 36.4 ± 51.9 30.0 ± 18.0 58.3 ± 18.5 148.7 ± 170.1 32.0 ± 17.0 18.0 ± 17.3 90.0 ± 78.3 N/A 101.5 ± 135.1 N/A N/A N/A N/A
Gastroschisis risk stratification index (0–10)
In-hospital mortality 5 (3.9) 1 (10.0) 1 (50.0) 1 (100.0) 1 (100.0) 0 0 0 0 0 0
Re-laparotomy for perforation/
necrosis
4 (3.1) 1 (10.0) 2 (100.0) 0 0 0 0 0 0 0 0
Re-laparotomy for occlusion 6 (4.7) 4 (40.0) 1 (50.0) 1 (100.0) 1 (100.0) 0 0 0 0 0 0
Short bowel syndrome 3 (2.3) 3 (30.0) 0 0 0 0 0 0 0 0 0
Positive blood culture 20 (16.7) 1 (11.1) 0 0 0 0 0 0 0 0 0
Parenteral nutrition time in days 42.7 ± 178.8 244.8 ± 363.9 14.5 ± 16.3 N/A N/A N/A N/A N/A N/A N/A N/A
In-hospital stay in days 36.3 ± 47.8 93.6 ± 61.3 17.5 ± 20.5 N/A N/A N/A N/A N/A N/A N/A N/A
Complex gastroschisis (simple vs. complex)
In-hospital death 6 (4.9) 3 (15.0)
Re-laparotomy for perforation/
necrosis
4 (3.3) 3 (15.0)
Re-laparotomy for occlusion 6 (4.9) 5 (25.0)
Short bowel syndrome 1 (0.8) 4 (25.0)
Positive blood culture 19 (16.2) 2 (12.5)
Parenteral nutrition time in days 40.5 ± 181.5 146.2 ± 270.0
In-hospital stay in days 33.2 ± 39.7 78.2 ± 84.2
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1381Pediatric Surgery International (2022) 38:1377–1383
1 3
1.66–24.51, p = 0.007, respectively. Complex gastroschisis
was associated with increased length of stay, p = 0.000.
We compared the areas under the ROC-curves of GPS,
GRSI and complex gastroschisis with DeLong (1988) test.
There were no significant differences between these risk
stratification scores in any of the outcome endpoints (in-
hospital mortality, re-laparotomy for perforation, ischemia,
necrosis, short bowel syndrome, positive blood culture,
intravenous nutrition time and in-hospital stay in days).
Discussion
The present study demonstrates the function of three differ-
ent risk stratification scores. Our comparison analysis shows
that their ability to predict specific outcome measures dif-
fered from each other. In our study cohort, only GRSI was an
independent predictor for in-hospital mortality, but not the
other studied outcome measures. Gastroschisis prognostic
score and complex gastroschisis classifications were only
able to predict reliably short bowel syndrome.
The literature has provided evidence that there are dif-
ferent types of gastroschisis with varying clinical outcomes
of morbidity and mortality [6, 7, 16, 17]. Our results are in
line with these studies.
Molik etal. and Arnold etal. showed in their studies with
103 and 4344 gastroschisis infants that cases with complex
gastroschisis had decreased survival [6, 18]. Complex gastro-
schisis was significantly associated with death according to
Arnold etal. (2007) [18]. Molik etal. reported 32 (31.0%)
complex cases in their study. All deceased patients were clas-
sified as complex, which resulted in a mortality rate of 28.0%
among this patient group [6]. The incidence of complex gas-
troschisis reported by Arnold etal. was 474 cases (10.9%) [18],
which is similar to our finding of 20 complex cases out of 143
gastroschisis infants (14.0%). Their study reported that coex-
isting bronchopulmonary dysplasia had a higher prevalence
in the complex group. Moreover, cardiac diseases were more
Table 4 The predictive abilities
of the risk scores
AUC area under the curve, CI confidence interval
α Statistical significance of the risk score in logistic/linear regression model
β Statistical significance of the produced area under the curve when the null hypothesis is: AUC = 0.5
* Represents statistical significance
Outcome Multi-variate
p value for the
risk scoreα
AUC and 95% confidence interval AUC
p-valueβ
Gastroschisis prognostic score
In-hospital mortality 0.582 0.531 95% CI 0.326–0.737 0.755
Re-laparotomy for perforation/necrosis 0.932 0.568 95% CI 0.325–0.811 0.546
Re-laparotomy for occlusion 0.053 0.731 95% CI 0.587–0.875 0.011*
Short bowel syndrome 0.023* 0.804 95% CI 0.585–1.000 0.012*
Positive blood culture 0.276 0.446 95% CI 0.318–0.574 0.431
Parenteral nutrition time in days 0.864 N/A
In-hospital stay in days 0.081 N/A
Gastroschisis risk stratification index
In-hospital mortality 0.007* 0.697 95% CI 0.479–0.914 0.049*
Re-laparotomy for perforation/necrosis 0.011* 0.680 95% CI 0.437–0.923 0.109
Re-laparotomy for occlusion 0.074 0.690 95% CI 0.500–0.881 0.036*
Short bowel syndrome 0.315 0.703 95% CI 0.454–0.952 0.094
Positive blood culture 0.314 0.469 95% CI 0.340–0.599 0.657
Parenteral nutrition time in days 0.782 N/A
In-hospital stay in days 0.690 N/A
Complex gastroschisis
In-hospital death 0.274 0.603 95% CI 0.393–0.813 0.301
Re-laparotomy for perforation/necrosis 0.189 0.652 95% CI 0.416–0.888 0.176
Re-laparotomy for occlusion 0.172 0.670 95% CI 0.481–0.860 0.061
Short bowel syndrome 0.036* 0.862 95% CI 0.686–1.000 0.003*
Positive blood culture 0.245 0.485 95% CI 0.352–0.618 0.829
Parenteral nutrition time in days 0.354 N/A
In-hospital stay in days 0.000* N/A
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1382 Pediatric Surgery International (2022) 38:1377–1383
1 3
common in this patient population. [18]. Furthermore, Laje
etal. evaluated outcomes and complications during initial hos-
pitalization of 125 simple and 58 complex gastroschisis cases.
There was no neonatal mortality. [19]. Complex gastroschisis
has been associated with longer mechanical ventilator time [6],
parenteral nutrition time and in-hospital stay [6, 19].
GPS and complex gastroschisis classifications are based
on bowel appearance after delivery [6–8, 18]. In the study
by Cowan etal., the interobserver correlation with GPS risk
score calculation was shown to be reliable between different
surgeons [8]. On the contrary, utilization of the GRSI score
requires additional examinations, such as ultrasound or addi-
tional postnatal imaging [10], which prevents the score from
being used at bedside or immediately after birth.
Arnold etal. developed GRSI to predict death in gastroschi-
sis using data consisting of 4310 patients with gastroschisis
from 1988 to 2002. They divided the patients into two sub-
groups according to the risk of mortality. High-risk patients
have scores greater or equal to 3 and low-risk patients fewer or
equal to 2. Infants classified in the high-risk group had greater
than a 10% risk of death compared to the low-risk group, with
an overall mortality of 3.0% [18]. Interestingly, there was a
statistically significant difference between mortality rates of
high-risk group (GRSI) and complex gastroschisis group [7],
29.4% vs. 9.6%, respectively, p = 0.02.
Indeed, it could be speculated that the small number of
patients and the relatively long follow-up periodin this study
could introduce a bias based on the improvement of care
over time. However, the treating hospital or the time-frame
of birth did not have an effect on mortality in a study by
Tauriainen etal. (2021), which was based mostly on the
same database [20]. On this basis, the results of the present
study can be considered reliable.
The limitations of present study include the retrospec-
tively collected data with some missing values and relatively
small sample size. We speculate that the small number of
patients in our high-risk groups might have prevented us
from obtaining significant results. We do not have photo-
graphs of the appearance of protruding intestines or organs.
The risk scoring was performed using only electronic and
paper patient records. In addition to before mentioned
scores, Score for Neonatal Acute Physiology, Version II
(SNAP-II) and Score for Neonatal Acute Physiology, Peri-
natal Extension, Version II (SNAPPE-II), are also designed
for measurement of illness severity for all neonates requiring
intensive care. SNAP-II is based on six different vital signs
and laboratory tests and SNAPPE-II adds to points for to
birth weight, low Apgar score and small for gestational age
(SGA) [21]. However, we were unable to utilize SNAP-II or
SNAPPE-II scoring methods due to lack of data.
Conclusions
In conclusion, there are three easily obtainable risk stratifica-
tion scores for outcome prediction in gastroschisis patients
with different predictive profiles. However, their predictive
ability did not have a statistical difference. The Gastroschisis
risk stratification index performed moderately well in mor-
tality prediction, whereas gastroschisis prognostic score and
complex gastroschisis were able to identify reliably patients
suffering from short bowel syndrome. Further studies with
larger databases are needed to compare these risk scores in
more detail.
Author contributions AT- study design, drafting of the manuscript,
data collection, acceptance of the final manuscript.AR- data collection,
critical review of the manuscript, acceptance of the final manuscript.
TT- study design, drafting of the manuscript, data collection, statisti-
cal analysis, acceptance of the final manuscript.KV- critical review of
the manuscript, acceptance of the final manuscript.US- critical review
of the manuscript, acceptance of the final manuscript.IH- critical
review of the manuscript, acceptance of the final manuscript.AH- data
collection, critical review of the manuscript, acceptance of the final
manuscript.
Funding Open access funding provided by University of Eastern Fin-
land (UEF) including Kuopio University Hospital.
Declarations
Conflict of interest None of the authors have any conflict of interests
to declare.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
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need to obtain permission directly from the copyright holder. To view a
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