Tropical Medicine and International Health doi:10.1111/tmi.

13294

volume 24 no 10 pp 1169–1197 october 2019

Systematic Review

Diagnostic accuracy and predictive value in differentiating the

severity of dengue infection
Gary Kim Kuan Low1, Jackob Kagize1, Katherine J. Faull2 and Aizad Azahar3

1 Department of Public Health, Torrens University, Pyrmont, NSW, Australia

2 Department of Public Health, Torrens University, Adelaide, SA, Australia
3 Anaesthesiology Unit, Universiti Putra Malaysia, Serdang, Malaysia

Abstract objective To review the diagnostic test accuracy and predictive value of statistical models in
differentiating the severity of dengue infection.
methods Electronic searches were conducted in the Cochrane Database of Systematic Reviews,
Cochrane Central Register of Controlled Trials, MEDLINE (complete), PubMed and Scopus. Eligible
studies to be included in this review were cohort studies with participants confirmed by laboratory
test for dengue infection and comparison among the different severity of dengue infection by using
statistical models. The methodological quality of the paper was assessed by independent reviewers
using QUADAS-2.
results Twenty-six studies published from 1994 to 2017 were included. Most diagnostic models
produced an accuracy of 75% to 80% except one with 86%. Two models predicting severe dengue
according to the WHO 2009 classification have 86% accuracy. Both of these logistic regression
models were applied during the first three days of illness, and their sensitivity and specificity were
91–100% and 79.3–86%, respectively. Another model which evaluated the 30-day mortality of
dengue infection had an accuracy of 98.5%.
conclusion Although there are several potential predictive or diagnostic models for dengue
infection, their limitations could affect their validity. It is recommended that these models be
revalidated in other clinical settings and their methods be improved and standardised in future.

keywords dengue, dengue severity, diagnostic models, accuracy, systematic review

Clinical classification of dengue infection is based on

Introduction
Dengue is a viral infectious disease with an estimated
390 million people infected per year globally [1].
WHO emphasises that dengue prevention and control
of the mosquitos are the most important measures to
curb dengue, but many people are still infected by the
dengue virus, leading to an increase in hospital admis-
sions [2].
The 1997 and 2009 dengue management guideline
developed by WHO, updated in 2012, provides an essen-
tial guide for the management and treatment of dengue
patients [3,4]. The important change among these two
guidelines is the clinical classification. The new clinical
classification has been revised into dengue without/with
warning signs (WS) and severe dengue (SD) to better
reflect clinical judgement than the older classification of
the four grades of dengue haemorrhagic fever (DHF) [5].
severity of dengue infection. Hence, accurate clinical
diagnosis can aid in the management of dengue patients
in hospital. The diagnostic accuracy of the WHO 2009
classification for SD has 96% sensitivity and 97% speci-
ficity, and the WHO 1997 classification of DHF/dengue
shock syndrome (DSS) has a sensitivity of 76% and a
specificity of 54% [5]. The WHO 2009 ‘dengue with
warning sign’ classification has a sensitivity between 87
and 100% and a specificity below 50% [6–8].
Several methods have been evaluated to improve the
accuracy of the currently used WHO 2009 classification,
all of which involve statistical modelling [9–11]. To our
knowledge, there is no review to summarise and recom-
mend a statistical model as a diagnostic tool for severity
of dengue infection. Hence, this study evaluates the diag-
nostic test accuracy and the predictive value of statistical
models in differentiating the severity of dengue infection.

© 2019 John Wiley & Sons Ltd 1169


Tropical Medicine and International Health
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue
Methods
Inclusion criteria for the included studies
The type of study design that was included in this review
was limited to cohort studies (both retrospective and
prospective) because the models predicting or diagnosing
the severity must precede the clinical diagnosis of dengue
for prediction purpose. Participants included in this
review were dengue patients of any age and gender, with
or without underlying comorbidities. Dengue infection
had to be confirmed by non-structural-1 (NS1) antigen
and/or immunoglobulin M (IgM) or positive viral detec-
tion via polymerase chain reaction (PCR). Mathematical
models, statistical models and any prediction models such
as decision tree and neural network were included. Cases
of dengue infection comparing grades of severity were
targeted. If the study was conducted using the WHO
1997 classification, comparison was between classical
dengue fever, the four grades of DHF and DSS. If the
study was conducted using the WHO 2009 classification,
comparison was between dengue without or with warn-
ing signs and SD. The details of the classification can be
found in the respective published guidelines [3,4].
Search methods for identification of studies
An electronic search on bibliographic databases was con-
ducted on 2 November 2018 in the Cochrane Database
of Systematic Reviews, Cochrane Central Register of
Controlled Trials, MEDLINE (complete), PubMed and
Scopus. No language, publication date and study design
restrictions were imposed.
Search strategy
Boolean operator ‘OR’ was used to combine keywords
such as ‘predict’, ‘prognosis’, ‘diagnosis’ and ‘classify’.
The ‘OR’ was also used to combine ‘mathematics’,
‘model’, ‘combined’ and ‘score’. These two combinations
were then combined with ‘dengue’ by using the Boolean
operator ‘AND’ (Appendix A). Keywords used were as
follows: predict, prognosis, diagnosis, classify, mathemat-
ics, model, combined, score and dengue.
Selection of studies
Titles were screened independently by paired reviewers
(KF, JK, AA and GL). Any disagreement on the selection
of papers was first resolved by discussion among the four
reviewers. Subsequently, full texts were retrieved for the
selected papers for full review. The studies excluded after
full-text review are tabulated in Appendix B.
1170
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volume 24 no 10 pp 1169–1197 october 2019
Data extraction and methodological quality
A pre-piloted data extraction form (Appendix C) was
used to extract the data, in accordance with the Checklist
for Critical Appraisal and Data Extraction for Systematic
Reviews of Prediction Modelling Studies (CHARMS)
[12]. The methodological quality was assessed using the
Revised Quality Assessment of Diagnostic Accuracy Stud-
ies (QUADAS-2) [13]. Any discrepancies between the
data extracted and quality assessment were resolved by
discussion among reviewers.
Statistical analysis and data synthesis
The initial plan was to perform meta-analysis by using a
hierarchical summary receiver operating characteristic
(HSROC) model. However, due to the heterogeneity
found in the included studies, such as the various models
being evaluated, the meta-analysis was not performed.
Instead, we present a summary score of accuracy and a
narrative synthesis in this review. The accuracy of the
model was calculated by addition of true positives and
true negatives divided by total sample size. Accuracy was
used as a measure to determine a well-balanced sensitiv-
ity and specificity of a model. We present the best-recom-
mended accuracy score when available, if the study was
evaluated upon few cut-offs.
The narration focuses on two accuracy aspects of the
models: predictive and diagnostic. ‘Predictive’ is defined
as a model applied at least one day prior to the targeted
diagnosis of dengue severity. ‘Diagnostic’ is defined as a
model applied at the same time as the targeted diagnosis
is being made. This study was registered in PROSPERO
(CRD42018116553).
Results
A total of 83 studies were identified from the databases
for full-text review, and 57 studies were excluded after
full-text review. The searches and reasons for exclusion
of studies are described using the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses
(PRISMA) 2009 Flow Diagram in Figure 1.
A total of 26 included studies conducted between
1994 and 2017 were published between 2008 and
2018 [9–11,14–,36]. However, two studies were
related, leaving a total of 25 studies of different set-
tings [23,24]. Five studies were conducted in Singapore,
four in Taiwan and Vietnam, three in Malaysia, two in
Thailand and Venezuela, and one each in French Gui-
ana, Cambodia, Honduras, Indonesia and Sri Lanka.
Altogether 27,534 patients were included in the 25
studies, with a range of 25 to 8123 each (Table 1).
© 2019 John Wiley & Sons Ltd
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Tropical Medicine and International Health volume 24 no 10 pp 1169–1197 october 2019

G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Identification

Records identified through Records identified through Records identified through

MEDLINE (n = 540) PubMed (n = 774) Scopus (n = 621)

Records screened
Screening

(n = 115)
Duplicates removed (n = 32)

Full-text articles assessed Full-text articles excluded, with reasons

for eligibility (total = 57)
Eligibility

(n = 83)
1. Not predicting the severity (n = 24)
2. No statistical model (n = 18)
3. No confirmatory dengue test (n = 9)
4. Not on dengue infection (n = 1)
Studies included in 5. Comparator was other infectious
qualitative synthesis disease (n = 1)
(n = 26) 6. Editorial comments, conference
paper (no full text) (n = 4)
Included

Studies included in
quantitative synthesis
(meta-analysis)
(Not applicable)

Figure 1 PRISMA flow diagram. [Colour figure can be viewed at wileyonlinelibrary.com]

The WHO 2009 classification was employed in nine
studies and the WHO 1997 classification in seven. The
remaining nine studies have various primary outcomes
(Table 4). Cut-off points used to classify age of children
and adults varied; nevertheless, the studies can be identi-
fied as either children or adult cohorts. Seven studies
were conducted with children, ten with adults and five
studies with both, and three studies did not specify the
participant’s age (Table 1).
Most studies chose multivariate logistic regression to
develop the prediction model, some in combination with
other types of statistical methods such as classification
and regression tree (CART), random forest classification
and structural equation model (SEM). Developed models
were validated in 17 studies. Handling of missing data is
tabulated in Table 1.
Almost all studies were deemed an ‘unclear’ risk of
bias (uncertain of its risk of bias) in all the domains in
QUADAS-2 except the ‘patient selection’ domain
(Appendix D), where all had a low risk of bias except
four studies whose design was unclear and which
employed a matched case–control design [16,19,33,35].
The ‘concerns regarding applicability’ of ‘patient selec-
tion’ domain were deemed low-risk for most of the stud-
ies except for three case–control studies and one with
unclear design [16,19,33,35].

© 2019 John Wiley & Sons Ltd 1171

 Table 1 The characteristics of the included studies

1172
Confirmatory Missing data Variables
Study ID Setting Age Country method n Validation management Model included

Brasier 2012 Clinics and Adult and Venezuela RT-PCR 38 CART decision None Bayesian variable PLT,
hospitals, or who children (15.8 tree, 10 trials selection for lymphocytes,
were identified by
7.8 years using 10-fold generalised additive IL-10
community-based and 19
cross-validation models, logistic
active 13.4 years) regression, CART,
surveillance, random forest
Maracay. classification
Carrasco 2014 2006–2008, Adult Singapore Dengue PCR 596 The fivefold Single Logistic regression or Female gender,
Department of (definite dengue) validation process imputation its equivalent below normal
Infectious and dengue IgM or repeated 1000 generalised linear HCT,
Diseases, Tan IgG times. models with a logit abdominal
Tropical Medicine and International Health

Tock Seng link function and distension,

Hospital binomial errors vomiting and
fever on
admission
Djossou 2017 17 March 2013–30 Children and French NS1, RT-PCR or 806 Bootstrapping with None Cox proportional HCT, protein,
September 2013 adult Guiana seroconversion 1000 replications hazards model sodium,
at Cayenne semi-external lymphocyte,
hospital validation. aches and
pains, extensive
purpura, rash,
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

serous effusion,
bleeding.
Fernandez 2009–2010, clinics Children and Honduras Dengue IgM and 320 Bootstrapping with None Logistic regression Headache,
2017 in Tegucigalpa adult viral isolation narrow model petechiae,
and San Pedro confidence ascites, PLT
Sula. intervals
Huang 2017a 1 September 2015– Young (65– Taiwan NS1 Ag, IgM and 627 None None Multivariate logistic Severe coma,
31 December 74 years), IgG regression model bedridden,
2015, Chi-Mei moderate (75 severe hepatitis,
Medical Center. –84 years), renal
and old impairment
elderly
(≥85 years)
Huang 2017b 1 September 2015– All ages (adult Taiwan NS1, IgM, and IgG; 2358 Bootstrapping None Multivariate logistic Elderly age
31 December and children) living in/travel to method with regression (≥65 years),
2015, Chi-Mei dengue-endemic 1000 hypothetical hypotension
Medical Center areas; and fever and study populations (systolic blood
two criteria (nausea by using random pressure
or vomiting, rash, sampling from <90 mmHg),
aches and pains, actual study haemoptysis,
positive tourniquet patients diabetes
test, leukopenia, mellitus and
and warning sign) chronic
bedridden.

© 2019 John Wiley & Sons Ltd

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 Table 1 (Continued)

Confirmatory Missing data Variables

Study ID Setting Age Country method n Validation management Model included

© 2019 John Wiley & Sons Ltd

Huy 2013 January 2002 and Ages 6 months Vietnam Virus isolation, if 444 The whole data set Multiple Logistic regression Admission day,
December 2007, to 15 years RNA was detected was randomly imputation prediction model purpura/
Center for by RT-PCR assay split into ten ecchymosis,
Preventive or if the serological equal subsets. For ascites/pleural
Medicine in Vinh assay was positive ten times, nine effusion, PLT
Long Province subsets were used and pulse
Tropical Medicine and International Health

and the to train the model pressure

Children’s and the remaining
Hospital No. 2 in subset was used
Ho Chi Minh to validate the
City AUC of each
model. The cross-
validation was
repeated 10 times
to yield a total of
100 AUC values
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

for each model

Ju 2013 Unclear Unclear Maracay, RT-PCR 51 None None Generalised PathSeeker IL-10,
Venezuela modelling was lymphocytes
recommended among and PLT
various models
Lam 2015 2003–2009, <15 years old Vietnam Dengue IgM and IgG 1207 Temporal Single Multivariable logistic Age, day of
Hospital for capture ELISAs validation: imputation model illness,
Tropical Diseases and/or RT-PCR models were temperature,
in Ho Chi Minh developed using pulse rate,
City 939 patients HCT,
enrolled before haemodynamic
2009 and status.
validated on the
268 patients
enrolled during
2009. Internal
validation: model
performance
repeated 10-fold
cross-validation.

1173
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 Table 1 (Continued)

1174
Confirmatory Missing data Variables
Study ID Setting Age Country method n Validation management Model included

Lam 2017 2001–2009, 5–15 years Vietnam Detection of DENV- 2301 10 times 10-fold Multiple Multivariate logistic PLT count
Hospital for RNA in plasma by cross-validation imputation regression model dynamics
Tropical Diseases RT-PCR, or by (stepwise backward (baseline or
in Ho Chi Minh seroconversion on model) current value,
City the capture ELISA or % change)
and other
predictors (age,
sex, history of
vomiting,
temperature,
palpable liver)
Tropical Medicine and International Health

Lee 2008 1 January to 31 Adult and Singapore Probable cases had 82 None None Predictive probability History of
December 2004 children compatible acute equation of bleeding, total
to the clinical illness with multivariate logistic protein, serum
Department of positive dengue regression urea and
Infectious IgM or IgG and lymphocyte
Diseases at Tan confirmed cases had (%).
Tock Seng positive PCR
Hospital
Lee 2016 1 July 2002–31 ≥18 years old Taiwan RT-PCR, a 49 1063 Validation: 190 None Multivariate logistic Model 1:
May 2015, increase in IgG regression model leukocytosis,
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Kaohsiung Chang antibody in the (forward Wald) minor

Gung Memorial convalescent serum gastrointestinal
Hospital and compared to in the bleeding, age
Kaohsiung acute-phase serum, and PLTModel
Medical and/or detection of 2: leukocytosis,
University NS1Ag. age.
Hospital
Liu 2013 July–November ≧18 years Taiwan RT-PCR, ELISA for 100 None None Combination of Other variables
2002, emergency IgM antibody in variables, e.g. were tested, but
Services or during acute-phase serum, variable A + B the 3 best
admission at and a 49 or higher models included
Kaohsiung Chang increase in prolonged
Gung Memorial haemagglutination APTT, normal
Hospital inhibition titres in PT, + PLT
(KSCGMH) convalescent serum count < 100 9
as compared to that 109 cells/L,
in acute-phase ALT > 40U/L
serum PLT count.
Low 2018 January 2016– ≧15 years Malaysia NS1 Ag, IgG and 82 Validation of None Multivariable logistic Gender, vascular
October 2017; IgM, virus isolation whole data set regression model endothelial
Ampang Health and RT-PCR growth factor,
Clinic, Ampang WBC, HCT,
Hospital and ALT
Serdang Hospital.

© 2019 John Wiley & Sons Ltd

volume 24 no 10 pp 1169–1197 october 2019

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 Table 1 (Continued)

Confirmatory Missing data Variables

Study ID Setting Age Country method n Validation management Model included

Nguyen 2017 1 October 2010– 1–15 years old Vietnam (1) Validated qRT- 2060 Model validation None Logistic regression Vomiting, PLT,
31 December PCR assay, (2) NS1 was examined by model NS1 rapid test
2013, outpatient ELISA or (3) IgM 2 approaches: (1) status and AST
departments of seroconversion in ‘leave-one-site-out level

© 2019 John Wiley & Sons Ltd

hospitals: paired blood cross-validation’ –
Hospital for samples that is repeatedly
Tropical Diseases, developing the
Children’s algorithm on all
Hospital No. 1, but 1 study site
Children’s and validation on
Hospital No. 2, the left-out study
Tropical Medicine and International Health

Tien Giang site; and (2)

Provincial temporal
Hospital, Dong validation with
Nai Children’s patients recruited
Hospital, Binh before 15 June
Duong Provincial 2012 as the
Hospital, and training set and
Long An patients recruited
Provincial thereafter as the
Hospital evaluation set
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Pang 2014 January 2004– Adult Singapore Dengue Duo IgM 8123 None None Stepwise forward and At presentation:
December 2008, and IgG and PCR backward elimination neutrophil (%),
Department of method, with the top ALT and serum
Infectious 10 most significantly urea.24 h prior
Diseases, Tan associated variables to ICU:
Tock Seng based on the P-value monocyte (%),
Hospital of the univariate blood pressure,
conditional regression pulse rate,
analyses lymphocyte
(%).
Pang 2016 2005–2008, ≥18 years old Singapore Dengue PCR 158 From 2009 to None Backward elimination Model 13:
primary care 2010 cohort estimation using CCL8, VPS13C,
polyclinics in validation: 115 multiple logistic uPAR; Model
Singapore regressions 14: CCL8,
VPS13C, PLT

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 Table 1 (Continued)

1176
Confirmatory Missing data Variables
Study ID Setting Age Country method n Validation management Model included

Park 2018 1994–1997, Queen 6 months– Thailand Viral isolation by 257 New 897 Multiple SEM The SEM for any
Sirikit National 15 years old mosquito validation set imputation dengue illness:
and Kamphaeng inoculation and/or age, AST,
Phet Provincial detection of viral WBC,
Hospital RNA by RT-PCR lymphocytes
in plasma, and/or (%), PLT and
by serological tourniquet test.
assays (IgM/G The SEM for
ELISA and DHF included
haemagglutination age, AST,
inhibition assay) of WBC, HCT,
Tropical Medicine and International Health

paired acute– PLT and

convalescent plasma tourniquet test.
samples The SEM for
DSS included
age, AST,
WBC,
lymphocytes
(%), PLT and
tourniquet test.
Phakhoun- 12 October 2009– Children Cambodia NS1 Ag or if paired 198 Cross-validation Single CART HCT, Glasgow
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

thong 2018 12 October 2010, <16 years old sera from acute and imputation Coma Scale,
Angkor Hospital convalescent time urine protein,
for Children points showed creatinine and
rising or static anti- PLT count
dengue IgM (and
anti-dengue IgM
was greater than
anti-Japanese
encephalitis IgM)

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volume 24 no 10 pp 1169–1197 october 2019

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 Table 1 (Continued)

Confirmatory Missing data Variables

Study ID Setting Age Country method n Validation management Model included

Potts 2010 Queen Sirikit 6 months– Thailand Serological assays 1227 Validation of None Multivariable models Age, PLT, WBC,
National Institute 15 years old IgM/IgG ELISA and QSNICH were constructed for AST, HCT,
of Child Health haemagglutination multivariable each outcome in a neutrophils,
(QSNICH) in inhibition assay), models to KPPPH manual stepwise gender,

© 2019 John Wiley & Sons Ltd

Bangkok during viral isolation, and/ data using procedure based on tourniquet test
the years 1994– or RT-PCR optimal the univariate
1997, 1999– probability cut-off indicators with the
2002, and 2004– best area under the
2007 and ROC curve. For
Kamphaeng Phet variables that were
Provincial highly correlated,
Tropical Medicine and International Health

Hospital (KPPPH) only the variable with

during the years the higher area under
1994–1997 the curve from
univariate analysis
was used in the
multivariable
modelling. Variables
that did not remain
significant at the
a = 0.05 level were
removed from the
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

model, and the

variable with the next
highest area under
the ROC was added
into the model
Premaratne Colombo South Unclear Sri Lanka NS1 early dengue 25 DHF None None Multivariate statistical Cumulative
2017 Teaching ELISA or with the patients analysis was effects of the
Hospital commercial and 11 performed to study PLT, NS1
capture-IgM and DF the characteristics Panbio levels,
IgG ELISA and interactions of IgG Panbio
parameters. Fuzzy levels and
logic fundamentals lymphocyte
were used to map the count
risk of developing
severe forms of
dengue. The
cumulative effects of
the parameters were
incorporated using
the Hamacher and
the OWA operators

1177
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 Table 1 (Continued)

1178
Confirmatory Missing data Variables
Study ID Setting Age Country method n Validation management Model included

Sani 2018 1 January 2014–31 ≥18 years old Malaysia NS1 Ag, high-titre 199 (20 None None Variable selection was Pulse rate,
December 2014, level of IgG or died) performed using bleeding, serum
Hospital Kuala positive IgM. fivefold cross- bicarbonate,
Lumpur validated Lasso serum lactate,
regression. Selected serum
variables were then creatinine, AST
used to build logistic and ALT were
regression models used to build
with cross-validation. models
composed of a
combination of
Tropical Medicine and International Health

a pair of these
variables, with
age and gender
adjustments
Suwarto 2016 Development of ≥14 years old Indonesia NS-1 Ag test 172 Validation: 207 None Multiple regression HCT increase
& 2018 model: March analysis using a ≥15.1%, serum
2010–August backward selection albumin
2015; Cipto algorithm ≤3.49 mg/dL,
Mangunkusumo PLT ≤49,500/
Hospital and lL and AST
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Persahabatan ratio ≥ 2.51.

Hospital, Jakarta.
Validation:
January 2011–
March 2016,
Pondok Indah
Hospital.
Tamibmaniam 1 February to 31 Unclear Malaysia Unclear (serologically 657 None None Multivariate logistic Vomiting, pleural
2016 May 2014, confirmed) regression followed effusion and
Hospital Kuala by decision algorithm low systolic
Lumpur blood pressure
Wong 2016 January 2005–31 Adult Singapore Dengue Duo IgM 4383 Training (80%) Single Multivariate logistic Gender,
December 2008 and IgG and RT- and validation imputation regression temperature,
Communicable PCR sets (20%) nausea or
Disease Center at vomiting,
Tan Tock Seng absolute
Hospital neutrophil
count, absolute
lymphocyte
count, HCT,
PLT

ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CART, classification and regression tree; HCT, haemat-
ocrit; n, total number of patients; PLT, platelet; PT, prothrombin time; ROC, receiver operating characteristic; SEM, structural equation model; WBC, white blood cell.

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Tropical Medicine and International Health
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue
WHO 2009 classification
All studies evaluated the models against SD and non-SD
as reference standard except two which evaluated against
DSS and WS with hospitalisation [18,27]. The DSS classi-
fication is a subcategory of SD under the WHO 2009
classification [18] (Table 2).
Diagnostic value
Most studies attempted to evaluate the models as early as
possible in the progression of dengue infection, but the
exact day of the diagnosis was not reported. Hence, we
could only assume that the model was made for the pur-
pose of clinical diagnosis. Most models produced an
accuracy of 75% to 80% except Nguyen’s 2017 model
with 86% [20] (Figure 2).
The logistic regression model developed by Nguyen
2017 has a sensitivity of 91% and a specificity of 86%.
The cohort of patients presented in the first three days of
illness, which could allow the diagnosis to be made early
and could predict the SD if the exact day of SD diagnosis
was known.
Lee 2016 had the second-best accuracy with two mod-
els: Model 1 for patients presenting in the first four days
of illness; and Model 2 for those who presented later
[22]. Model 1 had a sensitivity and specificity of 88.9%
and 76.0%, and Model 2 had a sensitivity and specificity
of 100% and 76.1% (Table 2).
Predictive value
Two studies clearly indicated that the analysis was prior
to the diagnosis of SD: Low 2018 and Carrasco 2014
[10,28]. Thus, these two studies could be considered as
predictive models. Accuracy was highest with 86% in
Low 2018 with its logistic regression model predicting
SD in the first three days of illness[10] (Figure 2). The
sensitivity was 100% and the specificity 79.3% (Table 2).
Carrasco 2014 has a low accuracy of about 40% mainly
due to the poor specificity of 27–29%, though sensitivity
was 90%.
WHO 1997 classification
All studies evaluated the statistical model using DHF case
classification, except Premaratne 2017 which used WHO
1997 as case classification but reclassified into severe and
non-SD with unclear definition [35]. Four studies also
evaluated DF case classification [9,31,32,36], and two
evaluated all dengue cases against other febrile illness or
non-dengue cases [31,36].
© 2019 John Wiley & Sons Ltd
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volume 24 no 10 pp 1169–1197 october 2019
Diagnostic value
Most studies with accuracy between 75% and 85% did
not state when the statistical models were evaluated
according to the phases of dengue infection (Table 3 and
Figure 3). Only Premaratne 2017 specified the day of ill-
ness of the patients, that is 96–120 h, when the model
was evaluated. Unfortunately, the accuracy of Pre-
maratne’s 2017 model was <52.8% (no sensitivity or
specificity provided).
Predictive value
Only the model of Park 2018 was evaluated in the early
phase of the disease but without a clear statement on
whether this was before the DHF diagnosis [9]. However,
this model was assumed to be predictive, and its accuracy
was around 65.5–91.8% with the best prediction of DSS
at day 3 of illness. The sensitivity and specificity for pre-
diction of DSS at day 3 of illness were 60% and 94.7%,
respectively (Figure 3).
Miscellaneous case classifications
Various case classifications apart from the WHO one
were employed. These classifications were mainly subcat-
egories of SD, that is the specific complications of dengue
infection (Table 4). The majority of studies had more
than 80% accuracy; two had an accuracy between 90%
and 97% [19,30]. Huang 2017b, which evaluated the 30-
day mortality with a cut-off ≥3, had the highest accuracy
of 98.5% [16] (Figure 4). The day of illness being evalu-
ated was unclear in all studies except in Pang 2014,
where data were obtained at first presentation in the hos-
pital and 24 h prior to admission to the intensive care
unit [33]. Sensitivity and specificity ranged between
88.2% and 88.9% and 76.0% and 88.9%, respectively.
Discussion
Several models using different case classifications have
more than 80% accuracy (proportion of cases correctly
identified), and some have potential value in predicting the
relevant classification with ideal sensitivity and specificity.
WHO 2009 classification
The models of Low 2018 and Nguyen 2017, developed
in reference to the WHO 2009 case classification, were
promising with an accuracy of 86% [10,20] they could
predict the SD, which has better sensitivity and specificity
in comparison with the ‘warning signs’ [10,20]. The
1179
 1180
Table 2 The accuracy of studies with WHO 2009 classification as reference standard

Reference Day of illness

Study ID standard evaluated Cut-off value AUC SENS (%) SPEC (%) PPV (%) NPV (%)

Carrasco 2014 WHO 2009 No SD at Well-resourced: 90; Well-resourced: 29;

presentation Resource-limited Resource-limited
settings (not settings (not
requiring requiring
laboratory laboratory
measurement): 90 measurement): 27
Fernandez WHO 1997 First 24 h of Probability < 0.75 (95% CI: 76.4 70.3
2017 reclassified admission 7% assigned as 0.66 to 0.83)
into WHO 0 (non-SD) and
Tropical Medicine and International Health

2009 ≥7% assigned

as 1
Lam 2017 DSS (WHO Days 1–4 of Day 3 is 0.68;
2009) illness days 4–5 for
DSS: 0.72–0.74
Lee 2016† WHO 1997 Model 1: 1 point Model 1: 0.90 Model 1: 88.9; Model 1: 76.0;
and 2009 ≤4 days; Model (95% CI, 0.83– Model 2: 100 Model 2: 76.1
dengue 2: >4 days 0.98); Model 2:
definitions 0.92 (95% CI,
reclassify into 0.83–1.0)
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

non-SD and
SD
Low 2018 WHO 2009 Days 1–3 of 0.34 0.84 (95% CI: 100 79.3
illness (analysis 0.73,0.94)
one day prior
to SD)
Nguyen 2017 WHO 2009 <72 h 0.96 (0.91–.098) 91.0 86.0 10.0 99.0
Pang 2016 WHO 2009 < 72 hrs from Probability: 0.2, Model 13: 96.0, Model 13: 49.1, Model 13: Model 13:
(WS+Hosp. acute onset of 0.5, 0.8 64.0, 40.0 76.4, 90.9 46.2, 55.2, 96.4,
and non- fever of ≥38°C. Model 14: 96.0, Model 14: 54.6, 66.7 82.4, 76.9
WS+non- 64.0, 32.0 78.2, 94.6 Model 14: Model 14:
Hosp.) 49.0, 55.6, 96.8,
72.7 81.1, 75.4
Phakhoun- WHO 2009 Unclear 0.616 60.5 65.0
thong 2018
Tamibmaniam WHO 2009 Unclear 81.0 54.0 16.0 96.0
2016

AUC, area under the curve; DSS, dengue shock syndrome; NPV, negative predictive value; PPV, positive predictive value; SD, severe dengue; SENS, sensitivity; SPEC,
specificity; WS, warning signs.
†
Model 1: the SD predictive score included 3, 2, 1 and 2 points for leucocytosis (WBC >10 9109 cells/L), minor gastrointestinal bleeding, age 65 years and platelet
count 100 9 109 cells/L, respectively; Model 2: 2 points for leukocytosis (WBC >109109 cells/L) and 1 point for age 65 years.

© 2019 John Wiley & Sons Ltd

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Tropical Medicine and International Health volume 24 no 10 pp 1169–1197 october 2019

G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Carrasco2014: Well-resourced
Carrasco2014: Resource-limited
Fernandez2017
Lee2016: Model 1
Lee 2016: Model 2
Low2018
Nguyen2017
Pang2016: Model 13, P = 0.2
Pang2016: Model 13, P = 0.5
Pang2016: Model 13, P = 0.8
Pang2016: Model 14, P = 0.2
Pang2016: Model 14, P = 0.5
Pang2016: Model 14, P = 0.8
Phakhounthong2018
Tamibmaniam2016

0 20 40 60 80 100
Accuracy (%)

Figure 2 The accuracy of models using WHO 2009 classification. Legend: ■ Predictive model; ● Diagnostic model. Abbreviation: p,
probability cut-off.

current recommended prediction is by using ‘warning
signs’, which has similar sensitivity but poor specificity of
<50% [6–8]. With a specificity of 80% or more, patients
who might not develop SD could be discharged from the
hospital safely, which would reduce the burden of the
hospital resources.
The models by Low 2018 and Nguyen 2017 have the
potential to be predictive because patients were recruited
and evaluated during the first three days of the illness;
most of the complications of SD occur later [37–39]. It is
worth noting that the model in Nguyen 2017 is applica-
ble to patients under 15 years while the model in Low
2018 is for those over 15. Hence, the models’ utility
should be confined to the appropriate age of the patients
and to the first three days of illness.
The logistic regression equation by Low 2018 was as
follows:
probability value ¼ 217:03 þ ð110:35Þ
Gender (Female = 1)
þ 0:33  VEGF þ ð16:86Þ  white blood cell count :
þ ð6:15Þ  haematocrit
þ 0:46  alanine aminotransferase
With this equation, clinicians can compute the proba-
bility value and determine if it is above the cut-off of
0.34 for predicting SD. The cut-off was selected based on
Youden’s index for the best sensitivity and specificity
[10].
The easy-to-use nomogram developed by Nguyen
2017 to predict the percentage of risk of developing SD
in children [20] has a simple diagram to follow by sum-
ming up the scores and matching the score against the
risk score.
The models of both Low 2018 and Nguyen 2017 were
validated but were not tested to assess their reliability
(Table 1). Although the validation procedures were dif-
ferent, we assume they were rigorous with validation
onto another data set. The validation in the studies of
Low 2018 and Nguyen 2017 is internal: the data set used
for validation was derived from the same cohort of
patients. (Authors: This sentence seems to contradict the
previous one. Please clarify.) This has implications for
judging the risk of bias assessment in both QUADAS-2
and Prediction model Risk Of Bias ASsessment Tool
(PROBAST). Domains such as ‘pre-specified threshold’,
‘interpretation blinded from reference standard’, ‘inter-
pretation blinded from index test’ and ‘any patients did
not receive either index test or reference standard’, which
were similar in PROBAST, could only be judged as ‘not
applicable’. These domains require the models to be
externally validated, that is testing in the ‘real-world’

© 2019 John Wiley & Sons Ltd 1181

 1182
Table 3 The accuracy of studies with the WHO 1997 classification as reference standard

Reference Day of illness

Study ID standard evaluated Cut-off value AUC SENS (%) SPEC (%) PPV (%) NPV (%)

Brasier WHO 1997 Unclear AUC: 0.87; average

2012 accuracy: 84.6%
(DHF) and 84.0%
(DF)
Ju 2013 1997 (Predict Unclear AUC: 0.98 (train),
Tropical Medicine and International Health

DHF. WHO 0.92 (test)

2009 Accuracy: 88.2%
reclassified (train), 80.4%
into 1997) (test)
Lee 2008 WHO 1997 Unclear ≥ 5.1 0.89 (95% CI: 0.85 97.6 60.2 13.9 99.9
–0.92)
Liu 2013† WHO 1997 Unclear Model OD 1: 0.84 Model OD 1: Model OD 1: Model OD 1: Model OD 1:
(OD/DF/DHF (0.78–0.90) 97.0; Model 70.0; 76.4; 95.9;
in comparison Model OD 2: 0.83 OD 2: 87.9 Model OD 2: Model OD 2: Model OD 2:
with non- (0.75–0.92) Model DF 1: 78.9 87.9 78.9
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

dengue) Model DF 1: 0.82 94.7; Model Model DF 1: Model DF 1: Model DF 1:

(0.75–089) DF 2: 88.9; 70.0; 64.3; 95.9;
Model DF 2: 0.84 Model DHF Model DF 2: Model DF 2: Model DF 2:
(0.74–0.94) 1: 100; 78.9 80.0 88.2
Model DHF 1: Model DHF Model DHF 1: Model DHF 1: Model DHF 1:
0.85 (0.79–0.91) 2: 86.7; 70.0; 58.9; 100;
Model DHF 2: Model DHF Model DHF 2: Model DHF 2: Model DHF 2:
0.83 (0.72–0.93) 3: 89.3 78.9; 76.5; 88.2;
Model DHF 3: Model DHF 3: Model DHF 3: Model DHF 3:
0.85 (0.76–0.94) 75.5 65.8 93.0
Park 2018 WHO 1997 Fever 38.5°C Dengue: 0.593 Days 2–5 for Dengue: 45.9– Dengue: 78.1– Dengue: 63.0– Dengue: 75.2–
< 72 h, –0.718; dengue are 0.73– 89.1; DHF: 90.4; 95.4; 82.2;
analysis on DHF: 0.189– 0.94; 35.3–80.8; DHF: 72.4–91.2; DHF: 21.4–54.1; DHF: 91.7–95.3;
days 3 0.282; DHF is 0.61–0.87; DSS: 60.0– DSS: 63.4–94.7 DSS: 5.7–19.4 DSS: 98.0–100
and 1 DSS: 0.044– DSS is 0.74–0.86 100
(defervescence 0.073
= day 0)

© 2019 John Wiley & Sons Ltd

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 © 2019 John Wiley & Sons Ltd
Table 3 (Continued)

Reference Day of illness

Study ID standard evaluated Cut-off value AUC SENS (%) SPEC (%) PPV (%) NPV (%)
‡
Potts 2010 WHO 1997 Unclear Optimal (1) DHF vs. (1) DHF vs. (1) DHF vs. (1) DHF vs. (1) DHF vs.
Tropical Medicine and International Health

(OFI, DF and probability DF = 0.86–0.87 DF = 76.9– DF = 79.3–80.6 DF = 68.0–76.9 DF = 80.6–87.8

DHF and cut-off: (2) DHF vs. 79.6 (2) DHF vs. (2) DHF vs. (2) DHF vs.
reclassify into (1) DHF vs. others = 0.91–0.94 (2) DHF vs. others = 85.4– others = 53.9– others = 89.3–
severe dengue DF = 0.35 (3) Dengue vs. others = 76.9 85.5 70.2 96.8
as defined by (2) DHF vs. OFI = 0.93–0.96 –85.8 (3) Dengue vs. (3) Dengue vs. (3) Dengue vs.
the study) others = 0.19 (4) Severe dengue (3) Dengue OFI = 88.4–90.9 OFI = 87.1–94.9 OFI = 70.4–90.1
(3) Dengue vs. others = 0.86– vs. (4) Severe dengue (4) Severe dengue (4) Severe dengue
vs. 92 OFI = 81.6– vs. others = 76.7 vs. others = 44.3 vs. others = (94.4
OFI = 0.45 89.2 –82.3 –49.2 –96.6)
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

(4) Severe (4) Severe

dengue vs. dengue vs.
others = 0.17 others = 83.0
–83.3
Premaratne 1997 (unclear: 96–120 h Accuracy of
2017 severe and classifying is
non-severe 52.8%.
categories)

AUC, area under the curve; SENS, sensitivity; SPEC, specificity; PPV, positive predictive value; NPV, negative predictive value; DF, dengue fever; DHF, dengue haemor-
rhagic fever; DSS, dengue shock syndrome; OD, overall dengue; OFI, other febrile illness.
†
Model 1: platelet count <1009109 cells/L; Model 2: prolonged activated partial thromboplastin + normal prothrombin time + platelet count <1009109 cells/L; Model
3: platelet count <1009109 cells/L + alanine aminotransferase>40U/L.
‡
Validation in two centres: Queen Sirikit National Institute of Child Health and Kamphaeng Phet Provincial Hospital.

1183
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Tropical Medicine and International Health volume 24 no 10 pp 1169–1197 october 2019

G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Brasier2012
Ju2013
Lee2008
Liu2013: Model OD 1
Liu2013: Model OD 2
Liu2013: Model DF 1
Liu2013: Model DF 2
Liu2013: Model DHF 1
Liu2013: Model DHF 2
Liu2013: Model DHF 3
Park2018: Dengue illness day 2
Park2018: Dengue illness day 3
Park2018: Dengue illness day 4
Park2018: Dengue illness day 5
Park2018: DHF illness day 2
Park2018: DHF illness day 3
Park2018: DHF illness day 4
Park2018: DHF illness day 5
Park2018: DSS illness day 2
Park2018: DSS illness day 3
Park2018: DSS illness day 4
Park2018: DSS illness day 5
Potts2010*: DHF vs. DF
Potts2010*: DHF vs. Others
Potts2010*: Dengue vs OFI
Potts2010*: Severe dengue vs others
Premaratne2017

0 20 40 60 80 100
Accuracy (%)

Figure 3 The accuracy of models using the WHO 1997 classification. Legend: ■ Predictive model; ● Diagnostic model. [Colour figure
can be viewed at wileyonlinelibrary.com]

situation with different cohort of patients and at different
time point. Perhaps a more relevant risk of bias domain
should be developed to assess studies at the developmen-
tal phase (internal validation), supplemented by QUA-
DAS-2 or PROBAST if the studies were externally
validated.
WHO 1997 classification
The majority of clinicians are now adopting the WHO
2009 classification, and thus, models based on the old
WHO 1997 classification are no longer applicable for
recommendation. However, identification of predictors
could be useful for future model development. In contrast
to most other models, which used logistic regression [9],
Park 2018 used a structural equation model (SEM) tech-
nique. SEM could be used to develop a predictive or
diagnostic model based on the WHO 2009 case classifica-
tion in future.
Miscellaneous case classification
Studies that developed models evaluating complications of
dengue infection could be useful. An example is that by
Djossou 2017 which determines the hypotension/shock in
all age groups [30]. However, the model has a limitation
as there was no information on when it was developed in
accordance with the diagnosis of hypotension; that is, pre-
dictive capability is uncertain. This was similarly a limita-
tion for studies which predict mortality/death of dengue
patients [11,16,19]. Otherwise, it could be a potential tool
to guide the clinical decision for admission of the patient
into the hospital or intensive care unit.
Overall discussion
As discussed, most models had several limitations: (1) the
overall risk of bias was unclear due to lack of reporting,
(2) they were not generalisable to other dengue-endemic
countries due to the differences in population which

1184 © 2019 John Wiley & Sons Ltd

 Table 4 The accuracy of studies with various outcome definitions as reference standard

Day of illness
Study ID Reference standard evaluated Cut-off value AUC SENS (%) SPEC (%) PPV (%) NPV (%)

Djossou 2017 Hypotension Unclear Not specified 0.85 50.0 94.2 70.0 87.4
(SBP<80 mm Hg

© 2019 John Wiley & Sons Ltd

in children
<5 years, and
SBP<90 mm Hg in
those >5 years of
age)
Huang 2017a Mortality Unclear ≥1 and ≥2 ≥1: 70.4; ≥2: ≥1: 88.2; ≥2: ≥1: 21.1; ≥2: ≥1: 98.5; ≥2:
predictor out 33.3 99.4 57.1 98.5
Tropical Medicine and International Health

of 4.
Huang 2017b 30-day mortality Unclear 1, 2, ≥3 0.85 (0.79– 1: 91.2; 2: 1: 68.8; 2: 1: 4.1; 2: 7.8; 1: 99.8; 2:
0.91) 55.9; ≥3: 14.7 90.4; ≥3: 99.7 ≥3: 45.5 99.3; ≥3: 98.8
Huy 2013 Recurrent shock of Not specified 154.5 0.73 68.3 68.2
dengue†
Lam 2015 Recurrent shock‡ <4, 4, 5, 6, ≥7 Not applicable Profound DSS:
0.69;
recurrent
shock: 0.65
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Pang 2014 Early clinical and The data at first First First First First First
laboratory risk presentation in presentation: presentation: presentation: presentation: presentation:
factors of ICU hospital and 24 h 1.4; 24 h 88.2; 24 h 88.9; 24 h 62.5; 24 h 97.3; 24 h
requirement. prior to ICU prior to ICU: prior to ICU: prior to ICU: prior to ICU: prior to ICU:
0.4 88.9 76.0 80.0 86.4
Sani 2018 Prediction of Unclear Not available 83.5 (72.4–
mortality from 94.6)
severe dengue of
WHO 2009
Suwarto 2016 Presence of pleural Unclear ≥2 0.88 (95% CI: 92.5 74.3 79.0 90.4
& 2018 effusion and/or 0.83–0.92)
ascites
Wong 2016 Clinically significant Unclear 3.919 0.76 87.0 38.0 6.0 98.0
bleeding

AUC, area under the curve; DSS, dengue shock syndrome; ICU, intensive care unit; NPV, negative predictive value; PPV, positive predictive value; SBP, systolic blood
pressure; SD, severe dengue; SENS, sensitivity; SPEC, specificity.
†
Recurrent shock definition: received adequate fluid according to the WHO 1997 guidelines for volume replacement and had tachycardia, abnormal coolness of limbs
and a pulse pressure ≤25 mmHg that had previously reached a level ≥30 mmHg.
‡
Recurrent shock definition: at least one episode after the initial resuscitation profound dengue shock syndrome, defined as either a) requirement for two or more colloid
boluses (either crystalloid resuscitation for compensated shock at presentation plus two or more episodes of recurrent shock, or colloid resuscitation for decompensated
shock at presentation plus one or more episodes of recurrent shock) or b) requirement for inotropes in addition to colloid therapy, to maintain cardiovascular stability.

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 13653156, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13294 by National Institutes Of Health Malaysia, Wiley Online Library on [18/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Tropical Medicine and International Health volume 24 no 10 pp 1169–1197 october 2019

G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Djossou2017: Hypotension

Huang2017a: Mortality ≥1 predictor

Huang2017a: Mortality ≥2 predictor

Huang2017b: 30-day mortality cut-

off 1
Huang2017b: 30-day mortality cut-
off 2
Huang2017b: 30-day mortality cut-
off ≥3
Huy2013: Recurrent shock of dengue

Pang2014: Risk factors of ICU

requirement at first presentation
Pang2014: Risk factors of 24 hours
prior ICU requirement
Suwarto2016&2018: Presence of
pleural effusion and/or ascites
Wong2016: Clinically significant
bleeding

0 20 40 60 80 100 120
Accuracy (%)

Figure 4 The accuracy of models using miscellaneous classification. [Colour figure can be viewed at wileyonlinelibrary.com]

might differ in clinical manifestation and virulent strain

of the dengue virus, (3) their use of sophisticated models
and expensive testing of biomarkers could hamper their
use in clinical practice, and (4) treatment could change
the clinical manifestation, which will affect their diagnos-
tic or predictive accuracy.
Apart from using QUADAS-2 as the risk of bias
assessment, PROBAST was also used for evaluation of
studies where we found unclear risk (not reported)
[40]. Thus, future reports should follow Standards for
Reporting of Diagnostic Accuracy Studies (STARD) or
Transparent Reporting of a multivariable prediction
model for Individual Prognosis Or Diagnosis (TRI-
POD), whichever is relevant [41,42], to enable assessing
the risk of bias.
Multicentre studies for developing prediction models
could strengthen the generalisability of the findings. Such
models could include location as a variable for prediction
and should also consider treatment effects. The next step
could be a randomised controlled trial putting such a
comprehensive model into practice and potentially chang-
ing the way patients are currently managed.
Conclusions
Although there are several predictive or diagnostic mod-
els in dengue infection, their limitations could affect their
validity. It is recommended that these models be revali-
dated in other clinical settings and their methods be
improved and standardised in future.
Acknowledgement
We thank Abela Barongo Mahimbo for proofreading the
manuscript.
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fever. Medicine (Baltimore) 2017: 96: e7878.
20. Nguyen MT, Nguyen TH, Tran NBC, Duong THK, Ho
TN, Wills B et al. An evidence-based algorithm for early
prognosis of severe dengue in the outpatient setting. Clin
Infect Dis 2017: 64: 656–663.
21. Lam PK, Hoai Tam DT, Dung NM, Hanh Tien NT, Thanh
Kieu NT, Simmons C et al. A prognostic model for develop-
ment of profound shock among children presenting with
dengue shock syndrome. PLoS ONE 2015: 10: e0126134.
22. Lee I-K, Liu J-W, Chen Y-H, Chen Y-C, Tsai C-Y, Huang
S-Y et al. Development of a simple clinical risk score for
early prediction of severe dengue in adult patients. PLoS
ONE 2016: 11: e0154772.
© 2019 John Wiley & Sons Ltd
13653156, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13294 by National Institutes Of Health Malaysia, Wiley Online Library on [18/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
volume 24 no 10 pp 1169–1197 october 2019
23. Suwarto S, Nainggolan L, Sinto R, Effendi B, Ibrahim E,
Suryamin M et al. Dengue score: a proposed diagnostic pre-
dictor for pleural effusion and/or ascites in adults with den-
gue infection. BMC Infect Dis 2016: 16: 322.
24. Suwarto S, Hidayat MJ, Widjaya B. Dengue score as a diag-
nostic predictor for pleural effusion and/or ascites: external
validation and clinical application. BMC Infect Dis 2018: 8:
90.
25. Fern
andez E, Smieja M, Walter SD, Loeb M. A retrospective
cohort study to predict severe dengue in Honduran patients.
BMC Infect Dis 2017: 17: 676.
26. Phakhounthong K, Chaovalit P, Jittamala P, Blacksell SD,
Carter MJ, Turner P et al. Predicting the severity of dengue
fever in children on admission based on clinical features and
laboratory indicators: application of classification tree analy-
sis. BMC Pediatr 2018: 18: 109.
27. Pang J, Lindblom A, Tolfvenstam T. Discovery and valida-
tion of prognostic biomarker models to guide triage among
adult dengue patients at early infection. PLoS ONE 2016:
11: e0155993.
28. Carrasco LR, Leo YS, Cook AR. Predictive tools for severe
dengue conforming to World Health Organization 2009 cri-
teria. PLoS Negl Trop Dis 2014: 8: e2972.
29. Lee VJ, Lye DCB, Sun Y, Fernandez G, Ong A, Leo YS. Pre-
dictive value of simple clinical and laboratory variables for
dengue hemorrhagic fever in adults. J Clin Virol 2008: 42:
34–39.
30. Djossou F, Vesin G, Elenga N, Demar M, Epelboin L, Wal-
ter G et al. A predictive score for hypotension in patients
with confirmed dengue fever in Cayenne Hospital, French
Guiana. Trans R Soc Trop Med Hyg 2017: 110: 705–713.
31. Liu J-W, Lee I-K, Wang L, Chen R-F, Yang KD. The useful-
ness of clinical-practice-based laboratory data in facilitating
the diagnosis of dengue illness. Biomed Res Int 2013: 2013: 1.
32. Brasier AR, Ju H, Garcia J, Spratt HM, Victor SS, Forshey
BM et al. A three-component biomarker panel for predic-
tion of dengue hemorrhagic fever. Am J Trop Med Hyg
2012: 86: 341–348.
33. Pang J, Thein T-L, Leo Y-S, Lye DC. Early clinical and lab-
oratory risk factors of intensive care unit requirement during
2004–2008 dengue epidemics in Singapore: a matched case–
control study. BMC Infect Dis 2014: 14: 649.
34. Wong JGX, Thein TL, Leo Y-S, Pang J, Lye DC. Identifying
adult dengue patients at low risk for clinically significant
bleeding. PLoS ONE 2016: 11: e0148579.
35. Premaratne MK, Perera SSN, Malavige GN, Jayasinghe S.
Mathematical modelling of immune parameters in the evolu-
tion of severe dengue. Comput Math Methods Med 2017:
2017: 1–9.
36. Potts JA, Thomas SJ, Srikiatkhachorn A, Supradish P, Li W,
Nisalak A et al. Classification of dengue illness based on
readily available laboratory data. Am J Trop Med Hyg
2010: 83: 781–788.
37. Rigau-P
erez JG, Clark GG, Gubler DJ, Reiter P, Sanders EJ,
Vorndam AV. Dengue and dengue haemorrhagic fever. Lan-
cet 1998: 352: 971–977.
1187

Tropical Medicine and International Health
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue
38. Gubler DJ. Dengue and dengue hemorrhagic fever. Clin
Microbiol Rev 1998: 11: 480–496.
39. Nishiura H, Halstead SB. Natural history of dengue virus
(DENV)–1 and DENV-4 infections: reanalysis of classic
studies. J Infect Dis 2007: 195: 1007–1013.
40. Wolff RF, Moons KGM, Riley RD, Whiting PF, Westwood
M, Collins GS et al. PROBAST: a tool to assess the risk of
bias and applicability of prediction model studies PROBAST
(prediction model risk of bias assessment tool). Ann Intern
Med 2019: 170: 51–58.
41. Bossuyt P, Reitsma J, Bruns D, Gatsonis C, Glasziou P,
Irwig L et al. Towards complete and accurate reporting of
studies of diagnostic accuracy: the STARD initiative. Clin
Chem Lab Med 2003: 41: 68–73.
42. Collins GS, Reitsma JB, Altman DG, Moons KGM. Trans-
parent reporting of a multivariable prediction model for
individual prognosis or diagnosis (TRIPOD): the TRIPOD
Statement. BMC Med 2015: 13: 1.
Appendix A
Scopus
((TITLE-ABS-KEY(dengue))AND((TITLE-ABS-KEY
(predict)ORTITLE-ABS-KEY(prognosis)ORTITLE-ABS-
KEY(diagnosis)ORTITLE-ABS-KEY(classify))))AND
((TITLE-ABS-KEY(mathematic)ORTITLE-ABS-KEY(-
model)ORTITLE-ABS-KEY(combined)ORTITLE-ABS-
KEY(score)))
PubMed
((“dengue”[MeSH Terms] OR “dengue”[All Fields])
AND (((predict[All Fields] OR (“prognosis”[MeSH Terms]
OR “prognosis”[All Fields])) OR (“diagnosis”[Subheading]
OR “diagnosis”[All Fields] OR “diagnosis”[MeSH Terms]))
OR (“classification”[MeSH Terms] OR “classification”[All
Fields] OR “classify”[All Fields]))) AND ((((“mathemat-
ics”[MeSH Terms] OR “mathematics”[All Fields] OR
“mathematic”[All Fields]) OR model[All Fields]) OR com-
bined[All Fields]) OR score[All Fields])\
EBSCOhost Research Databases: MEDLINE Complete
http://search.ebscohost.com.ezproxy.laureate.net.au/lo
gin.aspx?direct=true&db=mdc&bquery=dengue+AND+
((predict)+OR+(prognosis)+OR+(diagnosis)+OR+(classif
y))+AND+((mathematic)+OR+(model)+OR+(combined
)+OR+(score))&type=1&site=ehost-live
Cochrane Central Register of Controlled Trials
#1 (dengue):ti,ab,kw (Word variations have been
searched)
#2 (predict):ti,ab,kw OR (prognosis):ti,ab,kw OR (di-
agnosis):ti,ab,kw OR (classify):ti,ab,kw (Word variations
have been searched)
#3 (mathematic):ti,ab,kw OR (model):ti,ab,kw OR
(combined):ti,ab,kw OR (score):ti,ab,kw (Word varia-
tions have been searched)
#4 #1 AND #2 AND #3 30
1188
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volume 24 no 10 pp 1169–1197 october 2019
Appendix B
List of excluded studies after full-text review (n = 57)
I. Not predicting the severity (n = 24)
1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow
AW, Moyes CL, et al. The global distribution and burden
of dengue. Nature. 2013;496(7446):504–7.
2. World Health Organization. Dengue and severe den-
gue [Internet]. 13 Sept 2018. 2018 [cited 2019 Mar 20].
Available from: https://www.who.int/en/news-room/fact-
sheets/detail/dengue-and-severe-dengue
3. WHO/TDR. Handbook for clinical management of
dengue. Geneva, Switzerland: WHO Press; 2012.
4. World Health Organization. Dengue Haemorrhagic
Fever: Diagnosis, Treatment, Prevention and Control.
2nd ed. Geneva, Switzerland: WHO Press; 1997.
5. Alexander N, Balmaseda A, Coelho ICB, Dimaano
E, Hien TT, Hung NT, et al. Multicentre prospective
study on dengue classification in four South-east Asian
and three Latin American countries. Trop Med Int Heal.
2011;16(8):936–48.
6. Ahmad M, Ibrahim M, Mohamed Z, Ismail N,
Abdullah M, Shueb R, et al. The Sensitivity, Specificity
and Accuracy of Warning Signs in Predicting Severe Den-
gue, the Severe Dengue Prevalence and Its Associated
Factors. Int J Environ Res Public Health. 2018;15(9).
7. Thein T-L, Gan VC, Lye DC, Yung C-F, Leo Y-S.
Utilities and limitations of the World Health Organiza-
tion 2009 warning signs for adult dengue severity. PLoS
Negl Trop Dis. 2013;7(1):e2023.
8. Leo Y-S, Gan VC, Ng E-L, Hao Y, Ng L-C, Pok K-
Y, et al. Utility of warning signs in guiding admission
and predicting severe disease in adult dengue. BMC Infect
Dis. 2013;13(1):498.
9. Park S, Srikiatkhachorn A, Kalayanarooj S, Macareo
L, Green S, Friedman JF, et al. Use of structural equa-
tion models to predict dengue illness phenotype. PLoS Negl
Trop Dis [Internet]. 2018 Oct 1;12(10):e0006799. Avail-
able from: https://doi.org/10.1371/journal.pntd.0006799
10. Low GKK, Gan S-C, Zainal N, Naidu KD, Amin-
Nordin S, Khoo C-S, et al. The predictive and diagnostic
accuracy of vascular endothelial growth factor and pen-
traxin-3 in severe dengue. Pathog Glob Health [Internet].
2018 Aug 18;112(6):334–41. Available from: https://doi.
org/10.1080/20477724.2018.1516417
11. Md-Sani SS, Md-Noor J, Han W-H, Gan S-P, Rani
N-S, Tan H-L, et al. Prediction of mortality in severe
dengue cases. BMC Infect Dis [Internet]. 2018;18(1):232.
Available from: https://doi.org/10.1186/s12879-018-
3141-6
12. Moons KGM, de Groot JAH, Bouwmeester W,
Vergouwe Y, Mallett S, Altman DG, et al. Critical
© 2019 John Wiley & Sons Ltd

Tropical Medicine and International Health
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue
Appraisal and Data Extraction for Systematic Reviews of
Prediction Modelling Studies: The CHARMS Checklist.
PLOS Med [Internet]. 2014 Oct 14;11(10):e1001744.
Available from: https://doi.org/10.1371/journal.pmed.
1001744
13. Whiting P, Rutjes A, Westwood M, Mallett S,
Deeks J, Reitsma J, et al. QUADAS-2: A revised tool for
the Quality Assessment of Diagnostic Accuracy Studies.
Ann Intern Med. 2011;155(8):529–36.
14. Tamibmaniam J, Hussin N, Cheah WK, Ng KS,
Muninathan P. Proposal of a Clinical Decision Tree
Algorithm Using Factors Associated with Severe Dengue
Infection. PLoS One [Internet]. 2016 Aug 23;11(8):
e0161696. Available from: https://doi.org/10.1371/journa
l.pone.0161696
15. Ju H, Brasier AR. Variable selection methods for
developing a biomarker panel for prediction of dengue
hemorrhagic fever. BMC Res Notes [Internet]. 2013;6
(1):365. Available from: https://doi.org/10.1186/1756-
0500-6-365
16. Huang C-C, Hsu C-C, Guo H-R, Su S-B, Lin H-J.
Dengue fever mortality score: A novel decision rule to
predict death from dengue fever. J Infect [Internet].
2017;75(6):532–40. Available from: http://www.sciencedi
rect.com/science/article/pii/S0163445317303067
17. Huy NT, Thao NTH, Ha TTN, Lan NTP, Nga
PTT, Thuy TT, et al. Development of clinical decision
rules to predict recurrent shock in dengue. Crit Care
[Internet]. 2013;17:R280. Available from: https://doi.org/
10.1186/cc13135
18. Lam PK, Ngoc T Van, Thu Thuy TT, Hong Van
NT, Nhu Thuy TT, Hoai Tam DT, et al. The value of
daily platelet counts for predicting dengue shock syn-
drome: Results from a prospective observational study of
2301 Vietnamese children with dengue. PLoS Negl Trop
Dis [Internet]. 2017 Apr 27;11(4):e0005498. Available
from: https://doi.org/10.1371/journal.pntd.0005498
19. Huang H-S, Hsu C-C, Ye J-C, Su S-B, Huang C-C,
Lin H-J. Predicting the mortality in geriatric patients with
dengue fever. Medicine (Baltimore) [Internet]. 2017 Sep
15;96(37):e7878. Available from: https://www.ncbi.nlm.
nih.gov/pubmed/28906367
20. Nguyen MT, Nguyen TH, Tran NBC, Duong
THK, Ho TN, Wills B, et al. An Evidence-Based Algo-
rithm for Early Prognosis of Severe Dengue in the Outpa-
tient Setting. Clin Infect Dis [Internet]. 2017 Dec 28;64
(5):656–63. Available from: https://doi.org/10.1093/cid/c
iw863
21. Lam PK, Hoai Tam DT, Dung NM, Hanh Tien
NT, Thanh Kieu NT, Simmons C, et al. A Prognostic
Model for Development of Profound Shock among Chil-
dren Presenting with Dengue Shock Syndrome. PLoS One
© 2019 John Wiley & Sons Ltd
13653156, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13294 by National Institutes Of Health Malaysia, Wiley Online Library on [18/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
volume 24 no 10 pp 1169–1197 october 2019
[Internet]. 2015 May 6;10(5):e0126134. Available from:
https://doi.org/10.1371/journal.pone.0126134
22. Lee I-K, Liu J-W, Chen Y-H, Chen Y-C, Tsai C-Y,
Huang S-Y, et al. Development of a Simple Clinical Risk
Score for Early Prediction of Severe Dengue in Adult
Patients. PLoS One [Internet]. 2016 May 3;11(5):
e0154772. Available from: https://doi.org/10.1371/journa
l.pone.0154772
23. Suwarto S, Nainggolan L, Sinto R, Effendi B, Ibra-
him E, Suryamin M, et al. Dengue score: a proposed
diagnostic predictor for pleural effusion and/or ascites in
adults with dengue infection. BMC Infect Dis [Internet].
2016;16(1):322. Available from: https://doi.org/10.1186/
s12879-016-1671-3
24. Suwarto S, Hidayat MJ, Widjaya B. Dengue score
as a diagnostic predictor for pleural effusion and/or
ascites: external validation and clinical application. BMC
Infect Dis [Internet]. 2018;18(1):90. Available from:
https://doi.org/10.1186/s12879-018-2996-x
25. Fern
andez E, Smieja M, Walter SD, Loeb M. A ret-
rospective cohort study to predict severe dengue in Hon-
duran patients. BMC Infect Dis [Internet]. 2017;17
(1):676. Available from: https://doi.org/10.1186/s12879-
017-2800-3
26. Phakhounthong K, Chaovalit P, Jittamala P, Black-
sell SD, Carter MJ, Turner P, et al. Predicting the severity
of dengue fever in children on admission based on clini-
cal features and laboratory indicators: application of clas-
sification tree analysis. BMC Pediatr [Internet]. 2018;18
(1):109. Available from: https://doi.org/10.1186/s12887-
018-1078-y
27. Pang J, Lindblom A, Tolfvenstam T. Discovery and
validation of prognostic biomarker models to guide triage
among adult dengue patients at early infection. PLoS One
[Internet]. 2016;11(6):e0155993. Available from:
https://doi.org/10.1371/journal.pone.0155993
28. Carrasco LR, Leo YS, Cook AR. Predictive tools
for severe dengue conforming to World Health Organiza-
tion 2009 criteria. PLoS Negl Trop Dis [Internet]. 2014;8
(7):e2972. Available from: https://doi.org/10.1371/journa
l.pntd.0002972
29. Lee VJ, Lye DCB, Sun Y, Fernandez G, Ong A,
Leo YS. Predictive value of simple clinical and laboratory
variables for dengue hemorrhagic fever in adults. J Clin
Virol [Internet]. 2008;42(1):34–9. Available from:
https://doi.org/10.1016/j.jcv.2007.12.017
30. Djossou F, Vesin G, Elenga N, Demar M, Epelboin
L, Walter G, et al. A predictive score for hypotension in
patients with confirmed dengue fever in Cayenne Hospi-
tal, French Guiana. Trans R Soc Trop Med Hyg [Inter-
net]. 2017 Feb 27;110(12):705–13. Available from:
https://doi.org/10.1093/trstmh/trx004
1189

Tropical Medicine and International Health
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue
31. Liu J-W, Lee I-K, Wang L, Chen R-F, Yang KD.
The usefulness of clinical-practice-based laboratory data
in facilitating the diagnosis of dengue illness. Biomed Res
Int. 2013;2013(Article ID 198797).
32. Brasier AR, Ju H, Garcia J, Spratt HM, Victor SS,
Forshey BM, et al. A three-component biomarker panel
for prediction of dengue hemorrhagic fever. Am J Trop
Med Hyg. 2012;86(2):341–8.
33. Pang J, Thein T-L, Leo Y-S, Lye DC. Early clinical
and laboratory risk factors of intensive care unit require-
ment during 2004–2008 dengue epidemics in Singapore:
a matched case–control study. BMC Infect Dis [Internet].
2014;14(1):649. Available from: https://doi.org/10.1186/
s12879-014-0649-2
34. Wong JGX, Thein TL, Leo Y-S, Pang J, Lye DC.
Identifying Adult Dengue Patients at Low Risk for Clini-
cally Significant Bleeding. PLoS One [Internet]. 2016 Feb
5;11(2):e0148579. Available from: https://doi.org/10.
1371/journal.pone.0148579
35. Premaratne MK, Perera SSN, Malavige GN, Jayas-
inghe S. Mathematical modelling of immune parameters
in the evolution of severe dengue. Comput Math Meth-
ods Med. 2017;2017(Article ID 2187390).
36. Potts JA, Thomas SJ, Srikiatkhachorn A, Supradish
P, Li W, Nisalak A, et al. Classification of dengue illness
based on readily available laboratory data. Am J Trop
Med Hyg. 2010;83(4):781–8.
37. Rigau-P
erez JG, Clark GG, Gubler DJ, Reiter P,
Sanders EJ, Vorndam AV. Dengue and dengue haemor-
rhagic fever. Lancet. 1998;352(9132):971–7.
38. Gubler DJ. Dengue and dengue hemorrhagic fever.
Clin Microbiol Rev. 1998;11(3):480–96.
39. Nishiura H, Halstead SB. Natural history of den-
gue virus (DENV)–1 and DENV-4 infections: reanalysis
of classic studies. J Infect Dis. 2007;195(7):1007–13.
40. Wolff RF, Moons KGM, Riley RD, Whiting PF,
Westwood M, Collins GS, et al. PROBAST: A Tool to
Assess the Risk of Bias and Applicability of Prediction
Model Studies PROBAST (Prediction model Risk Of Bias
ASsessment Tool). Ann Intern Med [Internet]. 2019 Jan
1;170(1):51–8. Available from: https://doi.org/10.7326/
m18-1376
41. Bossuyt P, Reitsma J, E Bruns D, Gatsonis C, Glas-
ziou P, Irwig L, et al. Towards complete and accurate
reporting of studies of diagnostic accuracy: the STARD
initiative. Clin Chem Lab Med. 2003;41(1):68–73.
42. Collins GS, Reitsma JB, Altman DG, Moons KGM.
Transparent reporting of a multivariable prediction
model for individual prognosis or diagnosis (TRIPOD):
the TRIPOD Statement. BMC Med [Internet]. 2015;13
(1):1. Available from: https://doi.org/10.1186/s12916-
014-0241-z
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volume 24 no 10 pp 1169–1197 october 2019
II. No statistical model (n = 18)
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© 2019 John Wiley & Sons Ltd

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Rattarittamrong E, et al. Useful clinical features and hema-
tological parameters for the diagnosis of dengue infection
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1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow
AW, Moyes CL, et al. The global distribution and burden
of dengue. Nature. 2013;496(7446):504–7.
2. World Health Organization. Dengue and severe den-
gue [Internet]. 13 Sept 2018. 2018 [cited 2019 Mar 20].
Available from: https://www.who.int/en/news-room/fact-
sheets/detail/dengue-and-severe-dengue
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dengue. Geneva, Switzerland: WHO Press; 2012.
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4. World Health Organization. Dengue Haemorrhagic
Fever: Diagnosis, Treatment, Prevention and Control.
2nd ed. Geneva, Switzerland: WHO Press; 1997.
5. Alexander N, Balmaseda A, Coelho ICB, Dimaano
E, Hien TT, Hung NT, et al. Multicentre prospective
study on dengue classification in four South-east Asian
and three Latin American countries. Trop Med Int Heal.
2011;16(8):936–48.
6. Ahmad M, Ibrahim M, Mohamed Z, Ismail N,
Abdullah M, Shueb R, et al. The Sensitivity, Specificity
and Accuracy of Warning Signs in Predicting Severe Den-
gue, the Severe Dengue Prevalence and Its Associated
Factors. Int J Environ Res Public Health. 2018;15(9).
7. Thein T-L, Gan VC, Lye DC, Yung C-F, Leo Y-S.
Utilities and limitations of the World Health Organiza-
tion 2009 warning signs for adult dengue severity. PLoS
Negl Trop Dis. 2013;7(1):e2023.
8. Leo Y-S, Gan VC, Ng E-L, Hao Y, Ng L-C, Pok K-
Y, et al. Utility of warning signs in guiding admission
and predicting severe disease in adult dengue. BMC Infect
Dis. 2013;13(1):498.
9. Park S, Srikiatkhachorn A, Kalayanarooj S, Macareo
L, Green S, Friedman JF, et al. Use of structural equa-
tion models to predict dengue illness phenotype. PLoS
Negl Trop Dis [Internet]. 2018 Oct 1;12(10):e0006799.
Available from: https://doi.org/10.1371/journal.pntd.
0006799
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Nordin S, Khoo C-S, et al. The predictive and diagnostic
accuracy of vascular endothelial growth factor and pen-
traxin-3 in severe dengue. Pathog Glob Health [Internet].
2018 Aug 18;112(6):334–41. Available from: https://doi.
org/10.1080/20477724.2018.1516417
11. Md-Sani SS, Md-Noor J, Han W-H, Gan S-P, Rani
N-S, Tan H-L, et al. Prediction of mortality in severe dengue
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from: https://doi.org/10.1186/s12879-018-3141-6
12. Moons KGM, de Groot JAH, Bouwmeester W,
Vergouwe Y, Mallett S, Altman DG, et al. Critical
Appraisal and Data Extraction for Systematic Reviews of
Prediction Modelling Studies: The CHARMS Checklist.
PLOS Med [Internet]. 2014 Oct 14;11(10):e1001744.
Available from: https://doi.org/10.1371/journal.pmed.
1001744
13. Whiting P, Rutjes A, Westwood M, Mallett S,
Deeks J, Reitsma J, et al. QUADAS-2: A revised tool for
the Quality Assessment of Diagnostic Accuracy Studies.
Ann Intern Med. 2011;155(8):529–36.
14. Tamibmaniam J, Hussin N, Cheah WK, Ng KS,
Muninathan P. Proposal of a Clinical Decision Tree
Algorithm Using Factors Associated with Severe Dengue
Infection. PLoS One [Internet]. 2016 Aug 23;11(8):
1192
13653156, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13294 by National Institutes Of Health Malaysia, Wiley Online Library on [18/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
volume 24 no 10 pp 1169–1197 october 2019
e0161696. Available from: https://doi.org/10.1371/journa
l.pone.0161696
15. Ju H, Brasier AR. Variable selection methods for
developing a biomarker panel for prediction of dengue
hemorrhagic fever. BMC Res Notes [Internet]. 2013;6
(1):365. Available from: https://doi.org/10.1186/1756-
0500-6-365
16. Huang C-C, Hsu C-C, Guo H-R, Su S-B, Lin H-J.
Dengue fever mortality score: A novel decision rule to
predict death from dengue fever. J Infect [Internet].
2017;75(6):532–40. Available from: http://www.sciencedi
rect.com/science/article/pii/S0163445317303067
17. Huy NT, Thao NTH, Ha TTN, Lan NTP, Nga
PTT, Thuy TT, et al. Development of clinical decision
rules to predict recurrent shock in dengue. Crit Care
[Internet]. 2013;17:R280. Available from: https://doi.org/
10.1186/cc13135
18. Lam PK, Ngoc T Van, Thu Thuy TT, Hong Van
NT, Nhu Thuy TT, Hoai Tam DT, et al. The value of
daily platelet counts for predicting dengue shock syn-
drome: Results from a prospective observational study of
2301 Vietnamese children with dengue. PLoS Negl Trop
Dis [Internet]. 2017 Apr 27;11(4):e0005498. Available
from: https://doi.org/10.1371/journal.pntd.0005498
19. Huang H-S, Hsu C-C, Ye J-C, Su S-B, Huang C-C,
Lin H-J. Predicting the mortality in geriatric patients with
dengue fever. Medicine (Baltimore) [Internet]. 2017 Sep
15;96(37):e7878. Available from: https://www.ncbi.nlm.
nih.gov/pubmed/28906367
20. Nguyen MT, Nguyen TH, Tran NBC, Duong THK,
Ho TN, Wills B, et al. An Evidence-Based Algorithm for
Early Prognosis of Severe Dengue in the Outpatient Setting.
Clin Infect Dis [Internet]. 2017 Dec 28;64(5):656–63. Avail-
able from: https://doi.org/10.1093/cid/ciw863
21. Lam PK, Hoai Tam DT, Dung NM, Hanh Tien
NT, Thanh Kieu NT, Simmons C, et al. A Prognostic
Model for Development of Profound Shock among Chil-
dren Presenting with Dengue Shock Syndrome. PLoS One
[Internet]. 2015 May 6;10(5):e0126134. Available from:
https://doi.org/10.1371/journal.pone.0126134
22. Lee I-K, Liu J-W, Chen Y-H, Chen Y-C, Tsai C-Y,
Huang S-Y, et al. Development of a Simple Clinical Risk
Score for Early Prediction of Severe Dengue in Adult
Patients. PLoS One [Internet]. 2016 May 3;11(5):
e0154772. Available from: https://doi.org/10.1371/journa
l.pone.0154772
23. Suwarto S, Nainggolan L, Sinto R, Effendi B, Ibra-
him E, Suryamin M, et al. Dengue score: a proposed
diagnostic predictor for pleural effusion and/or ascites in
adults with dengue infection. BMC Infect Dis [Internet].
2016;16(1):322. Available from: https://doi.org/10.1186/
s12879-016-1671-3
© 2019 John Wiley & Sons Ltd

Tropical Medicine and International Health
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue
24. Suwarto S, Hidayat MJ, Widjaya B. Dengue score
as a diagnostic predictor for pleural effusion and/or
ascites: external validation and clinical application. BMC
Infect Dis [Internet]. 2018;18(1):90. Available from:
https://doi.org/10.1186/s12879-018-2996-x
25. Fern
andez E, Smieja M, Walter SD, Loeb M. A ret-
rospective cohort study to predict severe dengue in Hon-
duran patients. BMC Infect Dis [Internet]. 2017;17
(1):676. Available from: https://doi.org/10.1186/s12879-
017-2800-3
26. Phakhounthong K, Chaovalit P, Jittamala P, Black-
sell SD, Carter MJ, Turner P, et al. Predicting the severity
of dengue fever in children on admission based on clini-
cal features and laboratory indicators: application of clas-
sification tree analysis. BMC Pediatr [Internet]. 2018;18
(1):109. Available from: https://doi.org/10.1186/s12887-
018-1078-y
27. Pang J, Lindblom A, Tolfvenstam T. Discovery and
validation of prognostic biomarker models to guide triage
among adult dengue patients at early infection. PLoS One
[Internet]. 2016;11(6):e0155993. Available from:
https://doi.org/10.1371/journal.pone.0155993
28. Carrasco LR, Leo YS, Cook AR. Predictive tools
for severe dengue conforming to World Health Organiza-
tion 2009 criteria. PLoS Negl Trop Dis [Internet]. 2014;8
(7):e2972. Available from: https://doi.org/10.1371/journa
l.pntd.0002972
29. Lee VJ, Lye DCB, Sun Y, Fernandez G, Ong A,
Leo YS. Predictive value of simple clinical and laboratory
variables for dengue hemorrhagic fever in adults. J Clin
Virol [Internet]. 2008;42(1):34–9. Available from:
https://doi.org/10.1016/j.jcv.2007.12.017
30. Djossou F, Vesin G, Elenga N, Demar M, Epelboin
L, Walter G, et al. A predictive score for hypotension in
patients with confirmed dengue fever in Cayenne Hospi-
tal, French Guiana. Trans R Soc Trop Med Hyg [Inter-
net]. 2017 Feb 27;110(12):705–13. Available from:
https://doi.org/10.1093/trstmh/trx004
31. Liu J-W, Lee I-K, Wang L, Chen R-F, Yang KD.
The usefulness of clinical-practice-based laboratory data
in facilitating the diagnosis of dengue illness. Biomed Res
Int. 2013;2013(Article ID 198797).
32. Brasier AR, Ju H, Garcia J, Spratt HM, Victor SS,
Forshey BM, et al. A three-component biomarker panel
for prediction of dengue hemorrhagic fever. Am J Trop
Med Hyg. 2012;86(2):341–8.
33. Pang J, Thein T-L, Leo Y-S, Lye DC. Early clinical
and laboratory risk factors of intensive care unit require-
ment during 2004–2008 dengue epidemics in Singapore:
a matched case–control study. BMC Infect Dis [Internet].
2014;14(1):649. Available from: https://doi.org/10.1186/
s12879-014-0649-2
© 2019 John Wiley & Sons Ltd
13653156, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13294 by National Institutes Of Health Malaysia, Wiley Online Library on [18/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
volume 24 no 10 pp 1169–1197 october 2019
34. Wong JGX, Thein TL, Leo Y-S, Pang J, Lye DC.
Identifying Adult Dengue Patients at Low Risk for Clini-
cally Significant Bleeding. PLoS One [Internet]. 2016 Feb
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V. Comparator was other infectious disease (n = 1)
1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow
AW, Moyes CL, et al. The global distribution and burden
of dengue. Nature. 2013;496(7446):504–7.
2. World Health Organization. Dengue and severe den-
gue [Internet]. 13 Sept 2018. 2018 [cited 2019 Mar 20].
Available from: https://www.who.int/en/news-room/fact-
sheets/detail/dengue-and-severe-dengue
3. WHO/TDR. Handbook for clinical management of
dengue. Geneva, Switzerland: WHO Press; 2012.
4. World Health Organization. Dengue Haemorrhagic
Fever: Diagnosis, Treatment, Prevention and Control.
2nd ed. Geneva, Switzerland: WHO Press; 1997.
1193

Tropical Medicine and International Health
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue
5. Alexander N, Balmaseda A, Coelho ICB, Dimaano
E, Hien TT, Hung NT, et al. Multicentre prospective
study on dengue classification in four South-east Asian
and three Latin American countries. Trop Med Int Heal.
2011;16(8):936–48.
6. Ahmad M, Ibrahim M, Mohamed Z, Ismail N,
Abdullah M, Shueb R, et al. The Sensitivity, Specificity
and Accuracy of Warning Signs in Predicting Severe Den-
gue, the Severe Dengue Prevalence and Its Associated
Factors. Int J Environ Res Public Health. 2018;15(9).
7. Thein T-L, Gan VC, Lye DC, Yung C-F, Leo Y-S.
Utilities and limitations of the World Health Organiza-
tion 2009 warning signs for adult dengue severity. PLoS
Negl Trop Dis. 2013;7(1):e2023.
8. Leo Y-S, Gan VC, Ng E-L, Hao Y, Ng L-C, Pok K-
Y, et al. Utility of warning signs in guiding admission
and predicting severe disease in adult dengue. BMC Infect
Dis. 2013;13(1):498.
9. Park S, Srikiatkhachorn A, Kalayanarooj S, Macareo
L, Green S, Friedman JF, et al. Use of structural equa-
tion models to predict dengue illness phenotype. PLoS Negl
Trop Dis [Internet]. 2018 Oct 1;12(10):e0006799. Available
from: https://doi.org/10.1371/journal.pntd.0006799
10. Low GKK, Gan S-C, Zainal N, Naidu KD, Amin-
Nordin S, Khoo C-S, et al. The predictive and diagnostic
accuracy of vascular endothelial growth factor and pen-
traxin-3 in severe dengue. Pathog Glob Health [Internet].
2018 Aug 18;112(6):334–41. Available from: https://doi.
org/10.1080/20477724.2018.1516417
11. Md-Sani SS, Md-Noor J, Han W-H, Gan S-P, Rani
N-S, Tan H-L, et al. Prediction of mortality in severe
dengue cases. BMC Infect Dis [Internet]. 2018;18(1):232.
Available from: https://doi.org/10.1186/s12879-018-
3141-6
12. Moons KGM, de Groot JAH, Bouwmeester W,
Vergouwe Y, Mallett S, Altman DG, et al. Critical
Appraisal and Data Extraction for Systematic Reviews of
Prediction Modelling Studies: The CHARMS Checklist.
PLOS Med [Internet]. 2014 Oct 14;11(10):e1001744.
Available from: https://doi.org/10.1371/journal.pmed.
1001744
13. Whiting P, Rutjes A, Westwood M, Mallett S,
Deeks J, Reitsma J, et al. QUADAS-2: A revised tool for
the Quality Assessment of Diagnostic Accuracy Studies.
Ann Intern Med. 2011;155(8):529–36.
14. Tamibmaniam J, Hussin N, Cheah WK, Ng KS,
Muninathan P. Proposal of a Clinical Decision Tree
Algorithm Using Factors Associated with Severe Dengue
Infection. PLoS One [Internet]. 2016 Aug 23;11(8):
e0161696. Available from: https://doi.org/10.1371/journa
l.pone.0161696
1194
13653156, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13294 by National Institutes Of Health Malaysia, Wiley Online Library on [18/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
volume 24 no 10 pp 1169–1197 october 2019
15. Ju H, Brasier AR. Variable selection methods for
developing a biomarker panel for prediction of dengue hem-
orrhagic fever. BMC Res Notes [Internet]. 2013;6(1):365.
Available from: https://doi.org/10.1186/1756-0500-6-365
16. Huang C-C, Hsu C-C, Guo H-R, Su S-B, Lin H-J.
Dengue fever mortality score: A novel decision rule to
predict death from dengue fever. J Infect [Internet].
2017;75(6):532–40. Available from: http://www.sciencedi
rect.com/science/article/pii/S0163445317303067
17. Huy NT, Thao NTH, Ha TTN, Lan NTP, Nga
PTT, Thuy TT, et al. Development of clinical decision
rules to predict recurrent shock in dengue. Crit Care
[Internet]. 2013;17:R280. Available from: https://doi.org/
10.1186/cc13135
18. Lam PK, Ngoc T Van, Thu Thuy TT, Hong Van
NT, Nhu Thuy TT, Hoai Tam DT, et al. The value of
daily platelet counts for predicting dengue shock syn-
drome: Results from a prospective observational study
of 2301 Vietnamese children with dengue. PLoS Negl
Trop Dis [Internet]. 2017 Apr 27;11(4):e0005498.
Available from: https://doi.org/10.1371/journal.pntd.
0005498
19. Huang H-S, Hsu C-C, Ye J-C, Su S-B, Huang C-C,
Lin H-J. Predicting the mortality in geriatric patients with
dengue fever. Medicine (Baltimore) [Internet]. 2017 Sep
15;96(37):e7878. Available from: https://www.ncbi.nlm.
nih.gov/pubmed/28906367
20. Nguyen MT, Nguyen TH, Tran NBC, Duong
THK, Ho TN, Wills B, et al. An Evidence-Based Algo-
rithm for Early Prognosis of Severe Dengue in the Outpa-
tient Setting. Clin Infect Dis [Internet]. 2017 Dec 28;64
(5):656–63. Available from: https://doi.org/10.1093/cid/c
iw863
21. Lam PK, Hoai Tam DT, Dung NM, Hanh Tien
NT, Thanh Kieu NT, Simmons C, et al. A Prognostic
Model for Development of Profound Shock among Chil-
dren Presenting with Dengue Shock Syndrome. PLoS One
[Internet]. 2015 May 6;10(5):e0126134. Available from:
https://doi.org/10.1371/journal.pone.0126134
22. Lee I-K, Liu J-W, Chen Y-H, Chen Y-C, Tsai C-Y,
Huang S-Y, et al. Development of a Simple Clinical Risk
Score for Early Prediction of Severe Dengue in Adult
Patients. PLoS One [Internet]. 2016 May 3;11(5):
e0154772. Available from: https://doi.org/10.1371/journa
l.pone.0154772
23. Suwarto S, Nainggolan L, Sinto R, Effendi B, Ibra-
him E, Suryamin M, et al. Dengue score: a proposed
diagnostic predictor for pleural effusion and/or ascites in
adults with dengue infection. BMC Infect Dis [Internet].
2016;16(1):322. Available from: https://doi.org/10.1186/
s12879-016-1671-3
© 2019 John Wiley & Sons Ltd

Tropical Medicine and International Health
G. K. K. Low et al. Diagnostic accuracy in the severity of dengue
24. Suwarto S, Hidayat MJ, Widjaya B. Dengue score
as a diagnostic predictor for pleural effusion and/or
ascites: external validation and clinical application. BMC
Infect Dis [Internet]. 2018;18(1):90. Available from:
https://doi.org/10.1186/s12879-018-2996-x
25. Fern
andez E, Smieja M, Walter SD, Loeb M. A ret-
rospective cohort study to predict severe dengue in Hon-
duran patients. BMC Infect Dis [Internet]. 2017;17
(1):676. Available from: https://doi.org/10.1186/s12879-
017-2800-3
26. Phakhounthong K, Chaovalit P, Jittamala P, Black-
sell SD, Carter MJ, Turner P, et al. Predicting the severity
of dengue fever in children on admission based on clini-
cal features and laboratory indicators: application of clas-
sification tree analysis. BMC Pediatr [Internet]. 2018;18
(1):109. Available from: https://doi.org/10.1186/s12887-
018-1078-y
27. Pang J, Lindblom A, Tolfvenstam T. Discovery and
validation of prognostic biomarker models to guide triage
among adult dengue patients at early infection. PLoS One
[Internet]. 2016;11(6):e0155993. Available from:
https://doi.org/10.1371/journal.pone.0155993
28. Carrasco LR, Leo YS, Cook AR. Predictive tools
for severe dengue conforming to World Health Organiza-
tion 2009 criteria. PLoS Negl Trop Dis [Internet]. 2014;8
(7):e2972. Available from: https://doi.org/10.1371/journa
l.pntd.0002972
29. Lee VJ, Lye DCB, Sun Y, Fernandez G, Ong A,
Leo YS. Predictive value of simple clinical and laboratory
variables for dengue hemorrhagic fever in adults. J Clin
Virol [Internet]. 2008;42(1):34–9. Available from:
https://doi.org/10.1016/j.jcv.2007.12.017
30. Djossou F, Vesin G, Elenga N, Demar M, Epelboin
L, Walter G, et al. A predictive score for hypotension in
patients with confirmed dengue fever in Cayenne Hospi-
tal, French Guiana. Trans R Soc Trop Med Hyg [Inter-
net]. 2017 Feb 27;110(12):705–13. Available from:
https://doi.org/10.1093/trstmh/trx004
31. Liu J-W, Lee I-K, Wang L, Chen R-F, Yang KD.
The usefulness of clinical-practice-based laboratory data
in facilitating the diagnosis of dengue illness. Biomed Res
Int. 2013;2013(Article ID 198797).
32. Brasier AR, Ju H, Garcia J, Spratt HM, Victor SS,
Forshey BM, et al. A three-component biomarker panel
for prediction of dengue hemorrhagic fever. Am J Trop
Med Hyg. 2012;86(2):341–8.
33. Pang J, Thein T-L, Leo Y-S, Lye DC. Early clinical
and laboratory risk factors of intensive care unit require-
ment during 2004–2008 dengue epidemics in Singapore:
a matched case–control study. BMC Infect Dis [Internet].
2014;14(1):649. Available from: https://doi.org/10.1186/
s12879-014-0649-2
© 2019 John Wiley & Sons Ltd
13653156, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13294 by National Institutes Of Health Malaysia, Wiley Online Library on [18/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
volume 24 no 10 pp 1169–1197 october 2019
34. Wong JGX, Thein TL, Leo Y-S, Pang J, Lye DC.
Identifying Adult Dengue Patients at Low Risk for Clini-
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Appendix C
Data extraction form

Study ID First author, year of publication

Sampling method Consecutive/random
Year and setting
Participants:
Age:
Country/ethnicity (if any):
Confirmatory diagnostic method:
Total number of patients included for index test:
Index test
Mathematic model:
Formula (if any):
Software:
Reference standard
WHO classification: 1997/2009
Others:
Flow and timing
Number of excluded patients and reason:
Day of illness evaluated:

Data Sensitivity
AUC value: Specificity
Cut-off value: Positive predictive value
Negative predictive value

Appendix D

Flow and timing

Any patients did

Interpretation not receive
blinded from Interpretation either index test
Sampling Pre-specified reference blinded from Number of excluded or reference
Study ID method threshold standard index test patients and reason standard

Brasier 2012 Consecutive Not applicable. Not applicable. Not applicable. Unclear Not applicable.
Carrasco 2014 Consecutive Not applicable. Not applicable. Not applicable. Clear Not applicable.
Djossou 2017 Consecutive Development of Not applicable; Not applicable; Not applicable Not applicable.
model, no development of development of
pre-specified model model
threshold. and validation and validation
via data set. via data set.

1196 © 2019 John Wiley & Sons Ltd

 13653156, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13294 by National Institutes Of Health Malaysia, Wiley Online Library on [18/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Tropical Medicine and International Health volume 24 no 10 pp 1169–1197 october 2019

G. K. K. Low et al. Diagnostic accuracy in the severity of dengue

Appendix D (Continued

Fernandez 2017 Consecutive Development of Not applicable; Not applicable; Not applicable Not applicable;
model, no pre- development of development of development of
specified model and model and model and
threshold. validation via validation via data validation via
data set. set. data set.
Huang 2017a Case– Not applicable. Not applicable. Not applicable. Clear Not applicable
control
Huang 2017b Case– 1, 2, ≥3 Not applicable Not applicable Clear with reasons Not applicable
control
Huy 2013 Consecutive Not applicable. Not applicable. Not applicable. Clear Not applicable.
Ju 2013 Consecutive Unclear Not applicable Not applicable Unclear Not applicable
Lam 2015 Consecutive Not applicable. Not applicable Not applicable Clear with reasons Not applicable
Lam 2017 Consecutive Not applicable. Not applicable. Not applicable. Clear Not applicable
Lee2008 Consecutive Not applicable. Not applicable. Not applicable. Clear with reasons Not applicable.
Lee 2016 Consecutive 1 Not applicable Unclear Clear Not applicable
Liu 2013 Consecutive Not applicable. Not applicable. Not applicable. Unclear Not applicable.
Low 2018 Consecutive Not applicable. Not applicable. Yes Clear Not applicable.
Nguyen 2017 Consecutive Not applicable. Not applicable Not applicable Clear with reasons Not applicable
Pang 2014 Matched Not applicable. Not applicable. Not applicable. Not cohort study Not applicable
case–
control
Pang 2016 Consecutive Not applicable. Not applicable Not applicable Clear Not applicable
Park 2018 Consecutive Not applicable. Not applicable; Not applicable; Clear with reasons Not applicable.
development of development of
model and model and
validation via validation via data
data set. set.
Phakhounthong Consecutive Not applicable. Not applicable; Not applicable; Clear with reasons Not applicable.
2018 development of development of
model and model and
validation via validation via data
data set. set.
Potts 2010 Consecutive Unclear Not applicable Not applicable Clear with reasons Not applicable
Premaratne Unclear Not applicable. Not applicable. Not applicable. Unclear Not applicable
2017
Sani 2018 Consecutive Not applicable. Not applicable Not applicable Clear Not applicable
Suwarto 2016 Consecutive ≥2 Unclear Unclear Unclear None
and 2018
Tamibmaniam Consecutive Not applicable Not applicable Unclear Not applicable
2016
Wong 2016 Consecutive Not applicable. Not applicable. Not applicable. Clear Not applicable

Corresponding Author Gary Kim Kuan Low, Department of Public Health, Health Vertical, Pyrmont Campus, Torrens University
Australia, 5/235 Pyrmont St, Pyrmont, NSW 2009, Australia. E-mails: gary.low@laureate.edu.au and garishy@hotmail.com

© 2019 John Wiley & Sons Ltd 1197