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Prediction Models for Type 2 Diabetes Risk in the General Popula-

tion: A Systematic Review of Observational Studies
' Authors:

Samaneh Asgari 1 , Davood Khalili 1 , Farhad Hosseinpanah 2
, Farzad Hadaegh 1 , *

Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Be-
11
heshti University of Medical Sciences, Tehran, Iran

Obesity Research Center, Research Institute for Endocrine Sciences, Shaheed Beheshti University of Medical
22
Sciences, Tehran, Iran

* Corresponding Author: Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine
Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Email: [email protected]

International Journal of Endocrinology and Metabolism: Vol.19, issue 3; e109206

Published Online: March 22, 2021
Article Type: Systematic Review
 Received: September 20, 2020
(
) Revised: February 7, 2021

* Accepted: February 13, 2021

+ DOI: https://doi.org/10.5812/ijem.109206


How To Cite: Asgari S, Khalili D, Hosseinpanah F, Hadaegh F. Prediction Models for

Type 2 Diabetes Risk in the General Population: A Systematic Review of Observational
Studies. Int J Endocrinol Metab.
2021;19(3):e109206. https://doi.org/10.5812/ijem.109206.
:
 . Abstract

Objectives: This study aimed to provide an overview of prediction models of un-
diagnosed type 2 diabetes mellitus (U-T2DM) or the incident T2DM (I-T2DM) using the
transparent reporting of a multivariable prediction model for individual prognosis or
diagnosis (TRIPOD) checklist and the prediction model risk of the bias assessment tool
(PROBAST).
Data Sources: Both PUBMED and EMBASE databases were searched to guarantee
adequate and efficient coverage.
Study Selection: Articles published between December 2011 and October 2019
were considered.
Data Extraction: For each article, information on model development require-
ments, discrimination measures, calibration, overall performance, clinical usefulness,
overfitting, and risk of bias (ROB) was reported.
Results: The median (interquartile range; IQR) number of the 46 study popula-
tions for model development was 5711 (1971 - 27426) and 2457 (2060 - 6995) individuals
for I-T2DM and U-T2DM, respectively. The most common reported predictors were age
and body mass index, and only the Qrisk-2017 study included social factors (e.g.,
Townsend score). Univariable analysis was reported in 46% of the studies, and the vari-
able selection procedure was not clear in 17.4% of them. Moreover, internal and exter-
nal validation was reported in 43% the studies, while over 63% of them reported calibra-
tion. The median (IQR) of AUC for I-T2DM models was 0.78 (0.74 - 0.82); the correspond-
ing value for studies derived before October 2011 was 0.80 (0.77 - 0.83). The highest dis-
crimination index was reported for Qrisk-2017 with C-statistics of 0.89 for women and
0.87 for men. Low ROB for I-T2DM and U-T2DM was assessed at 18% and 41%, respectively.
Conclusions: Among prediction models, an intermediate to poor quality was re-
assessed in several aspects of model development and validation. Generally, despite its
new risk factors or new methodological aspects, the newly developed model did not
increase our capability in screening/predicting T2DM, mainly in the analysis part. It
was due to the lack of external validation of the prediction models.
:
 0 Keywords

Type 2 Diabetes Prediction Models Systematic Review TRIPOD PROBAST

1. Context
Type 2 diabetes mellitus (T2DM) is a major cause of blindness, kidney failure, heart at-
tacks, stroke, and death worldwide (1, 2). The global prevalence (95% CI) of T2DM in
adults aged 20 - 79 years was estimated to be 8.8% (7.2 - 11.3%) in 2017, and it is estimated
that 50% of them are unaware of their disease. This prevalence is estimated to increase
by 48% in 2045. The total healthcare expenditures for diabetes care worldwide were es-
timated to be $727 billion in 2017 and are expected to increase by 6.7% in 2045 (2). Thus,
it is essential to early identify those at high risk of T2DM.

Prediction models could be useful to estimate the probability of screening undiag-

nosed type 2 diabetes mellitus (U-T2DM) or predicting newly diagnosed T2DM in the
future (3). Various prediction models have been developed during the past decades to
predict the incident T2DM (I-T2DM). Well-known examples include the Finnish Dia-
betes Risk score (4), the Australian type 2 diabetes risk (5), QRISK (6), and the Framing-
ham Offspring (FOS) risk (7). The self-assessment screening score proposed by the
American diabetes association is included in the 2018 clinical guideline to detect U-
T2DM (1).

A multivariable prediction model is a mathematical formula that combines several

predictors to estimate individuals’ risk probability. The model-building strategy needs
to be explicitly stated to improve the reporting of the prediction models. The previous
review (8, 9) has shown that published papers highlight some methodological require-
ments. However, prediction models’ design, methods, and results have been less fre-
quently reported. Most prediction models are rarely used because of methodological
issues in model development and poor or unknown internal and external validity (8,
10).

2. Objectives
The prevalence and incidence of T2DM are increasing, and since about 50% of patients
are unaware of their disease (2), prediction models could be used to lower the rate of
undiagnosed diabetes. Due to the existing limitations in the prediction models’ re-
porting strategies, the transparent reporting of a 22-item multivariable prediction
:
 model for individual prognosis or diagnosis (TRIPOD) statement was published in 2015
(11). The risk of bias (ROB) assessment tool in line with the TRIPOD statement was pro-
posed in 2019. Since these tools did not evaluate previous studies, we extended previ-
ous systematic reviews in the field by focusing on prediction models’ methodological
aspects using the TRIPOD checklist for T2DM diagnosis or prognosis, including both
previously and newly published articles.

3. Methods
3.1. Data Sources
We followed the critical appraisal and data extraction for systematic reviews of predic-
tion modeling studies (CHARMS) standard checklist for diagnostic and prognostic pre-
diction models, tools, or scores of T2DM (11). For avoiding duplication, only papers pub-
lished between December 2011 and October 2019 were considered. Both PUBMED and
EMBASE databases were searched to guarantee adequate and efficient coverage. Arti-
cles published before 2011 were addressed in previously published systematic reviews
(8, 9). We included additional articles by searching references in the papers following
the same search strategy.

3.2. Study Selection

Observational studies were included to predict U-T2DM or I-T2DM. We also considered
studies based on the inclusion and exclusion criteria:

1) Original English articles were included.

2) Articles on gestational diabetes or type 1 DM were excluded.

3) Genetic studies, animal studies, validation studies of previously published models,

studies on children or adolescents, studies with a specific population, pre-selected risk
factors, and non-regression models, and articles with T2DM as a composite outcome
with other outcomes (e.g., cardiovascular disease: CVD) were excluded.

This review focused on regression-based prediction models, and other prediction mod-
els such as machine learning models were excluded.

4) Editorial articles, letters, congress abstracts, clinical trials, meta-analysis, or system-

atic review articles were also removed.
:
 5) The study search strategy included T2DM, undiagnosed diabetes, risk prediction,
prediction models, and predictive models.

The search strategy is available in Appendix 1 in Supplementary File.

3.3. Data Extraction

Search results from different origins were combined in a single Endnote library, and
duplicate articles were removed electronically and manually. Afterward, two people (S.
Asgari and D. Khalili) evaluated titles and abstracts separately and marked potentially
related articles for full-text reading. Disagreements were discussed with a third review-
er (F. Hadaegh). All the authors screened full-text articles. One of the reviewers (S. As-
gari) extracted data. Three independent people (D. Khalili, F. Hosseinpanah, and F.
Hadaegh) monitored the data collection process. Essential items extracted via a litera-
ture study included study type (case-control or cohort), country, publication year,
study name, sample size, follow-up duration, participant age, and outcome definition.
For model development, modeling methods (e.g., logistic regression and survival re-
gression), variable selection methods (e.g., univariate analysis and literature review),
treatment of continuous risk predictors (e.g., all categorized, all continue), treatment
of missing data (e.g., imputation and complete case), risk predictors in the model, dis-
crimination measures (e.g., sensitivity, specificity, positive or negative predictive value,
Youden index, are-under-the-curve: AUC, C-statistics, and D-statistics), overall perfor-
mance (e.g., Akaike information criteria: AIC and Bayesian information criteria: BIC),
clinical usefulness (e.g., net benefit) and overfitting (e.g., bootstrapping) were extract-
ed. Additionally, discrimination measurements, overall performance, and calibration
of both internal and external validation were evaluated. We treated prediction models
described in a single article as separate models.

3.4. Risk of Bias Assessment

The prediction studies were critically assessed by the Prediction Model Risk of Bias As-
sessment tool (PROBAST), which was introduced by Wolff et al. in 2019 (12). The risk of
bias (ROB) tool is categorized into four domains, including participants (two ques-
tions), predictors (three questions), outcome (six questions), and analysis (nine ques-
tions). ROB was reported for each article separately to screen U-T2DM and I-T2DM. The
overall judgment was performed as recommended by Wolff et al. (12). ROB was defined
low if all the four domains were rated low. ROB was defined high if at least one (≥ 1)
:
 had high ROB. Also, even if all the domains were defined low, a prediction model with-
out any external validation was judged to have high ROB. Unclear ROB was defined if at
least one domain had unclear ROB and it was low risk for all the other domains. The ap-
plicability of the prediction models was also assessed, and the majority of the models
regarding risk of bias.

3.5. Descriptive Analysis

We summarized the results using descriptive statistics for both model development
and validation for I-T2DM. Collins et al. (8) and Noble et al. (9) considered the same
characteristics for previously published reviews. The present study evaluated 18 out of
the 45 studies on risk prediction (Appendix 2 in Supplementary File).

This systematic review was reported in accordance with the Preferred Reporting Items
for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR)
(13) by removing meta-analysis items. We also considered the TRIPOD guideline (14) to
extract the prediction models’ required items.

4. Results
4.1. General Study Description
The search string retrieved 464 articles in PubMed and 600 articles in EMBASE. After
removing duplicates, our database search yielded 755 articles. We excluded 667 articles
after checking titles/abstracts and 54 articles after full-text consideration; the remain-
ing 34 articles met the inclusion criteria. A further nine articles were also included by
hand searching reference lists. In total, 24 articles on I-T2DM (15-38) and 19 articles on
U-T2DM screening (39-57) published between December 2011 and October 2019 were eli-
gible for the current review (Figure 1). For U-T2DM, two articles reported separate risk
diagnosis models with different populations. Thus, our review assessed 46 risk predic-
tion models from 43 articles.
:
 2 Figure 1.

The flowchart of study selection between November 2011 and 2019

Appendices 3 and 4 show basic information of studies for I-T2DM and U-T2DM, respec-
tively, including publication year, country, study design, study name, number of events
and sample size (model development), follow-up duration, participant age, outcome
definition, and the Newcastle-Ottawa scale. I-T2DM models have been developed in
nine countries, while U-T2DM has been developed in 15 countries (Appendix 12 in Sup-
plementary File). One article described the development of three risk models for U-
T2DM screening using three different populations from different countries (44).

The median (interquartile range; IQR) number of the study population for model de-
velopment was 5711 (1971 - 27426) and 2457 (2060 - 6995) individuals for I-T2DM and U-
T2DM, respectively. The most frequent age range in the reviewed articles for both I-
T2DM and U-T2DM was 40 years and older. Moreover, the median (IQR) number of the
:
 incident case of T2DM was 396 (171 - 1218) whereas the median (IQR) number of preva-
lent cases for U-T2DM screening was 207 (144 - 388). In 10 articles (17, 19, 20, 22, 26, 30-32,
35, 38) on I-T2DM and one article on U-T2DM (51), the study population was over 10,000
(Appendices 3 and 4 in Supplementary File).

4.2. Model Development

A summary and detailed characteristics of model development for I-T2DM are reported
in Table 1 and Appendix 5 in Supplementary File, respectively. Moreover, the detailed
characteristics of model development for U-T2DM screening are shown in Appendix 6
in Supplementary File.

2 Table 1.

Model Development Characteristics for the Current and Previous Reviews for incident Type 2 Diabetes
Mellitus

Updated Review (Current Review = 24) Previous Reviews Collins et al. ((88) and Noble

Treat-
ment of
contin-
uous
variable
s

All 4
kept
con-
tinu-
ous

All 18
cate-
gorize
d

Some 2
con-
tinu-
ous
and
:
 some
cate-
gorize
d

No -
in-
for-
matio
n

Treat-
ment of
missing
data

Com- 13
plete
case

Impu- 1
tation

No 10
in-
for-
matio
n

Predic-
tor
selectio
n

Step- 4
wise,
for-
ward,
back-
ward,
au-
tomat-
ic al-
gorith
:
 m
selec-
tion

Uni- 7
vari-
ate
analys
is

Liter- 6
ature
review

No 7
in-
for-
matio
n

The sta-
tistical
model
for
predic-
tion

Logis- 8
tic
regres
sion

Cox 15
regres
sion

Sub- 1
dis-
tribu-
tion
haz-
ard
model
:
 Type of
model

Lab- 13
based

Office- 3
based

Both 8

Sex-spe- 2
cific
model

Overfit- 7
ting
correc-
tion

The pre- 19
senta-
tion as a
risk
score

aOnly original development English articles without genetic concentration.

4.2.1. Outcome Definition

In six of the articles, I-T2DM was defined based on fasting blood sugar (FBS), 2 hour
blood sugar (2h-BS), and Hemoglobin A1c (HbA1c) (19, 20, 25, 26, 32, 36). In the remain-
ing studies, the following compounds were considered for definition of T2DM: FBS and
2h-BS in three of the studies (18, 23, 37), FBS and HbA1c in six of the studies (21, 27-29, 33,
34), FBS in six of the studies (15, 17, 24, 30, 31, 38), HbA1c in one of the studies (16), and
physician-diagnosed using electronic health records in two of the studies (22, 35).
Moreover, glucose-lowering mediation as another definition for T2DM was included in
14 of the studies (15, 17, 18, 20, 24, 26, 27, 29-34, 38). Almost the same variation in defini-
tion was observed to screen U-T2DM definition (Appendix 4 in Supplementary File).
:
 4.2.2. Treatment of Continuous Variables
The detailed information on the treatment of continuous variables for I-T2DM is re-
ported in Appendix 5 in Supplementary File. Eighteen prediction models categorized
all the continuous risk factors (15, 17, 18, 20, 23, 24, 26-30, 32-38), four risk factors (16, 22,
25, 31), and two continuous and categorical risk factor (19, 21). Considering model de-
velopment for U-T2DM screening (Appendix 6 in Supplementary File), all continuous
variables were categorized in 19 models (39-41, 43-54, 56, 57), and the variables kept
continuous in three models (42, 55).

4.2.3. Missing Strategy

With respect to the prognostic model for I-T2DM, complete case analysis was per-
formed on 13 of the studies (15, 18, 20, 21, 23, 24, 26-29, 32, 34, 38). Only one of the studies
used multiple imputations (22). The strategy of dealing with missing values was not
clear in 10 developed models (16, 17, 19, 25, 30, 31, 33, 35-37); thus, we assumed that com-
plete case analysis was performed.

Regarding screening U-T2DM, the missing treatment strategy was not clear in nine
models (44-46, 51, 54, 56, 57) (Appendix 6 in Supplementary File). Complete case analy-
sis was performed on 12 models (16, 41, 42, 47-50, 52, 53, 55, 57), and multiple imputa-
tion was reported for one model (43).

4.2.4. Predictor Selection

Seven of the studies reported using the univariable analysis to reduce the number of
risk predictors (16, 18, 20, 21, 24, 28, 30), and six of the studies included all literature-
based risk factors in multivariate analysis (19, 22, 27, 29, 31, 33). Automatic selection was
reported in five of the articles (32, 35-38), and no information on the model building
strategy was found in seven of the articles (15, 17, 19, 23, 25-27). In the current study, the
number of predictors included in the developed models ranged between 4 - 15 for I-
T2DM and 3 - 10 for U-T2DM screening (excluding the article with more than 40 predic-
tors (35)).

4.2.5. The Statistical Model for Prediction

Most prognostic models for I-T2DM were developed using Cox (n = 15) (15-20, 22, 28, 30-
33, 36-38) and logistic regression (n = 8) (21, 23, 25-27, 29, 34, 35) using enter, automatic
:
 forward selection, backward elimination, or stepwise procedure. The sub-distribution
hazard model was reported in one of the studies (24). As expected, all diagnostic mod-
els for U-T2DM screening used the logistic model for data analysis.

4.2.6. Overfitting in Prediction Models

For the I-T2DM model development, overfitting was controlled for seven of the studies
(Table 1), and for U-T2DM, overfitting was controlled for 12 models (Appendix 6 in Sup-
plementary File). Bootstrapping was the most used strategy to control overfitting in I-
T2DM and U-T2DM.

4.2.7. Extra Information on Model Development

Thirteen of the studies generated only laboratory-based (invasive) risk prediction
models (16, 17, 19, 20, 24, 28-32, 35, 37, 38) for I-T2DM, while an office-based (non-invasive)
risk method using demographic and clinical measurements (e.g. sex and BMI) was re-
ported in four of the studies (25, 27, 34). Eight of the studies reported both invasive and
non-invasive prediction models (15, 18, 21-23, 26, 32, 36) (Table 2). For U-T2DM, 18 models
were based solely on office-based measurements, three models were developed accord-
ing to lab measurements, and only one of the studies reported both invasive and non-
invasive models (Appendix 6 in Supplementary File).

2 Table 2.

Model Development and Validation Characteristics of Undiagnosed Type 2 Diabetes Mellitus (N = 19 Studies
and 22 Models)

Numbers

Model Performance Measures

Discrimination measures

C statistics/AUC 22

D statistic -

Sensitivity/specificity 19

Othersa 12

Calibration

Calibration plot 3
:
 Hosmer-Lemeshow test 7

Brier score -

Observed-predicted ratio -

Overfitting 12

Overall performance measures:

R2 -

AIC, BIC 2

Clinical usefulness 1

The performance as risk score 20

Model Development Measures

Validation

Apparent 15

Internal validation 8

External validation 11

Type of model

Invasive 3

Non-invasive 18

Both 1

Sex-specific model 2

Treatment of missing

Complete case 12

Imputation 1

No information 9

Statistical model for prediction

Logistic regression 22

Cox regression -

Survival analysis -

aPPV, NPV, LR+, LR-.

:
 aPPV, NPV, LR+, LR-.

Body mass index and age were the two most commonly used variables in model devel-
opment regarding screening U-T2DM and predicting newly diagnosed T2DM (Figure 2).
Sex was adjusted in 11 of the studies, and only two of the studies (19, 22) developed sex-
specific models. For I-T2DM, the interaction between variables was checked in three of
the studies (15, 22, 23). However, two of the studies (37, 52) on U-T2DM screening fo-
cused on interaction terms.

2 Figure 2.

The number of model predictors for incident and undiagnosed type 2 diabetes mellitus between No-
vember 2011 and 2019. BMI, body mass index; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; FHDM,
family history of diabetes; WC, waist circumference; WHR, waist to height ratio; Others, gestational
diabetes, C-reactive protein levels, statin, atypical antipsychotics, corticosteroids, antipsychotic,
learning disability, body mass index, Townsend score, CVD, schizophrenia or bipolar affective disor-
der, learning disability, balanitis or vulvitis, osmotic symptoms.

4.3. Model Validation

A summary and detailed characteristics of model validation for developing I-T2DM are
reported in Table 3 and Appendix 7 in Supplementary File, respectively. Moreover, the
detailed characteristics of model validation for U-T2DM screening are shown in Ap-
pendix 8 in Supplementary File.

2 Table 3.

Model Validation Characteristics for the Current and Previous Reviews for incident Type 2 DM
:
 Updated Review (Current Review = 24) Previous Reviews Collins et al. (

Validation

Apparent 10

Internalb 15

Boot- 1
strapping

Random 9
split
sample

Cross 5
validation

Jack- -
knifing

External 5

Perfor-
mance
measures

Overall

R2 3

AIC, BIC 2

Brier 1
statistics

Discrimi- 25
nation

AUC 20

C- 8
statistics

D- 1
statistics

Calibra- 19
tionc
:
 Calibra- 9
tion plot

Hosmer- 11
Lemeshow
test

Barrier -
score

Observed- 1
predicted
ratio

No 5
informa-
tion

Classificatio
n

NRI/IDI 5

Sensitivi- 15
ty/specifi-
city

Othersd 5

Clinical 1
usefulness

Abbreviations: AUC, area under the curve; HL, Hosmer-Lemeshow; IDI, integrated discrimination im-
provement; NRI, net reclassification index.

aOnly English articles without genetic concentration

bArticles reporting several validation methods

cArticles reporting several calibration measurements

dPositive/negative predictive values, NPV, Youden index

:
 4.3.1. Internal and External Validation
Fifteen out of the 24 development studies for I-T2DM reported internal validation (15,
16, 20, 22-24, 26, 27, 29-32, 35, 36, 38), 9 studies reported development and validation (n
= 9), cross-validation (n = 5), and bootstrapping (n = 1). Five of the studies conducted
external validation (18, 19, 21, 34, 35) (Table 3 and Appendix 7 in Supplementary File).
Eight models (40, 42, 45, 47, 50, 52, 53, 55) reported internal validation for U-T2DM
screening, and external validation was performed for 11 out of the total introduced
models (39-43, 46, 48, 51, 52, 54, 56) (Table 2 and Appendix 8 in Supplementary File).

4.3.2. Model Performance

With the aim of predicting newly diagnosed T2DM, all the studies reported at least one
measure of predictive performance, with 20 of the studies reporting the area under
the receiver curve (AUC) (15, 17, 18, 20, 21, 23, 24, 26-38), eight of the studies reporting C-
statistics (15-17, 19, 24, 28, 29), and one of the studies reporting discrimination with D-
statistics (15). Nineteen of the studies reported calibration, with the Hosmer-
Lemeshow goodness of fit test in 11 of the studies (17, 18, 21, 23, 26, 27, 29, 31, 34, 36, 37),
the observed-predicted plot in nine of the studies (16, 19, 22, 24, 26, 28, 32, 36, 38), and
the observed-predicted ratio in one of the studies (30). Moreover, 15 of the studies re-
ported classification analysis, and four of the studies reported the overall performance
measure.

All the introduced models reported AUC for U-T2DM screening (39-57), 10 of the studies
(39, 40, 43, 47-50, 52, 53) reported calibration, and three of the models (42, 47, 55) re-
ported overall performance measurements. The median (IQR) value of AUC or C-sta-
tistics was 0.78 (0.74-0.82) for I-T2DM, while the median (IQR) value of AUC was 0.77
(0.74-0.81) for U-T2DM screening.

4.4. Other Considerations

4.4.1. Risk of Bias Assessment
The PROBAST recommendations for ROB assessment were presented for both I-T2DM
(Appendix 9 in Supplementary File) and U-T2DM screening (Appendix 10 in Supple-
mentary File) models. All the studies used an appropriate data source. The overall judg-
ment of ROB assessment is shown in Figure 3. Low ROB was noted in three domains of
participants, predictors, and outcomes for both I-T2DM and U-T2DM. Forty-two percent
:
 of the prediction models were observed to have high ROB for I-T2DM, which was 18.2%
for U-T2DM. ROB was generally high or unclear for I-T2DM and low or unclear (82%) for
U-T2DM.
:
 2 Figure 3.

The overall judgment of risk of bias (ROB) for incident and undiagnosed type 2 diabetes mellitus be-
tween November 2011 and 2019

4.4.2. Citation Rate

The median duration from the publication date for the prognostic models was 3 years
with the 2.35 citation rate per year. Further, the median duration from the publication
date for the U-T2DM screening models was 4 years with the 2.26 citation per year (Ap-
pendix 11 in Supplementary File).

5. Discussion
To the best of our knowledge, this was the first systematic review to report require-
ments for major prediction models to predict I-T2DM or screen U-T2DM using the TRI-
POD and PROBAST checklist. Our systematic review yielded 45 published studies be-
tween December 2011 and October 2019 reporting all aspects of developing and validat-
ing prediction models according to the CHARMS checklist. According to the PROBAST
assessment tool introduced based on the TRIPOD statement, the majority of the pre-
diction models were observed to have high or unclear risk for I-T2DM but low or un-
clear risk for U-T2DM.

5.1. Study Design for Model Development

A variable selection strategy is a challenging part of prediction modeling. Several ap-
proaches are recommended, including pre-specified literature-based variable selec-
tion, univariable analysis, and automatic variable selection (forward selection, back-
ward elimination, or stepwise). In our review, univariable analysis (29%) was the most
commonly used method to build a statistical model. However, in the previously pub-
lished reviews, literature-based and automatic variable selection approaches were the
most reported ones (16.7%). Thirty-two percent of the studies in our review (55.5% of the
previously published reviews) failed to report any information regarding variable se-
lection strategies.

One of the problems in developing multivariable prediction models is to treat contin-

uous variables and examine whether they are categorized or kept continuous. With
categorizing continuous variables, important information might be lost, and we may
:
 lose power to detect real association (3). There is a firm opinion that continuous vari-
ables should be kept continuous, and in case of a non-linear association, other statisti-
cal methods (e.g., splines) are recommended (58). Nevertheless, researchers prefer to
categorize continuous variables because it is more applicable in clinical decision-mak-
ing (59). In our review, 75% of the studies on I-T2DMcategorized all variables and; In the
previously published articles 61% of articles categorized all variables.

5.2. Missing Data Strategy

Missing data is a serious problem in epidemiological and clinical studies as it can re-
duce statistical power and efficiency. A common way to manage missing data is to use
listwise methods, also known as complete case analysis. Although this strategy is
straightforward and easy to use, it decreases statistical analysis power and thus it is
not recommended. Multiple imputation (MI) is a superior approach to minimize the
missing information effect. MI can increase study precision and result in robust sta-
tistics (60). Single imputation (SI) may be a good alternative for prediction models de-
spite its limitations, such as uncertainty underestimation. Since point estimation, and
not variability, is our primary interest in the prediction models, statisticians advise SI
because it is easy to implement and since a score based on rounded coefficients gives
almost the same result as MI (3). As acknowledged by Steyerberg (3) “MI may, therefore,
have only minor advantages over SI for model prediction” (2009, clinical prediction
models, Part III, section 7, page 133). In our review, 54% of the studies (44% of the previ-
ously published reviews) followed complete case analysis and only one of the studies
reported MI. However, the method used to resolve the missing data issue was not re-
ported for I-T2DM in 42% of the studies; this was 66.7% of the previously published
reviews.

5.3. Statistical Models

Multivariable regression models such as logistic regression or Cox proportional haz-
ards regression commonly use statistical methods for deriving prediction models. We
used the same strategy in our study with the difference that researchers have recently
paid attention to family regression survival. Each of these statistical approaches has its
own assumptions and limitations that may reduce generalizability. The usual ap-
proach in driving prediction models is to use all available data and population risk fac-
tors to compute risk scores using only one measurement, known as “global predictive
models”. Patient-specific predictive models, introduced as “personalized prediction
:
 models”, are an alternative approach that use each individual’s dynamic information
to derive more relevant models. In recent years, time-varying regression models are be-
coming more common (61-63).

5.4. Overfitting in Model Development

Both model and parameter uncertainty result in occurring overfitting, indicating that
the prediction models are not valid for the new society. Bootstrapping is recommend-
ed by using a rule of thumb of 10 cases per predictor or reporting optimism-corrected
performance (3). Of the studies included in this review, 29% had overfitting correction,
while this rate was 16.7% in the previously published articles for I-T2DM.

5.5. Model Performance

The next crucial step after model development is to quantify model performance.
There are three types of performance: (1) apparent validation (using the same data set
as the model developed for reporting validation); (2) internal validation such as split
sampling, cross-validation, or bootstrapping methods; and (3) external validation (us-
ing completely different data). More than half of the studies in the current review for I-
T2DM reported internal validation, while this rate was 38.9% in the previously pub-
lished articles. In the current review, 21% of the studies reported external validation,
while this rate was 48% in the previously published articles.

Reporting overall performance (e.g., AIC/BIC and R2) with discrimination ability be-
tween events and non-events (e.g., AUC, C-index, sensitivity, and specificity) is informa-
tive and somehow necessary in model evaluation. In the current and previously pub-
lished reviews, all the articles reported at least one discrimination aspect. Overall per-
formance was reported only in four of the articles for I-T2DM. Moreover, demonstrat-
ing the calibration method (e.g., the Hosmer-Lemeshow test and the calibration plot),
especially for a binary outcome, is informative and shows the agreement level between
observed and predicted outcomes. More than 75% of the selected articles in the current
and previously published reviews reported calibration measurements for I-T2DM.

5.6. Strategies for Model Improvement

We focused on model development and validation requirements. However, some other
model improvement strategies, such as improving statistical methods, considering in-
teraction terms, and considering non-linear associations, are also recommended.
:
 Some epidemiologists advised to estimate prediction models including relevant inter-
action terms in addition to the main effects. A literature review may help us select the
proper interaction. However, it should be noted that interaction terms in the predic-
tion models do not necessarily increase model performance. Moreover, because of the
therapeutic improvement of medicine or disease-related definition, predictors’ effect
may change over time. For example, predictors’ effect for T2DM development is noted
to decrease with aging. The older population is more affected by other types of disease;
thus, considering “age × predictors” in the prediction models may be useful. In the cur-
rent review, only one of the studies reported age interaction (22). Further biological
and pre-specified relevant interactions such as ‘SEX×predictors’ are also
recommended.

5.7. Sex-specific Prediction Models

Evidence shows that gender differences are important in many diseases, particularly
non-communicable diseases (64, 65). According to the 2019 IDF Atlas in 2019, there
were 17 million more men diagnosed as having T2DM than women (66). Of the studies
included in this review, sex-specific prediction models were reported only in two (8%);
this number was four (22.2%) among the previously published reviews on I-T2DM. Vari-
eties in endocrine (e.g., biology and sex-hormones), as well as in behavioral (e.g., life-
style and socioeconomic status), cultural, environmental, and epidemiological con-
text, Indicates the difference between male and females. For example, overweight/obe-
sity is the major risk factor of T2DM in both genders, with the difference that men are
overweight/obese in their younger age whereas women are overweight/obese in their
middle age. Also, diabetes-related comorbidities differ in men and women and require
specific management strategies (65, 67, 68). A systematic review showed that microvas-
cular complications were higher among men with T2DM, while CVD morbidity and
mortality, as well as psychological problems, were higher among women with T2DM
(69). Despite the importance to consider sex differences in awareness, diagnosis, treat-
ment, prediction, and prevention strategies, few studies have focused on the issue
(69). In the current study, we observed a downward trend of sex-specific models (8%)
compared to the previously published articles for I-T2DM, although not significant
(22.2%).

5.8. Age-specific Prediction Models

The global prevalence of T2DM is expected to rise from 9.3% to 10.2% between 2019 and
:
 2030 (70). Even though most of this increase has been reported in the middle-aged and
elderly population, several studies showed a decrease in the age of diagnosis (71-73). In
the current review, the prediction models were mostly developed in the middle-aged
and older population, and only two studies recruited a younger population for I-T2DM
(15, 30). Previous reviews show that the early onset of T2DM is a serious concern in vari-
ous ethnic groups and is strongly associated with the development of micro/macrovas-
cular complications. A better understanding of potential risk factors and a possible
disease mechanism of the early onset of T2DM in the young population could be help-
ful in controlling future complications of the disease on individuals and the health-
care system (73, 74).

5.9. Role of Non-traditional Risk Factors in Prediction Models

Besides biological factors, psychological disorders are also responsible for increased
blood glucose. Epidemiological studies implicate that psychological factors, socioeco-
nomic status, poverty, education level, occupational stress, and sleep disorders are re-
lated to a higher risk of T2DM (75, 76). In our review, over 90% of the studies did not use
these factors, and only one of the studies used a depression score (22) and sleep apnea
(35). For example, low education is related to a higher risk of diabetes among Aus-
tralian women (76), while higher education increases I-T2DM among Iranian men (77).
Adding psychological factors may improve the fit of models predicting or screening
T2DM, as even shown in QRISK 2017 (22). Evidence supports the existence of a two-way
relationship between T2DM and poverty, with T2DM increasing the risk of falling into
poverty, especially in men, and poverty is associated with a higher risk of I-T2DM along
with inequality of diabetes care (78, 79). However, using simple and reliable covariates
is the main point of prediction models. Clinicians recommend improving these mod-
els with even subjective measurements.

Two systematic reviews (80, 81) suggested that the presence of endocrine-disrupting
chemicals (EDCs) in the environment, such as bisphenol A, phthalates, and persistent
organic pollutants or dioxins, may also be associated with I-T2DM. Plastic bottles, met-
al cans, toys, and many other manufacturer products are considered EDCs. They impair
the normal activity of hormones and cause a wide range of adverse events. Several epi-
demiological studies evaluated the association between EDCs such as air pollution (82)
and T2DM. However, the causality and a whole mixture of toxicants as well as duration
of being at risk in the human study have not been demonstrated yet (80). Recently, sci-
:
 entists have shown that both nitrogen dioxide (NO2) as a measure of traffic-exposure
and annual concentrations of particular matter < 2.5 µm (PM 2.5) as a measure of both
traffic-related and transported particles, are statistically associated with a quick de-
cline in the whole-body insulin sensitivity and a faster increase in BMI among children
aged 8 - 15 years (83, 84). However, the roles of air pollution and endocrine disrupters
have not been yet considered in studies including the current one, despite the high
prevalence of air pollution in some countries (33-39).

5.10. Ethnicity in Prediction Models

Evidence is accumulating on the significance of specific ethnic groups at the increased
risk of T2DM. According to the IDF report, the Middle East and African countries have
the highest age-standardized prevalence of T2DM, and the number of people with
T2DM is expected to increase by 94% and 143% between 2019 and 2045 in these regions,
respectively. Globally, the lower increasing rate of prevelance is estimated in the Eu-
ropean ethnicity by 15% (70). Several risk prediction models have been developed for U-
T2DM prognosis or screening worldwide (8). However, the significance of country-
based models is still controversial. In the current review, over 70% of the prediction
models for I-T2DM were derived in the East Asian countries (17, 29-31, 36, 38). While in
the previously published articles, more than 50% of the prediction models were devel-
oped in the American and European populations (6, 7, 85-93). By comparing the risk
prediction models’ performance in the current review and the previously published
articles, a similar median discrimination index (0.78 for the current review and 0.8 for
the previously published reviews) with almost similar predictors was observed, irre-
spective of the geographical location. Our findings are supported by the studies of
Tanamas (94) and Rosella et al. (95). Tanamas et al. (94) examined several T2DM predic-
tion models in two cohort studies: AusDiab and Mauritian south population survey.
The discrimination power was reported to be higher in the mixed population. They
found that ethnicity did not improve model performance. Their findings are in line
with the previous study (95) considering that ethnicity information did not improve
the discrimination and accuracy of the prediction models. They emphasized that the
similarity of ethnicity or diabetes risk could not determine the appropriate model per-
formance in another population. This could be due to the fact that ethnicity is affected
by other diabetes risk factors including a family history of diabetes, BMI, physical activ-
ity, and diet. According to the discussion above, compared to development of new
models, external validation and calibration of the existing models are preferred and
:
 cost-neutral (96).

5.11. External Validation ad Recalibration on Prediction Models

To the best of our knowledge, none of the studies in the current review was externally
validated in an independent study. However, some previously developed models were
externally validated and recalibrated several times by independent researchers (4, 7,
91, 97). Masconi et al. (98) investigated the external validation and recalibration of dia-
betes risk prediction models in their systematic review of 94 articles, including 70
models and 236 validations on T2DM. The most commonly validated model for I-T2DM
was FOS (7) (10.1%), followed by the San Antonio risk model (91) (9.5%). For U-T2DM
screening, the Finish diabetes risk score (4) (14.8%) was the most frequently validated
prediction model, followed by the Rotterdam model 1 (97) (12.5%). Recalibration was
performed on 22.9% of the validation models in the validation study for I-T2DM.

5.12. Strengths and Limitations

The strength of this study is that it was reported in accordance with the PRISMA-ScR
checklist. This review also included a comprehensive report of model development
(e.g., the outcome definition, variable selection, statistical analysis, and treatment of
continuous variables) and validation (e.g., calibration and net benefit) requirements
according to the TRIPOD guideline. Study quality control and ROB assessment were
also reported using the Newcastle-Ottawa scale and the PROBAST checklist. Our study
is very informative since previously published articles examined in previous systemat-
ic reviews were also evaluated and compared with the currently selected articles based
on the TRIPOD prediction model guideline. However, there are also some limitations.
Firstly, only English articles were included and thus we may have missed some articles.
Secondly, we decided to exclude Genetic risk prediction or non-regression based mod-
els (e.g., neural networks or decision tree) due to their different nature.

6. Conclusions
Among prediction models of I-T2DM progression or U-T2DM screening between De-
cember 2011 and October 2019, we observed intermediate to poor quality were assessed
in several aspects of model development and validation, mainly from the analysis part.
It poses the question whether we could rely on the current prediction models or we
should develop new models. Another major concern is that a newly developed model
can be easily disregarded if it has no added value for health policymakers or clinicians.
:
 Using pre-specific risk factors or traditional statistical approaches is similar to the ex-
isting prediction models; for example, the mean (SD) of AUC has been 0.78 (0.06) in the
last twenty years. It may be required to develop personalized comprehensive predic-
tion models by considering additional risk factors so that the prediction models’ per-
formance could be improved more effectively. It has been shown that time-varying pre-
diction models can outperform global models (63). External validation and recalibra-
tion could help us tailor the available prediction models to local populations, which is
a better option than developing a new model.

6 Acknowledgements

This article was derived from the PhD thesis of Samaneh Asgari, at the Research Insti-
tute for Endocrine Sciences of the Shahid Beheshti University of Medical Sciences.

7 Footnotes

Authors’ Contribution:
Contribution:SA, FH, and DK designed the research. SA and DK con-
ducted the literature search and literature screening. SA extracted data. FH and DK
evaluated data extraction. All the authors interpreted the data, read the man-
uscript, and approved the final version. The corresponding author attests that all
the listed authors meet the authorship criteria and that no others meeting the cri-
teria were omitted.
Conflict of Interests:
Interests:None.
Ethical Approval:
Approval:This study was approved by the Institutional Review Board
(IRB) of the Research Institute for Endocrine Sciences (RIES), the Shahid Beheshti
University of Medical Sciences, Tehran, Iran.
Funding/Support:
Funding/Support:None.
Informed Consent:
Consent:All the participants provided written informed consent.

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