Diagnostics
Original Article
1
School of Pharmacy, Memorial
University of Newfoundland, St.
John’s, Canada
2
Health Services and Systems
Research, Duke NUS Medical
School, Singapore
3
Department of Endocrinology,
Singapore General Hospital,
Singapore
Correspondence to
Dr Hai Van Nguyen, School of
Pharmacy, Memorial University
of Newfoundland, St. John’s,
A1B 3V6, Canada; ​hvnguyen@​
mun.c​ a
Received 15 March 2017
Revised 20 July 2017
Accepted 21 July 2017
Published Online First
23 August 2017
To cite: Nguyen HV,
Finkelstein EA, Mital S, et al.
J Med Genet
2017;54:747–753.
Incremental cost-effectiveness of algorithm-driven
genetic testing versus no testing for Maturity Onset
Diabetes of the Young (MODY) in Singapore
Hai Van Nguyen,1 Eric Andrew Finkelstein,2 Shweta Mital,2 Daphne Su-Lyn Gardner3
Abstract
Background  Offering genetic testing for Maturity Onset
Diabetes of the Young (MODY) to all young patients with
type 2 diabetes has been shown to be not cost-effective.
This study tests whether a novel algorithm-driven genetic
testing strategy for MODY is incrementally cost-effective
relative to the setting of no testing.
Methods  A decision tree was constructed to estimate
the costs and effectiveness of the algorithm-driven MODY
testing strategy and a strategy of no genetic testing over
a 30-year time horizon from a payer’s perspective. The
algorithm uses glutamic acid decarboxylase (GAD) antibody
testing (negative antibodies), age of onset of diabetes (<45
years) and body mass index (<25 kg/m2 if diagnosed >30
years) to stratify the population of patients with diabetes
into three subgroups, and testing for MODY only among
the subgroup most likely to have the mutation. Singapore-
specific costs and prevalence of MODY obtained from local
studies and utility values sourced from the literature are
used to populate the model.
Results  The algorithm-driven MODY testing strategy has
an incremental cost-effectiveness ratio of US$93 663 per
quality-adjusted life year relative to the no testing strategy.
If the price of genetic testing falls from US$1050 to
US$530 (a 50% decrease), it will become cost-effective.
Conclusion  Our proposed algorithm-driven testing
strategy for MODY is not yet cost-effective based on
established benchmarks. However, as genetic testing prices
continue to fall, this strategy is likely to become cost-
effective in the near future.
Introduction
Maturity Onset Diabetes of the Young (MODY)
is a monogenic form of diabetes that accounts for
up to 2% of all diabetes cases.1 It is characterised
by the onset of diabetes under the age of 25 years,
autosomal dominant inheritance and non-insulin
dependence.2 To date, mutations in up to 14 genes
have been identified to cause MODY, of which the
majority of the MODY cases have been attributed to
one of the following four genes: HNF1A, HNF4A,
GCK and HNF1B. Each mutation, depending on
its downstream effect on the insulin pathway, may
provide insight into modifying diabetes treat-
ment. For instance, HNF1A and HNF4A mutations
respond better to sulphonylureas than other treat-
ments including metformin (usual first-line medica-
tion for type 2 diabetes (T2D)).3 Patients who are
previously diagnosed with insulin-requiring diabetes
and require regular monitoring of their glycaemic
Nguyen HV, et al. J Med Genet 2017;54:747–753. doi:10.1136/jmedgenet-2017-104670
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control may be successfully switched to oral sulpho-
nylurea tablets on diagnosis of HNF1A/HNF4A
MODY, obviating the need for regular self-moni-
toring of blood glucose.4 Adapting treatment plans
to include sulphonylureas may improve quality of
life by reducing the need for daily injections. It is also
likely to save costs given that sulphonylureas are less
expensive than insulin.
Recent advancements in next-generation
sequencing (NGS) technology afford the opportu-
nity to screen multiple MODY genes at one time
for an estimated cost of US$1000. However, prior
to implementing this new clinical tool, it is neces-
sary to understand whether the benefits of genetic
testing and targeted treatment are likely to justify
the cost. In a recent US-based study, simultaneously
testing for the three most common MODY genes
(HNF1A, HNF4A and GCK) among all newly diag-
nosed patients with T2D aged 25–40 years was
shown not to be cost-effective with a cost-effec-
tiveness ratio of US$205 000 per quality-adjusted
life year gained.5 However, the authors suggested
that such universal testing would be cost-effective
if MODY prevalence increased from 2% to 6% in
the target population. One strategy for increasing
the prevalence rate of the target population is to
identify a subset of patients most at risk for MODY
prior to gene testing.
This study aims to customise and extend the
prior analysis to assess whether a cost-effective algo-
rithm-driven genetic testing strategy for MODY could
be identified by better targeting the subset of the
population identified for genetic testing. The algo-
rithm involves testing for beta-cell autoantibodies,
and then among those who test negative, identifying
a subset who are less than age of 30 years or who are
between the ages of 30 and 45 years with body mass
index (BMI) of less than 25 kg/m2. MODY genetic
testing is done only for this subset. Using cost and
prevalence data from Singapore, we test whether
this new algorithm-driven genetic testing approach is
cost-effective relative to no testing.
Methods
The algorithm
Starting population
Traditional criteria for gene screening include a
family history of diabetes and diabetes onset under
age of 25 years; however, using these criteria alone,
up to 50% of MODY patients will not have fulfilled
the criteria for screening.6 To be more inclusive, our
747
 Diagnostics
proposed strategy starts with considering individuals diagnosed
with diabetes at age of 45 years or lower.
Excluding type 1 diabetes (T1D)
The algorithm first identified people with T1D in the starting
population. Those who tested positive for GAD antibodies Ab
(GADAb) were classified as having T1D or latent autoimmune
diabetes of adulthood. GADAb was analysed in the core labo-
ratory (IASP 2015 Lab number 1501), Lee Kong Chian School
of Medicine, by radioligand assay using 35S-labelled full-length
GAD65 according to a harmonised protocol.7 GADAb positivity
was determined as the 99.5th percentile of 1192 healthy German
control subjects (age range 18–70 years; mean age 39.7 years)
and 145 healthy Singaporean control subjects (age range 20–69
years; mean age 49.1 years). Greater than or equal to 21 DK
units/mL for GADAb was defined as positive. Those who tested
positive for GADAb did not undergo further genetic testing and
would continue with their current treatment. While conceding
that MODY has been found in individuals previously misdiag-
nosed as having T1D,8 and beta cell autoantibody positivity has
been found in those with MODY, this was an uncommon occur-
rence9 (<1%) and associated with GADAb positivity rather than
IA-2A Ab.9 In Asians, previous studies have consistently demon-
strated the low prevalence of GADAb positivity in those with
clinically classified T1D compared with Caucasian populations
(40% versus >84%10–13). GADAb appears to be the most preva-
lent antibody among Asian autoantibody-positive T1D patients,
even in studies incorporating other antibodies like the zinc trans-
porter 8 antibody.14 We anticipate that in our Asian cohort, the
low background incidence of T1D (2.46 per 100 000 in Asian
cohorts compared with 60 per 100 00015 in Caucasian popula-
tions16) and a low prevalence of beta cell autoimmunity among
those with clinically diagnosed T1D point towards a greater
likelihood of T1D rather than MODY in an Asian patient with
diabetes and positive GADAb.
Subgroup targeted for MODY testing
Patients who are GADAb negative were classified as non-T1D.
While this group will inevitably include those with GADAb-neg-
ative T1D, we felt that it was important to include these
Figure 1  Decision tree.
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individuals for genetic testing given the heterogeneity of diabetes
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aetiologies and overlapping clinical phenotypes in Asians.17
Among these patients, genetic testing for MODY was targeted
at those with features that are less consistent with T2D. These
included those with diabetes onset under age of 30 years (ie, very
young onset of T2D) or patients with diabetes diagnosed at age
between 30 and 45 years and BMI less than 25kg/m2 (ie, young
onset of T2D but slim).
We used a NGS gene panel that contains known/putative genes
associated with MODY (ie, HNF1A, HNF4A, GCK, HNF1B,
INS, KNCJ11, ABCC8, IPF1, CEL, NEUROD1, PAX4, KLF11,
BLK, INSR, LMNA and PPARG). The 14th MODY gene APPL1
was not included in this panel as it was discovered only after this
panel and study was designed.18 Those who tested negative for
all 16 genes were classified as having T2D and continued their
pre-existing medications in the same ratio as per usual treatment.
Those who tested positive for a particular gene received tailored
treatment (or no treatment) depending on which gene was iden-
tified. In particular, for those who tested positive for HNF1A
and HNF4A, sulphonylurea (oral) treatment was given, while
those who tested positive for GCK did not receive medication.
For the rest of the rarer MODY genes, treatment was tailored
according to mutation (eg, patients with INS MODY required
insulin treatment, as did patients with HNF1B MODY). Patients
aged between 30 and 45 years who had BMI greater than 25
continued with their pre-existing treatment.
This study was approved by Singhealth Centralized Institu-
tional Board (No. 2013/651/C).
Decision tree model
A decision tree was constructed to estimate the incremental
costs and effectiveness of the algorithm-driven testing
strategy relative to no genetic testing over a 30-year time
horizon (figure 1). We chose a decision tree model due to the
non-recursive nature of genetic testing for MODY as well as
the rigour (yet simplicity) of this model in capturing the costs
and effectiveness associated with the strategies considered.
No genetic testing was chosen as the comparator since genetic
testing for MODY is not currently performed as standard of
care in Singapore. Patients in the no testing arm are treated
Nguyen HV, et al. J Med Genet 2017;54:747–753. doi:10.1136/jmedgenet-2017-104670
 Diagnostics
with one of the usual treatment options. These involve insulin

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Table 1  Model inputs
injections, oral glucose-lowering agents or controlling blood
glucose levels by diet and exercise. The algorithm-driven Value Source
testing strategy models the testing and treatment pathways Probabilities
described above. Our model does not consider future diabe- Prevalence of positive GADAb in patients under age
tes-related complications associated with MODY or T2D 45 years 0.068 (*)
because inclusion of complications in the model would not Prevalence of negative GADAb in patients under age
alter our incremental cost-effectiveness ratio (ICER) esti- 45 years 0.932 (*)
mate. The algorithm-driven genetic testing does not influence Composition of GADAb-negative patients:
the risks of developing diabetes-related complications and  Diabetes onset under age 30 years 0.118 (*)
patients’ survival, and thus, as our cost-effectiveness anal-  Diabetes onset between age 30–45 years, BMI <25 0.297 (*)
ysis compares the algorithm-driven genetic testing versus no  Diabetes onset between age 30–45 years, BMI >25 0.517 (*)
testing for the same study population, effects of complica- Proportion of patients receiving diet control under usual
tions, if any, would be cancelled out. In fact, Naylor et al5 care 0.1 (*)
included diabetes-related complications in their model and Proportion of patients receiving insulin treatment under
found that genetic testing had no effect on the risks of compli- usual care 0.3 (*)
cations and life expectancy. Overall prevalence of MODY mutations 0.039 (*)
Positive mutation for one of 12 rare genes 0.003 (*)
Positive HNF1A or HNF4A mutation 0.023 (*)
Model inputs Positive GCK mutation 0.0043 (*)
Prevalence Positive HNF1B mutation 0.009 (*)
Prevalence parameters displayed in table 1 were estimated Costs†
based on a sample of 4630 patients who were diagnosed with
 GADAb test 59.43 20
diabetes under age of 45 years and enrolled in one of two
 16 gene panel test 1050 20
diabetes cohorts in Singapore: the Singapore Diabetes Cohort
 Insulin treatment‡ 761.39 20
Study (SDCS) and the Singapore Young Adults with Diabetes
 Oral glucose lowering agent‡ 61.32 20
(SYD) Study. SDCS consists of patients aged 21–75 years old
 Diet control 0
with diabetes who were recruited from four public healthcare
hospitals and six public sector primary care clinics in Singa-  Gene specific treatment‡ 61.32 20
pore. SYD consists of patients recruited from a single hospital  Sulphonylurea treatment‡ 61.32 20
who were diagnosed with diabetes under age of 45 years.  Glucose strip‡ 766.5 20
The prevalence of positive GADAb in this sample was 6.8%. Utilities
The negative GADAb group (93.2% of the sample) consists  Insulin treatment‡ 0.75 22
of three subgroups: (1) patients with diabetes onset under  Oral glucose lowering agent‡ 0.82 22
age of 30 years (11.8%); (2) patients with diabetes diagnosed  Diet control‡ 0.82 22
between age of 30–45 years and BMI less than 25 kg/m2  No treatment‡ 0.92 22
(29.7%); and (3) patients who were diagnosed between age *Based on 687 samples from Singapore Diabetes Cohort Study and Singapore
30–45 years and have a BMI greater than 25 kg/m2 (51.7%). Young Adults with Diabetes Study cohorts (see text), using targeted resequencing
According to the algorithm, patients from subgroups (1) panel.
and (2) are most likely to have MODY mutations. Among †All costs are before discounting. Converted to US$ using exchange rate
S$1=US$0.7.
these patients, 687 (36%) with sufficient stored serum and
‡Annual costs/utilities. Cost per daily dosage for insulin treatment is US$2.086
DNA provided samples for DNA analysis. These samples and for oral glucose lowering agent, gene-specific treatment and sulphonylurea
were sequenced using a target-enriched exon-capture NGS treatment is US$0.168. Cost of twice daily use of glucose strip is US$2.1.
16-gene panel. The test results indicated that overall MODY BMI, body mass index; GADAb, GAD antibodies Ab; MODY, Maturity Onset Diabetes
prevalence rate was 3.93% (2.3% for HNF1A/HNF4A, of the Young.
0.9% for HNF1B, 0.43% for GCK and 0.3% for the 12 rare
genes). There were no significant differences in BMI and age
of onset of diabetes between those who were tested versus Costs
those who were not tested (BMI: 24.4+4.3 vs 24.0+4.3 kg/ We assume that screening based on demographic variables (age
m2; age of onset of diabetes: 34.2+7.3 vs 35.0+8.2 years, and BMI) does not involve any additional costs as capturing
both p>0.05). All variants found on NGS were confirmed these variables is part of standard practice. GADAb screening
with Sanger sequencing. We assigned pathogenicity only to is assumed to occur in the first year of the study period and
variants that have been previously reported as implicated costs US$59.20 Annual treatment costs are the cost of average
in monogenic diabetes and that are usually considered to daily dosage of medicine/insulin injection based on restruc-
be clearly pathogenic as per the Association for Clinical tured hospital pricing to patients20 multiplied by 365 days.
Genomic Science's (ACGS) best practice guidelines.19 Those The discounted sum of annual costs over a 30-year period
with unknown pathogenicity have been categorised as vari- is used to generate the total costs of treatment. The use of
ants of unknown significance until further published reports glucose strips to measure blood sugar levels is assumed to
from continued sequencing efforts allows a reclassification occur twice daily over the 30-year horizon among insulin-de-
of their status. For those who continue to receive usual care, pendent patients. All costs are presented in US dollars (using
the proportion of patients who adopt each treatment strategy exchange rate as on 18 November 2015: S$1=US$0.7) and
(ie, insulin treatment, oral glucose lowering agent and diet discounted at 3.5% per year.21 It is assumed that those who do
control) are based on best estimates for Singapore based on not require any treatment, including those who control their
provider experience. diabetes with diet and exercise only, incur no additional costs.
Nguyen HV, et al. J Med Genet 2017;54:747–753. doi:10.1136/jmedgenet-2017-104670 749
 Diagnostics
Table 2  Cost-effectiveness of algorithm-driven MODY testing versus no testing
Strategy Cost Incremental cost
No genetic testing 9426
Algorithm driven MODY testing 9888 462
All costs are in US$.
C/E ratio, cost/effectiveness ratio; MODY, Maturity Onset Diabetes of the Young.
Effectiveness
Effectiveness is measured in terms of quality-adjusted life years
(QALYs), a measure of a person’s length of life weighted by
utility, a valuation of their health-related quality of life. A utility
value of 1 indicates a year spent in perfect health. In our anal-
ysis, patients who have T2D are assigned a utility value of 0.75
if they are on insulin treatment, 0.82 if on oral medications and
0.82 if on diet and exercise only, as obtained from Zhang et al.22
A utility value of 0.92, which was estimated for a non-insulin
diabetes patient without diabetes complications and without risk
factors for cardiovascular diseases in Zhang et al22 is used as a
proxy for diabetes patients with no treatment. All utility values
are discounted at 3.5% per year.21
Cost-effectiveness analysis
We use the decision tree to estimate the costs and effectiveness
of the two strategies. The ICER is the difference between the
overall costs of the two strategies divided by the difference
in QALYs. To account for uncertainty, one-way and probabi-
listic sensitivity analyses are conducted. These analyses model
the impact of a change in any of the costs or probabilities on
the ICER. In the one-way sensitivity analysis, all relevant costs
and probabilities are varied over a reasonably large range,
namely, ±25%.23 We also conduct threshold analysis to iden-
tify the threshold values of prevalence and costs that render
the algorithm-driven MODY testing strategy cost-effective. In
probabilistic sensitivity analysis, we assign distributions to all
Figure 2  Tornado diagram. ICER, incremental cost-effectiveness ratio.
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Effectiveness Incremental effectiveness Incremental C/E ratio
15.210
15.215 0.005 93 663
input parameters and perform 10 000 Monte Carlo simula-
tions where each simulation generates an ICER of the algo-
rithm-driven genetic testing relative to no testing. We assume
beta distributions for all probabilities, normal distributions
for utilities and gamma distributions for testing and treatment
costs.23 Results are presented graphically showing the proba-
bility that genetic testing is cost-effective for a range of cost-ef-
fectiveness thresholds that decision makers may consider.
Furthermore, to establish the robustness of our results, we vary
the utility values used in our analysis by using those reported
in other studies.
Results
Base case cost-effectiveness analysis
The base case cost-effectiveness results are presented in table 2.
The cost of the genetic test is US$1050. Total cost of the algo-
rithm-driven testing strategy is, on net, higher than that of the
no testing strategy by US$462 (US$9888 vs US$9426). The algo-
rithm-driven testing strategy generates slightly more QALYs on
average: 15.215 versus 15.210. These additional QALYs result
from the reduced need for insulin treatment in the subset of
patients with GCK mutation and the switch from insulin to oral
sulphonylurea for patients with HNF1A or HNF4A mutations.
Combining the cost and effectiveness estimates, the ICER for the
algorithm-driven genetic testing strategy relative to no testing is
US$93 663/QALY.
Nguyen HV, et al. J Med Genet 2017;54:747–753. doi:10.1136/jmedgenet-2017-104670

Figure 3  Cost-effectiveness (CE) acceptability curve. MODY, Maturity Onset Diabetes of the Young.
Sensitivity analyses
Results of the one-way sensitivity analyses (figure 2) show that
the ICER is most sensitive to the prevalence of MODY muta-
tions (ie, HNF1A/HNF4A, GCK and HNF1B) in the target
population (ie, those who receive the gene panel), currently esti-
mated to be 3.93% for Singaporean patients whom we identify
should get the algorithm. It is also sensitive to the proportion of
patients receiving insulin treatment under usual treatment. The
cost-effectiveness acceptability curve (figure 3) shows that, for a
commonly applied willingness-to-pay threshold of US$50 000/
QALY, the algorithm-driven testing strategy is currently cost-ef-
fective in 30% of iterations. The threshold analysis further
reveals that provided all other factors remain constant, if the
prevalence of HNF1A/HNF4A mutation among those under-
going the gene panel test increases to 4.1% (currently 2.3%) or
the prevalence of GCK mutation increases to 0.85% (currently
0.43%), or the cost of the genetic test drops below US$530, then
the algorithm-driven MODY testing strategy would be cost-ef-
fective using the threshold of US$50 000/QALY.
As Zhang et al's study22 is based on a sample of patients with
diabetes aged 62 years on average while our study population
consist of younger people (aged 45 years and below), we conduct
two additional sensitivity analyses to examine the robustness of
our results with respect to our use of utility values from Zhang
et al.22 In the first test, we use utility values by treatment type
from another study, namely, Redekop et al.24 As that study does
not provide a utility value for diabetes with no treatment, we
assign a utility of 0.84 for no treatment (as reported in Ara and
Brazier25). The value of ICER increases only slightly in the sensi-
tivity analysis (ie, US$93 663/QALY to US$99 469/QALY). In the
second test, we attempt to estimate the utilities by treatment type
for the age group less than 45 years using data from Zhang et
al22 and Redekop et al.24 To do this, we first use the utility value
for age group 45 years and below reported in Zhang et al22 and
assume that to be the utility for oral therapy. (Note that Zhang
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Diagnostics
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et al22 reported utility by age group but not by age-type of treat-
ment needed for our model.) We then assign utility values for
insulin, diet and no treatment such that their differences from
the utility value for oral therapy match that reported in Redekop
et al.24 Specifically, difference is 0.13 between oral therapy and
insulin, 0.03 between oral therapy and diet and 0.08 between
oral therapy and no treatment. We rerun the model using these
utility values. The results are similar to our base case estimate.
Discussion
This study reported the results of a cost-effectiveness analysis
comparing an algorithm-driven testing strategy to detect MODY
versus no testing using Singapore as a case study. We found that
compared with the no testing strategy, the algorithm-driven
MODY test incurred higher costs while generating slightly higher
QALYs, resulting in an ICER of US$93 663 per QALY. The cost
difference (ie, US$462) results from the GADAb screening costs
(US$59) and MODY testing cost (US$1050) offset by savings
from (1) patients with MODY mutations switching to cheaper
oral medications or no treatment (from more expensive insulin
treatment) and (2) the elimination of the need for glucose strips
for self-blood glucose monitoring. The greater utility is due
to the switch to oral medications/no treatment. This ICER of
US$93 663 per QALY is not cost-effective using the conventional
threshold of US$50 000/QALY, but our analysis indicates that
if the cost of MODY testing were to decrease to US$530, the
algorithm-driven MODY testing would become cost-effective.
This is likely to happen in the near future as costs of genetic tests
continue to fall.26
Our study differs from Naylor et al,5 who found an ICER of
US$205 000 per QALY, in two important ways. First, the testing
strategy considered in Naylor et al5 is not algorithm based; all
individuals with T2D aged between 25 and 40 years are subjected
to MODY testing. Using the algorithm-based approach, we were
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 Diagnostics
able to identify a subgroup of patients most likely to test posi-
tive for MODY, thus reducing screening and testing costs and
increasing the chances of finding MODY cases. This approach
generates significant cost savings relative to the strategy of
universal MODY testing.
The second difference between our study and Naylor et al5
concerns the testing and treatment costs. In Naylor et al,5 the
cost of conventional Sanger single gene testing for the three
most common MODY subtypes (HNF1A, GCK and HNF4A)
was reported to be US$2580 per patient. This cost in Singapore
is US$1050 due to the use of NGS technology, which allows
screening of multiple genes (16 in this panel) simultaneously.
Their treatment costs are also higher than those used in our
study. Cost of insulin treatment (including self-blood glucose
monitoring) is almost twice the cost in Singapore (US$2641 vs
US$1528). Costs for oral medications are nearly 12 times greater
(US$767 vs US$61), and costs of sulphonylureas are 1.5 times
greater (US$96 vs US$61). To estimate the influence of these
cost differences on the ICER, we re-estimated our model using
the US testing and treatment cost data as well as utility values
used in their study. The resulting ICER is US$148 050 per QALY.
This ICER is higher than the ICER estimated for Singapore but
is still substantially lower than the ICER for the US estimated in
Naylor et al.5 This suggests that the relatively low ICER obtained
in our study and the relatively high ICER in Naylor et al5 are
partly due to the higher cost of genetic testing and treatment in
the USA compared with Singapore. It also confirms the value
of our proposed algorithm in reducing the testing costs, leading
to more favourable cost-effectiveness estimates. In fact, using
the US costs and utilising our proposed algorithm, the cost of
genetic testing would only need to be reduced from US$2580
to US$1066 for the genetic test to become cost-effective in the
USA. Without the algorithm, it would have to be reduced further
to US$700 for the genetic test to be cost-effective.5
Our study has a number of limitations. First, our algorithm
has not been validated in other population groups or ethnicities
or in other cohorts in Singapore. Asians tend to have lower BMI
values, different distributions of fat mass and different rates of
diabetes for any given BMI as compared with Caucasians.27 28 As
such, results would not be expected to generalise to Caucasians.
Moreover, the prevalence of the MODY gene appears to vary
by ethnicity even among Asians. Further analyses on additional
cohorts within and beyond Singapore are needed to confirm
these results and to test whether the algorithm-driven testing
strategy would be cost-effective in other settings. Our model also
did not include possible improvement in glycaemic control asso-
ciated with optimal treatment following a diagnosis of MODY.
Although possible, efficacy of sulfonylurea on glycaemic control
is mixed. Shepherd et al4 and Thanabalasingham et al6 reported
an HbA1c fall of 0.8%–1.5% in small numbers of patients
(n=6–8 per study) following a switch to sulfonylurea therapy, but
follow-up was limited to an average of 3 months in one study6
and a median duration of 6 months in the other.4 Bacon et al29
did not find a significant fall in HbA1c when switching patients
with HNF1A MODY from insulin to sulfonylureas. Therefore,
we did not model better glycaemic control as an outcome of
MODY testing. We used utility data based on a group of older
patients than those in our study population (62 vs 45) due to the
lack of utility data for younger diabetes patients by treatment
type in the literature. However, our sensitivity analyses show
that our base cost-effectiveness estimates change little when we
used utility values from other studies as well as when we used
our estimated utility values for lower age groups. Finally, overall
MODY prevalence in our sample population was estimated to be
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only 0.58% (27/4630), which is lower than in previous studies.30
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If the true prevalence in this or other populations is greater, then
MODY testing becomes more cost-effective.
In conclusion, in combination with a simple algorithm to
select individuals for targeted screening, NGS panel sequencing
could soon be a cost-effective strategy to tailor diabetes treat-
ment based on genetic variants.
Contributors  HVN led the model development and contributed to data analysis;
SM contributed to data analysis; EF and DS-LG conceptualised the initial idea; DS-LG
conducted clinical investigations that provided model inputs. All authors contributed
to manuscript writing and manuscript revisions. HN and DS-LG are the overall
guarantors of the manuscript.
Funding  DS-LG and EF received funding from the Stratified Medicine Programme
Office, a joint initiative by the Biomedical Research Council and the National Medical
Research Council, Singapore.
Competing interests  None declared.
Provenance and peer review  Not commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
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