Economic evaluations of exome and genome sequencing in pediatric genetics: considerations towards a consensus strategy

Figures & data

Figure 1. Overview of systematic database search.

Table 1. Overview of characteristics of studies included in this review.

Study	Country	Health condition	Total sample size	Genetic test	Time horizon	Conclusion
Soden et al.^12	United States	Neurodevelopmental disorders	119	Standard ES versus rapid GS	First 33 months of diagnostic trajectory	Sequencing exomes or genomes should become an early part of the diagnostic workup for NDD
van Nimwegen et al.^13	Netherlands	Neurological disorders	50	Standard diagnostic trajectory versus: (1) ES, by which ES replaces: All genetic tests currently used (2) ES, by which ES replaces: All genetic tests Repeated and burdensome tests 50% of the physician visits	From first physician visit in the university hospital until a diagnosis was found	Novel diagnostic strategies, including NGS, should be evaluated
Valencia et al.^14	United States	Genetic disorders	40	Standard ES in addition to or replacing standard diagnostic trajectory	All diagnostic tests performed before ES	Implementing ES is clinically useful and cost-effective
Joshi et al.^15	United States	Early onset epileptic encephalopathies	4	ES versus standard diagnostic trajectory	From inclusion until diagnosis was found	Cost savings if ES was performed early in diagnostic trajectory
Sabatini et al.^16	United States	Non-small cell lung cancer, sensorineural hearing loss, neurodevelopmental disorders	—	Three different diagnostic trajectories including ES	Complete diagnostic trajectory	Both sequencing technology and cost savings will improve over time, so cost-impact will be refined in the future
Nolan and Carlson^17	United States	Pediatric neurological disorders	53	ES versus secondary genetic and metabolic testing	All diagnostic tests performed before ES	ES could allow for more efficient and fruitful diagnostic neurological evaluations
Monroe et al.^18	Netherlands	Intellectual disability	17	ES versus standard diagnostic trajectory: Diagnosed patients: ES replaces all genetic costs (except aCGH and SNP arrays) and metabolic assessments Undiagnosed patients: ES replaces all genetic costs (except aCGH and SNP arrays) Both groups: assumption that ES results in cost reduction of 50% for health-care visits, imaging, biochemical investigations, and patient day admission	From first visit to hospital until initiation of ES	Early implementation of ES is relevant and cost-effective
Schofield et al.^19	Australia	Muscle diseases	56	Standard diagnostic trajectory versus molecular diagnostic trajectory (Neuromuscular gene panel or ES)	From referral of patients with suspicion of a diagnosis until genetic diagnosis or return of ES if no genetic diagnosis was found	Cost-effectiveness of implementing ES increases data reanalysis, testing first-degree relatives and parental reproductive outcomes are taken into account
Vissers et al.^20	Netherlands	Neurological disorders of suspected genetic origin	150	ES versus standard diagnostic trajectory	From first visit to hospital clinic until diagnosis was established	ES results in a higher diagnostic yield without increasing the costs
Hayeems et al.^21	Canada	Developmental delay	101	GS versus CMA	All clinical care activities prompted by CMA or GS	The clinical and economic consequences of implementing GS depend on the evaluation of downstream care and cost consequences
Stark et al.^22	Australia	Childhood syndromes	40	ES versus standard diagnostic trajectory, by implementing ES three different moments in time: (1) ES after basic & complex investigations (2) ES after basic investigations (3) ES immediately after admission	From age of onset symptoms until a diagnosis was established or an uninformative ES report was issued	Implementing ES early in the diagnostic trajectory significantly increases diagnostic rate and decreases cost per diagnosis
Tan et al.^23	Australia	Suspected monogenic disorders	40	ES versus standard diagnostic trajectory, by comparing four pathways: (1) Standard diagnostic trajectory without ES (2) Standard diagnostic trajectory with ES (3) ES applied at first clinical genetics assessment (4) ES at tertiary presentation	Children suspected of having a monogenic condition were followed for 7 months	ES is associated with a higher diagnostic yield and cost-effectiveness is maximized by implementing ES early in the diagnostic trajectory
Tsiplova et al.^24	Canada	Autism spectrum disorder	300	Three models, comparing: CMA and ES versus CMA CMA versus GS CMA and ES versus GS	Fixed time period of 5 years	The added value of ES and GS will increase over time, since costs will decrease and clinical benefit will increase
Dillon et al.^25	Australia	Suspected monogenic disorders	145	ES versus three disease-specific panels recommended by clinical experts	Complete diagnostic trajectory	ES has a broader coverage with no change in diagnostic costs
Yuen et al.^26	Canada	Autism spectrum disorder	1,000	Four models, comparing: CMA only CMA and ES ES only GS only	Two years, starting from time of autism spectrum disorder diagnosis	At the moment, ES or GS does not lead to cost savings, but can become cost-effective. Focus should not only be on diagnostic yield, but also on utility and the increasing need for genetic services
Stark et al.^27	Australia	Rare diseases	80	Re-analysis of ES results compared with ongoing standard diagnostic testing	From ES disclosure (February 2014) until the end of study (October 2016) with a minimum follow-up of 12 months	This study supports early implementation of ES
Howell et al.^28	Australia	Epilepsy	114	ES at different stages during diagnostic tract	From epilepsy onset until diagnosis found	Early implementation of ES leads to an increase in diagnostic yield associated with lower costs
Vrijenhoek et al.^29	Netherlands	Intellectual disability	370	ES at different stages during diagnostic tract	From first visit to hospital until a fixed moment in time	Implementing ES can be cost-effective
Stark et al.^30	Australia	Pediatric care	40	Rapid ES versus standard diagnostic trajectory	From age of onset symptoms until a diagnosis was established or an uninformative ES report was issued	Rapid ES is associated with high diagnostic and clinical utility and is cost-effective
Palmer et al.^31	Australia	Epileptic encephalopathy	32	ES versus standard diagnostic trajectory	Complete diagnostic trajectory	Use of ES is cost-effective and has a higher clinical utility
Demos et al.^32	Canada	Early-onset epilepsy	180	ES versus standard diagnostic trajectory	From genetic counseling until research validation of the variant	Performing ES early in the diagnostic trajectory affects diagnostic yield, clinical utility and potential cost-effectiveness positively
Radio et al.^33	Italy	Rare diseases	324	ES versus standard diagnostic trajectory	Onset of symptoms until an ES was performed	ES decreases the diagnostic trajectory and positively influences management of undiagnosed patients
Schofield et al.^34	Australia	Suspected monogenic disorders	80	ES versus standard diagnostic trajectory, by implementing after basic investigations	From age of onset symptoms until 473 days post-result	Use of ES is cost-effective
Yokoi et al.^35	Japan	Multiple congenital anomalies and intellectual disability	200	ES versus aCGH	Complete diagnostic trajectory	ES saves costs and time
Dragojlovic et al.^36	Canada	Suspected genetic disorders	498	Standard diagnostic trajectory including GS versus standard diagnostic trajectory without GS	Complete diagnostic trajectory until GS was performed	For economic models, longer time horizons need to be included. Especially for patients without a conclusive diagnosis, long-term costs may influence conclusions about the cost-effectiveness of GS
Kosaki et al.^37	Japan	Suspected monogenic disorders	360	ES at different stages during diagnostic trajectory	Complete diagnostic trajectory	ES as first tier test leads to cost-savings, but more research is needed to see whether this also applies to other countries
Smith et al.^38	United States	Suspected genetic disorders	368	ES versus standard diagnostic trajectory	One year, starting from the first genetics consult	More research is needed in order to define the most optimal use of ES
Yeung et al.^39	Australia	Complex, suspected monogenic disorders	92	GS versus standard diagnostic trajectory	Fixed time period of 3 years after diagnosis	GS leads to increased diagnostic yield and decrease in costs

Abbreviations. ES, exome sequencing; GS, genome sequencing; aCGH, microarray-based comparative genomic hybridization; CMA, Chromosomal microarray.

Table 2. Included costs categories according to Drummond et al.¹⁰ and Buchanan et al.⁷.

	Soden et al.^12	van Nimwegen et al.^13	Valencia et al.^14	Joshi et al.^15	Sabatini et al.^16	Nolan and Carlson^17	Monroe et al.^18	Schofield et al.^19	Vissers et al.^20	Hayeems et al.^21	Stark et al.^22	Tan et al.^23	Tsiplova et al.^24	Dillon et al.^25	Yuen et al.^26	Stark et al.^27	Howell et al.^28	Vrijenhoek et al.^29	Stark et al.^30	Palmer et al.^31	Demos et al.^32	Radio et al.^33	Schofield et al.^34	Yokoi et al. ^35	Dragojlovic et al.^36	Kosaki et al.^37	Smith et al.^38	Yeung et al.^39
Included cost categories according to Drummond et al.^10
Costs within the healthcare sector
- Costs incurred during life years gained
Internal costs
- Costs genetic diagnostics	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X
- Costs other diagnostics	X	X		X		X	X	X	X	X	X	X			X	X	X	X	X	X	X	X	X		X	X	X	X
- Other medical costs		X		X			X			X		X			X	X	X	X	X	X		X	X		X	X	X	X
External costs
- Diagnostic costs in different hospitals		X			X	X		X	X	X	X					X	X		X				X
- Other medical costs in different hospitals		X								X						X									X
Costs for patient and family
- Travel expenses												X													X
- Own contributions/co-payments
- Time spending costs															X										X
- Costs of informal care
Costs in other sectors
- Non-medical costs (e.g. municipal services, education or voluntary work)
Included cost categories according to Buchanan et al.^7
Patient recruitment
Sample collection	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X
Sample testing	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X
Data analysis	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X
Communication of test results		X		X			X			X		X			X	X		X		X		X			X	X	X	X
Action taken based on test results		X		X			X			X		X	X			X		X										X
Training and infrastructure
Indirect costs												X			X										X

Table 3. Effect measures of the studies included in this review.

Year of publication	2014		2015		2016				2017						2018							2019			2020
Study		Soden et al.^12	van Nimwegen et al.^13	Valencia et al.^14	Joshi et al.^15	Sabatini et al.^16	Nolan and Carlson^17	Monroe et al.^18	Schofield et al.^19	Vissers et al.^20	Hayeems et al.^21	Stark et al.^22	Tan et al.^23	Tsiplova et al.^24	Dillon et al.^25	Yuen et al.^26	Stark et al.^27	Howell et al.^28	Vrijenhoek et al.^29	Stark et al.^30	Palmer et al.^31	Demos et al.^32	Radio et al.^33	Schofield et al.^34	Yokoi et al. ^35	Dragojlovic et al.^36	Kosaki et al.^37	Smith et al.^38	Yeung et al.^39
Clinical effect measures
Clinical effectiveness		X
Diagnostic yield		X	X	X			X	X	X	X		X	X		X		X		X		X	X		X	X		X	X	X
Diagnostic sensitivity		X
Duration of diagnostic trajectory			X																	X		X		X	X	X
Diagnostic rate							X																				X
Healthcare consequences											X																		X
Number of diagnoses																X		X
Number of ongoing pregnancies																	X							X
Number of reproductive genetic services used																	X							X
Differences in short-term resource use and wait time between genetic testing strategies																X
Survival																												X
Economic effect measures
Cost-effectiveness		X		X					X			X	X				X				X			X
Cost savings					X		X	X		X							X		X	X	X	X		X			X		X
Cost impact						X					X
Cost ranges						X																	X
Healthcare resource use			X														X
Associated direct medical costs			X
Costs in general														X	X			X	X						X	X	X	X	X
Incremental costs per additional positive finding in (hypothetical) testing scenarios														X	X
Cost per diagnosis																	X	X		X	X			X	X	X		X
Cost per patient																X	X	X		X	X	X	X	X					X
QALY																	X							X
Cost of reanalysis																	X							X
Incremental cost per additional diagnosis																X	X	X			X
Costs after diagnosis																			X
Yearly costs of diagnostic trajectory																										X
Total and yearly cost of diagnostic delay																							X
ICER																								X
Costs of parental reproductive costs																								X

Abbreviations. QALY, Quality-adjusted life year; ICER, Incremental cost-effectiveness ratio.

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