Reflex single-gene non-invasive prenatal testing is associated with markedly better detection of fetuses affected with single-gene recessive disorders at lower cost

Figures & data

Figure 1. Schematic diagram of the decision tree model used for traditional carrier screen workflow (A) and reflex sgNIPT carrier screen workflow (B).

Table 1. A summary of clinical decision probabilities and test performance as part of the key assumptions for the decision-analytic model used in our analyses.

Variables	Input value
Clinical decision probabilities (base scenario)
MFM referral rate upon positive maternal carrier result	36%*
Follow-up paternal carrier screening uptake	41.5%^5
Clinical decision probabilities (UNITY scenario)
MFM referral rate upon positive maternal carrier result	80%**
sgNIPT test performance
Sensitivity	98.5%^8
Specificity	99.9%^8
sgNIPT no-call rate	0.5%***

Abbreviations. MFM, maternal-fetal medicine; sgNIPT, single-gene non-invasive prenatal testing; OBGYN, obstetrics and gynecology.

*Based on internal OBGYN market research results. Four out of 11 OBGYNs (36%) interviewed refer patients to MFM clinic upon positive maternal carrier screen results.

**Uptake for invasive diagnostic testing upon high-risk trisomy NIPT results are 73% for Trisomy 21, and 90% for Trisomy 18 and Trisomy 13¹⁹. Assuming a similar MFM referral rate for high-risk sgNIPT results to those for trisomy NIPT, we estimated the referral rate to be 80%.

***Based on internal data.

Table 2. Clinical outcomes per 100,000 individuals screened in the base and reflex sgNIPT scenarios of our decision-analytical model and the differences between these two scenarios.

Clinical outcomes	Base scenario	Reflex sgNIPT scenario	Difference
Number of positive maternal carriers	16,067*	16,067*	–
Number of paternal tests performed	6,668	–	(6,668)
Number of affected fetuses detected	46	108	62
Number of affected fetuses missed	64	2	(62)
Affected fetus detection rate (sensitivity)	41.5%^5	98.5%^8	57.0%

Abbreviations. sgNIPT, single-gene non-invasive prenatal testing.

*This number is based on the carrier frequency computed in Table S1 per 100,000 individuals (100,000 × 16.1%).

Table 3. Total cost savings from reflex sgNIPT follow-up testing costs per 100,000 pregnancies.

Item	Base Scenario	Reflex sgNIPT Scenario	Follow-up cost savings
Follow-up cost with positive results ($MM)	$9.2	$0.7	$8.5
% carrier results that need follow-up (%)—ACOG panel	16.1%	–
% follow-up needed for UNITY panel	–	1%
% patients completing paternal testing	42%	–
Paternal Test follow-up cost per case (Test and Admin)	$944	–
% patients referred to MFM	36%	80%
Additional MFM follow-up cost per case	$1,236	$1,236
Follow-up diagnostic testing cost ($MM)	$0.1	$0.3	−$0.2
% of positive paternal result	2.7%	–
% diagnostic testing uptake	50%	50%
Cost of diagnostic testing	$730	$730
Total follow-up cost ($MM)	$9.3	$1.0	$8.3

Abbreviations. MFM, maternal-fetal medicine; SMA, spinal muscular atrophy.

Figure 2. Comparison of healthcare costs to detected one affected pregnancy between base and reflex sgNIPT scenarios. Cost was calculated by dividing the total screening cost by the number of affected pregnancies detected.

Table 4. Available prenatal and neonatal interventions for conditions screened by the reflex sgNIPT workflow.

Condition	Disease description	Prenatal and neonatal interventions
Spinal muscular atrophy (SMA)	Severe muscle weakness and wasting Loss of motor skills Breathing problems Life expectancy for Type 1 (most severe) if untreated = 2 years Most common genetic cause of infant death	Spinraza, Zolgensma, and Evrysdi (genetic treatments administered after birth) increase survival and improve symptoms Early treatment before onset of symptoms is crucial for effectiveness
Cystic fibrosis (CF)	Breathing problems Severe lung damage Serious digestive problems Symptoms worsen over time Average life expectancy = mid-thirties.	Medication and therapies improve symptoms and quality of life Early diagnosis and careful lifelong management may increase life expectancy
Sickle cell disease/beta hemoglobinopathies	Fewer healthy red blood cells Fatigue and pain Complications, such as poor growth, infection, heart problems, and stroke Shortened life expectancy	Medications, regular blood transfusions, and bone marrow/stem cell transplants manage disease Gene therapy may be available for some patients Prenatal screening helps identify pregnancies at risk that may benefit from cord blood banking at birth
Alpha thalassemia	Fewer healthy red blood cells Alpha thalassemia major (most severe) results in death before birth or shortly after in untreated	Prenatal care essential to reduce risk of maternal complications for pregnancies with alpha thalassemia major Prenatal treatment may increase survival likelihood

Abbreviations. sgNIPT, single-gene non-invasive prenatal testing; SMA, spinal muscular atrophy; CF, cystic fibrosis.

Table 5. Total cost savings associated with SMA treatment selection per 100,000 pregnancies.

Item	Base scenario	Reflex sgNIPT scenario	Cost savings
Number of SMA fetuses per 100,000 births (prevalence)	9	9	–
% SMA patients diagnosed before age 2 (prenatally or postnatally)	70%	99%	–
% eligible patients (= diagnosed under age 2) choosing Zolgensma as treatment	90%	90%	–
Per SMA patient lifetime treatment cost ($MM)	$6.8	$3.5	–
Total SMA treatment cost for 100,000 births ($MM)	$60.3	$31.1	$29.3

Abbreviations. SMA, spinal muscular atrophy.

Figure 3. Sensitivity to inputs of reflex sgNIPT scenario cost savings per 100,000 pregnancies. The cost savings were calculated using a high and low value for each indicated input. The input value range is annotated next to each bar. The input values used in the model to yield $37.6 M in cost savings are as follows: % SMA Diagnosed Before Age 2 (Base) = 70%; % Eligible SMA Patients Choose Zolgensma = 70%; Paternal Follow-Up Rate = 41.5%; MFM Referral Rate (Base) = 36%; Paternal Testing Cost = $944; MFM Cost = $1,236; MFM Referral Rate (sgNIPT) = 80%; Diagnostic Testing Rate (sgNIPT) = 50%; Diagnostic Testing Cost = $730; Diagnostic Testing Rate (Base) = 50%.

Figure 4. Pricing simulation for carrier screen with reflex sgNIPT using two different unit costs to determine the price-parity point with base scenario costs: (A) the cost to identify one affected fetus and (B) the cost per 100,000 pregnancies. Percentages refer to the percent of value (determined by the base costs) passed to the reflex sgNIPT costs.

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