A Cost-Effectiveness Analysis Of An Adenocarcinoma Risk Prediction Multi-Biomarker Assay For Patients With Barrett’s Esophagus

Figures & data

Figure 1 Decision tree and Markov model for patients with Barrett’s esophagus: (A) Decision tree: patient options at decision node include standard of care (SOC) surveillance and treatment and Assay-guided surveillance and treatment. Parameters used in decision tree are detailed in Table 1. A summary of the Assay guided surveillance and treatment protocol for BE is provided in Table 2. (B) Markov model: Patients can be in one of the 8 health states. Patients start from the health state of BE (NDBE, IND and LGD) and the arrows indicate the possible transitions from one state to another.

Note: Post Endoscopic State = BE and no BE.
Abbreviations: LGD, low-grade dysplasia; IND, indefinite for dysplasia; NDBE, nondysplastic Barrett’s esophagus.

Table 1 Model Inputs

Description	Base case	Low	High	Source(s)
Initial cohort distributions^a
NDBE	0.8854	0.8737	0.8967
IND	0.075	0.0525	0.098	Geisinger Pathology data^Citation8
LGD	0.0396	0.0283	0.0508	Geisinger Pathology data^Citation8
Assay Result Probabilities
Low-risk	0.77	0.7	0.83	^Citation18
Intermediate-risk	0.15	0.03	0.25	^Citation18
High-risk	0.08	0.05	0.14	^Citation18
Assay performance parameters
Sensitivity	0.6560	0.3	1	^Citation18^b
Specificity	0.9002	0.8	1	^Citation18^b
Surveillance and treatment protocol
Endoscopic surveillance frequency
SOC for NDBE	1 per 3 years			^Citation2,Citation21
SOC for IND (annual)	1			^Citation2,Citation21
SOC for LGD (annual)	1.5	1	2	^Citation2,Citation21
Assay low-risk	1 per 5 years			Clinical Expert opinion^Citation18
Endoscopy for post-RFA treatment^c
Year 1	4			^Citation2
Year 2	2			^Citation2
Year ≥3	1			^Citation2
Endoscopy for post-EAC treatment
Year 1	4			^Citation2,Citation33
Year 2	2			^Citation2,Citation33
Year ≥3	1			^Citation2,Citation33
Annual number of RFA treatment
SOC for LGD patients who undergo RFA	2	2	3	^Citation25
SOC/Assay for HGD patients	3	2	3.5	^Citation34,Citation35
Assay high risk BE patients	2	2	3	Clinical Expert Opinion
Probability of LGD patients receiving RFA	0.05	0	0.2	Clinical Expert Opinion^h
Probability of HGD patients receiving RFA	1	1	1	Clinical Expert Opinion
Receive RFA alone	0.87	0.7	0.9	Clinical Expert Opinion
Receive RFA+EMR^d	0.13	0.1	0.3	Clinical Expert Opinion^Citation36
Physician’s adherence to Assay based approach	0.75	0.5	1	Clinical Expert Opinion^Citation28
Disease state annual transition probabilities
NDBE
SOC
To NDBE	0.9454	0.9334	0.9537
To IND	0.0123	0.0099	0.0148	^Citation6
To LGD	0.0348	0.0314	0.0407	^Citation6
To HGD	0.0048	0.0034	0.0068	^Citation6
To EAC	0.0027	0.0017	0.0043	^Citation6
Low-Risk (True Negative)
To NDBE	0.9525	0.943	0.962
To IND	0.0124	0.0099	0.0149	Assumption^g
To LGD	0.035	0.028	0.0421	Assumption^g
False Positive
(RFA) to NNDBE and BE	1	1	1
(RFA) to HGD	0	0	0	^Citation18
(RFA) to EAC	0	0	0	^Citation18
High-Risk (True Positive)
(RFA) to NNDBE and BE	0.9797	0.9757	0.9838
(RFA) to HGD	0.0152	0.0121	0.0182	Assumptionf,^Citation15
(RFA) to EAC	0.0051	0.0041	0.0061	Assumptionf,^Citation15
False Negative^e
To HGD	0.1668	0.1334	0.2001	^Citation6
To EAC	0.0809	0.0647	0.0971	^Citation6
IND
SOC
To NDBE	0.1342	0.1073	0.161	^Citation8
To IND	0.8226	0.7616	0.8585
To LGD	0.0348	0.0314	0.0407	Assume same as NDBE to LGD
To HGD	0.0064	0.0023	0.0178	^Citation8
To EAC	0.0021	0.0005	0.0188	^Citation8
Low-Risk (True Negative)
To NDBE	0.1353	0.1082	0.1624
To IND	0.8296	0.7955	0.8637	Assumption^g
To LGD	0.0351	0.0281	0.0421	Assumption^g
False Positive
(RFA) to NNDBE and BE	1	1	1
(RFA) to HGD	0	0	0	^Citation18
(RFA) to EAC	0	0	0	^Citation18
High-Risk (True Positive)
(RFA) to NNDBE and BE	0.9797	0.9757	0.9838
(RFA) to HGD	0.0152	0.0121	0.0182	Assumptionf,^Citation15
(RFA) to EAC	0.0051	0.0041	0.0061	Assumptionf,^Citation15
False Negative^e
To HGD	0.1668	0.1334	0.2001	^Citation6
To EAC	0.0809	0.0647	0.0971	^Citation6
LGD
SOC
To NDBE	0.1791	0.1701	0.1791	^Citation9,Citation37
To IND	0.0157	0.012	0.0157	^Citation9,Citation37
To LGD	0.7849	0.7712	0.8054
To HGD	0.0159	0.0104	0.0243	^Citation7,Citation37
To EAC	0.0044	0.002	0.0098	^Citation7,Citation37
(RFA) to NNDBE and BE	0.9797	0.9757	0.9838
(RFA) to HGD	0.0152	0.0121	0.0182	^Citation15
(RFA) to EAC	0.0051	0.0041	0.0061	^Citation15
Low-Risk (True Negative)
To NDBE	0.1828	0.1462	0.2193
To IND	0.0161	0.0128	0.0193	Assumption^g
To LGD	0.8012	0.7614	0.8409	Assumption^g
False Positive
(RFA) to NNDBE and BE	1	1	1
(RFA) to HGD	0	0	0	^Citation18
(RFA) to EAC	0	0	0	^Citation18
High-Risk (True Positive)
(RFA) to NNDBE	0.9797	0.9757	0.9838
(RFA) to HGD	0.0152	0.0121	0.0182	^Citation15
(RFA) to EAC	0.0051	0.0041	0.0061	^Citation15
False Negative^e
To HGD	0.4092	0.3273	0.491	^Citation7
To EAC	0.0553	0.0443	0.0664	^Citation7
HGD
SOC/Assay
(RFA) to NNDBE and BE	0.728	0.6736	0.7824	^Citation15
(RFA) to HGD	0.266	0.2128	0.3192
(RFA) to EAC	0.006	0.0048	0.0072	^Citation15
EAC
SOC/Assay
To LGD	0			Assumed
To HGD	0			Assumed
To EAC	0.657	0.478	0.657
To BE Death	0.343	0.343	0.522	^Citation38
Costs (2012 US dollars)
Assay cost per test	$1475	$1000	$2000	Cernostics, Inc. data
Endoscopy with biopsy	$2038	$760	$3750	Geisinger Health System data
Office visit	$138	$90	$252	Geisinger Health System data
RFA procedural cost	$2154	$1238	$4000	Geisinger Health System data
EMR procedural cost	$1817	$1247	$4147	Geisinger Health System data
Annual cost of EAC treatment	$76,411	$51,200	$94,414	Geisinger Health Plan claims data^Citation23
Utilities
NNDBE, NDBE, IND	0.91	0.79	1	^Citation39
LGD	0.85	0.6148	1	^Citation39
HGD	0.77	0.4956	1	^Citation39
EAC	0.67	0.2976	1	^Citation39
Disutility per RFA	−0.035	−0.042	−0.028	^Citation40
Discount rate	0.03	0.03	0.05	^Citation41,Citation42

Notes: ^aWe assumed initial/baseline health states of NDBE, IND and LGD representing the population for which the Assay is clinically indicated since these are the BE patients who can benefit from risk prediction and optimization of surveillance and treatment. ^bSensitivity and Specificity were back-calculated based on published NPV and PPV of 0.98 and 0.26, respectively, and their based prevalence. ^cPost-RFA endoscopy frequency was the same regardless of health state prior to endoscopic therapy. ^dWhen patients receive both RFA and EMR, these treatments occur in a single episode. ^eWe assumed the false negative population in the Assay arm progressed to HGD/EAC within 5 years. ^fNo published data for NDBE and IND transition rates post RFA, assumed same transition probability as LGD post RFA. ^gThe probability is based on normalization of SOC cohort’s transition probability distribution supported by literature and to make total transition probabilities equal to 1, and the assumption of no transition to HGD/EAC in low risk (true negative) cohort based on published results.¹⁸ hAssumed 5% (range of 0–20%) of LGD cases received RFA treatment in the SOC arm based on expert opinion that only a subset of LGD cases are confirmed upon review by a gastrointestinal subspecialist, and that only a subset of confirmed LGD cases receive RFA treatment.

Abbreviations: IND, indefinite for dysplasia; NDBE, nondysplastic Barrett’s esophagus; EAC, adenocarcinoma; EMR, endoscopic mucosal resection; HGD, high-grade dysplasia; LGD, low-grade dysplasia; NBE, no Barrett’s esophagus (normal squamous); NCCN, National Comprehensive Cancer Network; NPV, negative predictive value; PPV, positive predictive value; PY, per-year; RFA, radiofrequency ablation; SOC, standard of care.

Table 2 Summary Of Assay Guided Surveillance And Treatment Protocol For BE

Assay Result	Cohort Sub-Groups	Progression To HGD/EAC*	Endoscopic Surveillance**	Endoscopic Treatment (RFA)**
High-risk	True positive	Yes	Post-RFA endoscopic surveillance protocol	Yes
High-risk	False positive	No	Post-RFA endoscopic surveillance protocol	Yes
Intermediate-risk	Intermediate risk	Yes, same as SOC based on disease state	Yes, Same as SOC based on disease state	Yes, Same as SOC based on disease state
Low-risk	True negative	No	1 per 5 years	No
Low-risk	False negative	Yes	1 per 5 years	No

Notes: Patients in the Assay approach arm fell into one of five subgroups: true positives (progress to HGD/EAC and score high-risk with the Assay), false positives (do not progress, but score high-risk), intermediate-risk, true negatives (do not progress, and score low-risk), and false negatives (progress to HGD/EAC, but score low-risk). All patients who tested high-risk (true and false positive) received RFA alone (87%) or RFA with EMR (13%) and then followed the post-RFA endoscopic surveillance protocol. Patients who tested low-risk (true and false negative) received endoscopic surveillance every 5 years but no endoscopic treatments. Patients who tested intermediate-risk followed the SOC. Patients who did not follow the Assay approach due to nonadherence of physicians to the Assay approach followed the SOC. *Progression assumptions based on Critchley-Thorne et al study.¹⁸ **Details on endoscopic surveillance and treatment are provided in Table 1.

Abbreviations: SOC, standard of care; RFA, radiofrequency ablation; HGD, high-grade dysplasia; EAC, adenocarcinoma.

Table 3 Base-Case Analysis Of Assay vs SOC 1–5 Years: Total Costs, QALYs And ICER

	SOC		Assay		ICER
	Years Of Implementation	Total Costs (US$)	Total QALYs	Total Costs (US$)	Total QALYs
1 year	$21,003,058	8879	$38,003,814	8843	Dominated
2 years	$35,415,348	17,384	$49,595,851	17,360	Dominated
3 years	$51,030,738	25,527	$60,478,152	25,519	Dominated
4 years	$67,129,338	33,314	$71,282,089	33,330	$259,974
5 years	$72,543,194	40,762	$74,695,333	40,803	$52,483

Abbreviations: SOC, standard of care; QALY, quality-adjusted life-year; ICER, incremental cost-effectiveness ratio for Assay versus SOC.

Figure 2 One-way sensitivity analysis: selected parameters with the largest impact on the ICER. (A–C) NDBE, IND and LGD annual progression rates to EAC in SOC, respectively; (D) assay cost; (E) cost of endoscopy with biopsy; (F) physician adherence rate to the Assay strategy (5-year surveillance interval for low risk, SOC surveillance for intermediate risk, endoscopic treatment for high risk).

Figure 3 Probabilistic sensitivity analysis.

Abbreviation: SOC, standard of care.

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