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. 2023 Jul 26;18(7):e0289144. doi: 10.1371/journal.pone.0289144

Cost-effectiveness of repeat delayed imaging for spontaneous subarachnoid hemorrhage

Wenru Shang 1,2,3,#, Huajie Jin 3,*,#, Amisha Vastani 4, Asfand Baig Mirza 4, Benjamin Fisher 4, Neeraj Kalra 5, Ian Anderson 5, Ahilan Kailaya-Vasan 4,*
Editor: Alfred Pokmeng See6
PMCID: PMC10370759  PMID: 37494367

Abstract

Background

In patients with intracranial aneurysm presenting with spontaneous subarachnoid hemorrhage (SAH), 15% of them could be missed by the initial diagnostic imaging. Repeat delayed imaging can help to identify previously undetected aneurysms, however, the cost-effectiveness of this strategy remains uncertain.

Objective

The aim of this study is to assess the cost-effectiveness of repeat delayed imaging in patients with SAH who had a negative result during their initial imaging.

Methods

A Markov model was developed to estimate the lifetime costs and quality-adjusted life-year (QALY) for patients who received or not received repeat delayed imaging. The analyses were conducted from a healthcare perspective, with costs reported in UK pounds and expressed in 2020 values. Extensive sensitivity analyses were performed to assess the robustness of the results.

Results

The base case incremental cost-effectiveness ratio (ICER) of repeat delayed imaging is £9,314 per QALY compared to no-repeat delayed imaging. This ICER is below the National Institute for Health and Care Excellence (NICE) £20,000 per QALY willingness-to-pay threshold. At the NICE willingness-to-pay threshold of £20,000 per QALY, the probability that repeat delayed imaging is most cost-effective is 0.81. The results are sensitive to age, the utility of survived patients with a favorable outcome, the sensitivity of repeat delayed imaging, and the prevalence of aneurysm.

Conclusions

This study showed that, in the UK, it is cost-effective to provide repeat delayed imaging using computed tomographic angiography (CTA) for patients with SAH who had a negative result in their initial imaging.

Introduction

Subarachnoid hemorrhage (SAH), a severe type of hemorrhagic stroke, is characterized by substantial morbidity, mortality, and an imposing economic burden [1, 2]. It was estimated that the annual economic burden of SAH is £510 million in the UK [3–5]. The rupture of an intracranial aneurysm stands as the overwhelmingly predominant cause of spontaneous SAH [6, 7]. The mortality for patients with untreated aneurysmal SAH is up to 50% in the first month, mainly due to the consequences of re-rupture [8, 9]. Therefore, early identification and treatment of the underlying (causative) ruptured aneurysm is crucial. Digital subtraction angiography (DSA) and computed tomographic angiography (CTA) are commonly used diagnostic modalities for detecting and characterizing intracranial aneurysms [3, 10]. DSA is one of the most sensitive diagnostic tests and is the gold standard diagnostic test for the detection of intracranial aneurysms. However, DSA is expensive and invasive [11, 12]. It was reported that 0.5% of patients who received DSA experienced neurological complications [10]. Compared with DSA, CTA is less sensitive, but it is also less expensive and non-invasive [13]. The European Stroke Organization Guidelines recommend that CTA plus DSA should be used for the initial diagnosis of spontaneous SAH [3]. CTA plus DSA is also the most commonly used imaging strategy for patients with SAH in the UK. However, not all patients with an aneurysm can be identified by the initial diagnostic imaging [3, 14–16].

The European Stroke Organization Guideline recommends that if no aneurysm is identified during the initial imaging, then delayed imaging should be repeated using either CTA or DSA [3]. Some hospitals in the UK, such as the King’s College Hospital, routinely provide a repeat delayed CTA to patients who had a negative result during their initial imaging. However, there is a lack of economic evidence about the cost-effectiveness of repeat delayed imaging in the UK or EU. To our knowledge, only two published economic evaluations assessed the cost-effectiveness of repeat delayed imaging, however, both studies were conducted in the US [17, 18]. In addition, neither of these two studies assessed patients with SAH who had a negative result during their initial imaging using both CTA and DSA.

To fill the evidence gap and to inform clinical decision-making in the UK, this study developed a Markov model to evaluate the cost-effectiveness of using a repeat delayed imaging strategy in SAH patients who initially had a negative result on CTA and DSA. This study was reported according to the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) Statement for reporting health economic evaluations [19].

Materials and methods

A Markov model was developed in TreeAge Pro (Version 2020, TreeAge Software, Inc, Williamstown, Massachusetts) to estimate the cost-effectiveness of delayed repeating imaging versus no further imaging for a hypothetical cohort of 55-year-old patients with perimesencephalic SAH who had a negative result during their initial imaging. A lifetime horizon was adopted for the cost-effectiveness analysis, which means that the patients’ health outcomes and costs were calculated until their death. In line with the European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Hemorrhage and the current UK practice, the initial imaging tests were assumed to be conducted using CTA followed by a DSA [3]. The repeat delayed imaging was assumed to be conducted using CTA, which is the clinical practice implemented at ‘King’s College Hospital, London. Since no individual patient information was utilized for this study, neither informed consent nor Institutional Review Board (IRB) approval was required.

This study applied the perspective of the NHS and Personal Social Services, as recommended by the National Institute for Health and Care Excellence (NICE) [20]. All costs were expressed in UK pounds (£) (2020 value). The primary measure of effectiveness in this study was quality-adjusted life-years (QALYs), a comprehensive metric that combines both the quality of life and survival aspects. Cost-effectiveness is quantified using the incremental cost-effectiveness ratio (ICER), which denotes the additional cost incurred per additional unit of QALY gained. The willingness-to-pay (WTP) threshold set by NICE is £20,000–30,000 per QALY, representing the pound value of a year in perfect health [20]. The intervention with an ICER lower than the predetermined WTP threshold is considered to be cost-effective.

Model design

The model structure was shown in Fig 1. Patients in the "No repeat delayed imaging" arm (Fig 1A) would be discharged from the hospital following a negative result of their initial imaging using DSA and CTA. A proportion of these patients would remain free from re-bleeding until death. The cost and utility for those patients were assumed to be the same as the general population. Those patients who did not receive repeat delayed imaging and experience re-bleeding would require emergent treatment, and some patients may die before or during the emergent treatment. Patients who survived emergent treatment would enter a Markov process (Fig 1C), where ‘patients’ long-term prognosis was grouped into three health states based on the modified Rankin Scales (mRS): favorable (score 0 to 2), unfavorable (score 3 to 5), and death (score 6) [21]. The time period of the model is divided into cycles of time. After discussion with clinicians, a one-year cycle length was adopted for this study considering the growth rate of SAH, frequency of re-bleeding, the time interval adopted by the long-term follow-up studies, and computational burden of the model [22]. A one-year cycle length was also adopted by previous economic analysis assessing similar decision question [23]. At the end of each one-year cycle in the Markov process, individuals could either transition to a different health state or continue residing in their current state. Probabilities are assigned for either staying in the same state or transitioning to a different state within the model.

Fig 1. The pathway of no repeat delayed imaging and repeat delayed imaging (CTA) for patients assessed as a negative result during the first-line test.

Fig 1

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CTA, computed tomographic angiography; DSA, digital subtraction angiography. (An mRS score of 0 to 2 corresponded to a favorable state, mRS score of 3 to 5 corresponded to an unfavorable state, mRS score of 6 corresponded to death).

Patients in the "Repeat delayed imaging" arm (Fig 1B) would receive a repeat delayed imaging using CTA, seven days after their initial imaging. Patients were assumed to stay in the hospital during the 7-day interval between the initial and repeat delayed imaging. After receiving the repeat delayed imaging, those patients with a negative result would be discharged from the hospital without receiving any treatment. Those false negatives–patients with aneurysms that have not been identified by the initial or repeat delayed imaging–were assumed to be at continuous risk of re-bleeding and would receive emergent treatment if they did re-bleed. Patients found to harbor a vascular lesion during the repeat delayed CTA would receive a DSA to confirm the existence of an aneurysm before receiving non-emergent treatment, such as endovascular coiling and surgical clipping. The specificity of DSA, being the reference standard, was assumed to be 100% (i.e., zero false positive) [11]. Patients with an aneurysm who survived emergent or non-emergent treatment would enter the Markov process, as described above.

Model parameters

Model input data were informed by published literature, supplemented by expert opinion (Table 1). The sensitivity and specificity of CTA were assumed to be 98.00% and 100%, based on a recent systematic review that assessed the accuracy of CTA in diagnosing cerebral aneurysms in patients with SAH [24]. The incidence of vascular abnormality in SAH patients with negative initial vascular imaging was assumed to be 17.3% based on a recent systematic review [16]. The annual probabilities of re-bleeding for SAH patients were obtained from a 10-year cohort study of 364 patients with cerebral aneurysms in England [25], shown in S1 Table. The transitional probabilities between different health states were taken from a 10-year follow-up of a UK cohort—the International Subarachnoid Aneurysm Trial—which reported the annual probability of favorable and unfavorable outcomes after aneurysm treatment [26], shown in S1 Table.

Table 1. Model input parameters.

Description Base-line value Range Distribution Source
Clinical parameters
Age 55 50∼80 / A
The prevalence of aneurysm (after initial negative imaging result) 17.30% 5.00%∼ 35.00% Beta (α = 5.26, β = 21.05) [3, 15, 16]
Probability of functional outcome in re-bleeding SAH patients
  favorable outcome 0.0752 —— Dirichlet (0.0752, 0.3948, 0.4700) [27]
  unfavorable outcome 0.3948 —— [27]
Probability of functional outcome in no re-bleeding patients
  favorable outcome 0.51 —— Dirichlet (0.51, 0.34, 0.15) [27]
  unfavorable outcome 0.34 —— [27]
Probability of functional outcome in SAH patients with no aneurysm
  favorable outcome 0.8708 0.8030 ∼ 0.9160 Beta (α = 1740.8400, β = 258.2900) [28–30]
  unfavorable outcome 0.0792 0.0791∼0.0793 Beta (α = 9.9500, β = 1246.2100) [28–30]
The mortality of functional outcome
  favorable outcome 0.1067 —— Dirichlet (0.1067, 0.7778, 0.1155) [31]
  unfavorable outcome 0.7778 —— [31]
The accuracy for CTA
  sensitivity 98.00% 20.00% ∼ 99.00% Beta (α = 737.51, β = 15.05) [24, 32]
  specificity 100.00% 20.00% ∼ 100.00% Beta (α = 247.50, β = 3.76) [24, 32]
Cost (£)
 CTA per test 331.00 ±25% Gamma (α = 144.00, λ = 0.43) A
 DSA per test 1,919.00 ±25% Gamma (α = 143.99, λ = 0.075) A
Hospital stay during delay imaging (per day) a 380.75 ±25% Gamma (α = 144.01, λ = 0.051) [29]
 Treatment for aneurysm b per patient (coiling) 14,030.80 ±25% Gamma (α = 144.00, λ = 0.01) [29]
 Treatment for aneurysm b per patient (clipping) 13,212.19 ±25% Gamma (α = 144.00, λ = 0.01) [29]
 Emergency treatment for aneurysm b per patient (coiling) 19,983.87 ±25% Gamma (α = 144.00, λ = 0.007) [29]
 Emergency treatment for aneurysm b per patient (clipping) 20,275.02 ±25% Gamma (α = 144.00, λ = 0.007) [29]
 Cost of nursing for unfavorable outcome states per year 84,346.39 ±25% Gamma (α = 144.00, λ = 0.002) [30]
The length of stay (LOS) for inpatient (day) 7 Assume
 Utility
Utility of favorable outcome 0.87 0.60 ∼ 1.00 Beta (α = 20.82, β = 6.05) [30, 33]
 Utility of unfavorable outcome 0.44 0.11 ∼ 0.71 Beta (α = 3.82, β = 5.50) [15, 33]
 Utility of death 0 [34]
 Utility of no re-bleeding states 0.60 0.41–0.72 Assumed to be the same as Stroke survivors [3]
Discounting
Discount rate for QALYs 0.035 —— —— [20]
 Discount rate for cost 0.035 —— —— [20]
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A. NIHR Industry Costing Template. Investigation and Intervention Tariff 2019/2020.

a It was assumed that before receiving repeated delayed imaging, patients were managed in vascular wards.

b Treatment for aneurysm included the cost of radiology, graft, blood, theatre, additional theatre, and hospital stay.

Cost

Cost of delayed CTA imaging was obtained from the NHS reference cost 2018/2019 [35]. Cost of aneurysm treatment was obtained from published literature, which included the cost of Imaging, healthcare consumables, surgical equipment, blood products, and hospital bed occupancy [29]. Duration of hospital stay before the delayed imaging was assumed to be seven days. The annual treatment cost of nursing for unfavorable outcome states per year was obtained from the published literature [30]. No costs were assigned to patients in the “no re-bleeding and favorable state”. All costs were discounted by 3.5% each year, in accordance with the National Institute for Health and Care Excellence (NICE) reference case [20].

Utilities

The health state utility weights were obtained from published literature [30, 33]. Death was assigned a utility value of 0. The utility weight for the “no re-bleeding” state was assumed to be the same as that of stroke survivors with minor or moderate disability—defined as with some or significant restrictions in lifestyle [34]. All QALYs were discounted by 3.5% each year [20].

Cost-effectiveness analysis

Sensitivity analysis

Two types of sensitivity analysis were performed: deterministic one-way sensitivity analysis and probabilistic sensitivity analysis (PSA). Deterministic one-way sensitivity analysis aimed to evaluate the influence of individual parameter variations on the model’s outcomes. The range for sensitivity analysis was established by considering the upper and lower values of the variable as reported in the published literature. If these values were not reported, a range of ±25% of the base case value was applied for sensitivity analysis (Table 1). The Tornado diagram in Fig 2 showed the relative importance of key parameters on the ICER. The horizontal bars in the diagram represent the range of each parameter. For example, the range of the utility of a favorable outcome is 0.6–1. The width of each bar indicates the magnitude of its impact on the ICER–the longer the bar, the greater influence the parameter has on ICER [36]. As shown in Fig 2, the top four most influential variables to our model are age, the utility of a favorable outcome, sensitivity of CTA, and prevalence of aneurysm. PSA was conducted to assess the overall uncertainty in the cost-effectiveness of the model, taking into account the combined impact of all key parameters. Five thousand Monte Carlo simulation was conducted. The distributions used in the PSA are reported in Table 1. Cost-effectiveness acceptability curves (CEACs) were conducted to illustrate the likelihood that each intervention is cost effectiveness at various WTP threshold for an additional QALY.

Fig 2. A tornado diagram of 1-way sensitivity analyses to demonstrate the effects of varying parameters on the incremental cost-effectiveness ratio (ICER) for no second-line strategy vs delayed CTA imaging strategy.

Fig 2

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The wider bars at the top have the greatest effect on the ICER, while variations in inputs at the bottom have small effects. The willingness-to-pay (WTP) line is at an ICER of £20,000. Numbers in parentheses after the variables are the parameter ranges. CTA, computed tomographic angiography; DSA, digital subtraction angiography; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Results

Base case scenario

In the base case scenario (Table 2), no repeat delayed imaging strategy was associated with an expected cost of £ 7,430 per patient and an expected effectiveness of 4.656 QALY per patient. Repeat delayed imaging strategy using CTA was found to be associated with an anticipated cost of £10,065 per patient and an expected effectiveness of 4.939 QALYs per patient. The ICER of the repeat delayed imaging strategy was £ 9,314 per QALY, which was below the NICE £ 20,000 ⁄per QALY WTP threshold.

Table 2. Result of cost-effectiveness (basic case scenario).

Strategy Costs (£) Effectiveness (QALYs) Incremental Cost (£) Incremental Effectiveness (QALYs) Incremental C/E Ratio, ICER(£/QALY)
No repeated delayed imaging 7,430 4.656 - - -
Repeated delayed imaging using CTA a 10,065 4.939 2635.29 0.283 9,314
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a CTA, computed tomographic angiography.

Sensitivity analysis

The tornado diagram in Fig 2 illustrates the outcomes of one-way sensitivity analyses, specifically evaluating the effects of uncertainty associated with each input parameter on the ICER estimate of repeat delayed imaging using CTA in comparison to no repeat delayed imaging. The base case conclusion (repeat delayed imaging using CTA being the most cost-effective intervention) is sensitive to the following parameters:

  • age of the patient increased to 73.25 years old (base case value: 55 years old)

  • utility of favorable outcome decreased to 0.69 (base case value: 0.87)

  • sensitivity of CTA decreased to 40.90% (base case value: 98.00%)

  • prevalence of aneurysm in patients with SAH who had a negative result in their initial imaging decreased to 7.41% (base case value: 17.30%)

The results of the one-way sensitivity analysis for key parameters tested are reported in detail in the (S1 Fig).

The CEAC shown in Fig 3 indicated that at the NICE WTP threshold of £20,000 per QALY, the probability of repeat delayed imaging being cost-effective is 81.05%.

Fig 3. Acceptability curve demonstrating the percentage of iterations that were cost-effective for each strategy over varied willingness-to-pay thresholds.

Fig 3

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QALY, Quality Adjusted Life Year.

Discussion

Our results of cost-effectiveness analysis demonstrate that it is cost-effective to repeat delayed imaging using CTA for patients with SAH who had a negative result on their initial imaging, compared with no imaging. Although repeat delayed imaging was associated with an increased cost compared to no repeat delayed imaging, its additional cost can be justified by the additional QALY gains resulting from early identification and early treatment for patients with an aneurysm. The cost-effectiveness of the repeat delayed imaging strategy was most sensitive to age, the utility of favorable outcomes, the sensitivity of CTA, and the prevalence of aneurysms in patients with SAH who had a negative result in their initial imaging.

Before our study, the cost-effectiveness of repeat delayed imaging was only assessed by two US studies [17, 18]. Jethwa et al. assessed the cost-effectiveness of providing delayed DSA to patients with SAH who were diagnosed as negative during their initial imaging using CTA. They found that delayed imaging (using DSA) is not cost-effective unless the negative predictive value of delayed imaging is above 93.73%. Kalra et al. compared twelve imaging strategies for both initial imaging and follow-up imaging in patients with perimesencephalic SAH. They found that conducting a CTA without follow-up imaging is the most cost-effective strategy. However, our model showed that compared with no repeat delayed imaging, repeat delayed imaging (using CTA) is cost-effective in patients with SAH who had a negative result during their initial imaging, as long as the sensitivity of CTA exceeded 40.90%. This might be because of three reasons. Firstly, Jethwa et al. used CTA as the first-line test and DSA as the second-line test, whilst our study used DSA+CTA as the first-line test and CTA as the second-line test. Secondly, both Jethwa et al. and Kalra et al adopted a short time horizon (i.e., only covered the time period from patients receiving the initial imaging to patients receiving a definitive diagnosis), whilst our study adopted a lifetime horizon. Therefore, the two US studies are likely to underestimate the QALY losses and future treatment costs for those patients with aneurysms who were missed by the initial imaging. If those lifetimes QALY losses and future treatment costs were considered, repeat delayed imaging would appear to be more cost-effective. Last but not least, due to the difference in financing mechanisms of healthcare system, payment structure and approaches to healthcare delivery, the price of healthcare services and procedures in the US is consistently higher than the price in the UK. According to the Organisation for Economic Co-operation and Development (OECD) Health Statistics 2022, the per capita health spending in the U.S. was more than two times higher than other developed countries, including the UK, Australia, France, Canada and New Zealand [37]. As a result, the cost-effectiveness results of studies conducted in the US might not be transferable to the UK setting.

Implication for clinical practice and future research

Our findings support the provision of repeat delayed imaging using CTA to patients with SAH who had a negative result in their initial imaging compared to no imaging. Given CTAs can be done without the expertise of a neuro-interventionalist, unlike a DSA, this choice of imaging provides a quick and cost-effective method to exclude a potential aneurysm in this cohort of patients. We would hope this study generates further interest in the management of patients with SAH who had a negative result during their initial imaging and potentially a national guideline in the delayed radiological investigation of choice in identifying an intracranial aneurysm in these patients. Notably, the results of sensitivity analysis showed that the conclusion is most sensitive to patients’ age, the utility of a favorable outcome and prevalence of aneurysm in patients with SAH who had a negative result in their initial imaging. These findings suggest that repeat delayed imaging might not be cost-effective for patients who are over 73 years old, have a quality of life lower than 0.69 after surviving SAH and achieved a favorable outcome, or when the prevalence of aneurysm is lower than 7.41%. Potential strategies to improve the quality of life for aneurysm survivors include developing a follow-up care plan with the patient, providing rehabilitation services, monitoring blood pressure and headaches, and promoting a healthy life-style that includes abstaining from smoking and engaging in regular exercise [38]. Further evidence on the utility of favorable outcomes for aneurysm survivors and local prevalence of aneurysm in patients with SAH who had a negative result in their initial imaging is needed to robustly demonstrate the cost-effectiveness of repeat delayed imaging.

Strengths and limitations

Our study has three strengths. First, to our knowledge, this is the first lifetime cost-effectiveness analysis that directly compares the repeat delayed imaging with no imaging for patients with SAH who had a negative result in their initial imaging in the UK. Our findings have important implications for clinical practice and can improve the health outcomes of patients aneurysmal with SAH. Secondly, previous economic evaluations did not include the nursing cost of SAH patients, whilst our study considered the lifetime cost for patients with unfavorable outcomes. Thirdly, to assess the robustness of the conclusion under various input data scenarios, both deterministic and probabilistic sensitivity analyses were conducted.

There are a number of limitations of our study, so the results must be interpreted cautiously. First, there is a lack of nursing costs for patients who survived SAH with unfavorable outcomes in the UK. We had to use the nursing cost reported by a Dutch study (£ 84,346.39) for patients over age 70 as a proxy. Therefore, a wide range of nursing costs (£ 63,260 to £ 105,433) was tested using one-way sensitivity analyses, and the base case conclusion remained unchanged. Second, the potential complications of CTA, such as acute allergic reactions and contrast-induced nephropathy, were not included in our model due to a lack of long-term cost and health outcome data for patients experiencing those complications. However, existing evidence suggests that the risk of severe allergic reactions and contrast-induced nephropathy is extremely low or even negligible for patients who undergo CTA [39, 40]. Therefore, we do not anticipate that the omission of these complications would significantly alter the conclusions of our study. Third, given that the prevalence of aneurysms is likely to be low in those patients with SAH who had a negative result during their initial imaging, the accuracy of CTA might be affected. A wide range of sensitivity (20.00% ∼ 99.00%) and specificity (20.00% ∼ 100.00%) for CTA was tested using one-way sensitivity analyses. We found that the conclusion remains the same unless the sensitivity of CTA below 40.90%. Fourth, we assumed that the health utility for patients with SAH in the "no re-bleeding" health state was the same as the utility for minor stroke survivors, due to a lack of utility data for the former patients. This assumption contradicts the use of repeat delayed imaging since the primary advantage of employing repeated tests is to identify patients with aneurysms earlier and mitigate the risk of re-bleeding. Five, as we only evaluated one repeat delayed imaging, the results were not explored on other delayed imaging techniques.

Conclusions

Our analyses showed that it is cost-effective to repeat delayed imaging using CTA compared with no repeat delayed imaging for patients with SAH who had a negative result in their initial imaging in the UK. Further evidence on the utility of favorable outcomes for survivors of aneurysms and the local prevalence of aneurysms in patients with SAH who had a negative result in their initial imaging is needed to robustly demonstrate the cost-effectiveness of repeat delayed imaging.

Supporting information

S1 Fig. Results of one-way sensitivity analysis.

(PDF)

Click here for additional data file. (376.9KB, pdf)
S1 Table. Model input parameters.

(DOCX)

Click here for additional data file. (18.5KB, docx)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Alfred Pokmeng See

10 May 2023

PONE-D-22-31987Cost effectiveness of repeat delayed imaging for spontaneous subarachnoid hemorrhagePLOS ONE

Dear Dr. Jin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://doi.org/10.1161/CIRCOUTCOMES.119.006406

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

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Additional Editor Comments:

Thank you Dr. Jin et al. The manuscript nicely models a cost-effectiveness of imaging. I would recommend modifications according to the attached reviewer comments.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

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Reviewer #1: This study evaluated the cost-effectiveness of repeat delayed imaging in patients with

SAH who had a negative result during their initial imaging from a healthcare perspective.

The manuscript was very well-written and logically constructed.

I totally agree to accept for publication, while some minor revisions are needed.

1.In abstract, the control group should be clarified in the description of results.

2.Some minor grammar errors need to be revised, for example, in line 110 should say ‘were’ instead of ‘was’.

3.The time horizon ‘lifetime’ may need to be clarified in methods section.

4.Complications for patients with SAH were not explicitly modeled in this study, the authors have illustrated this as a limitation, this is acceptable.

5.Line 130-136: Sensitivity Analysis: the range of sensitivity and specificity should be clarified.

Reviewer #2: The authors investigated the cost effectiveness of using repeat delayed imaging to diagnosis unruptured aneurysms that were missed after initial imaging. To do so, the authors developed a Markov model using available data relating to costs of imaging and treatment in the UK and the utility of certain outcomes. The authors presented their results as they related to the lifetime costs and QALY that patients were estimated to experience. This paper was well-written and easily digestible; however, the below points should be considered before the work is published.

1. Given that the model was specifically designed using assumptions for 55-year-old patients, it would be prudent for the authors to explicitly note this limitation in the ability to generalize their findings to a more diverse patient population.

2. Why did the authors choose to divide the time period of the study into one year cycles? A brief description of the reasoning and a relevant citation would help ground this decision.

3. The authors do not specify what aneurysm treatment method was used in the model (i.e. clipping versus coiling), which would be helpful in determining the overall applicability of their findings. Were both treatment methods accounted for or only one? If only one was factored into the analysis, this limitation should be noted.

4. The tornado diagram was difficult to understand; a more detailed explanation of how to interpret the diagram would be helpful in parsing the key points, as well as a higher-resolution image.

5. The authors mention two studies that were conducted in the US (Jethwa et al. and Kalra et al.) but do not comment on the fundamental differences in healthcare systems and overall healthcare costs between the two countries; the authors should consider briefly discussing these differences in the estimated costs used in the US studies versus their own UK study and how these differences, if any, may account for the difference in their findings.

6. Additionally, the authors note that one of the limitations of their study includes not explicitly modeling complications due to a lack of evidence. It is not clear to me what is meant by "lack of evidence". Are the authors referring to a lack of available data about the cost of complications from SAH in the UK? Given that Jethwa et al. includes complication-associated costs in their analysis, it may be prudent to explain in more detail how this limitation came about and the possible effect its exclusion may have on the results.

7. Finally, a more detailed explanation of how to interpret the utility and mortality of functional outcome would aid in understanding the results of the model and its sensitivity. For example, what factors may influence "the utility of survived patients with a favorable outcome"?

**********

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Reviewer #1: No

Reviewer #2: No

**********

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Attachment

Submitted filename: ONE-D-22-31987-recommendation.docx

Click here for additional data file. (16.2KB, docx)

Decision Letter 1

Alfred Pokmeng See

13 Jul 2023

Cost-effectiveness of Repeat Delayed Imaging for Spontaneous Subarachnoid Hemorrhage

PONE-D-22-31987R1

Dear Dr. Jin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Alfred Pokmeng See, M.D.

Academic Editor

PLOS ONE

Acceptance letter

Alfred Pokmeng See

17 Jul 2023

PONE-D-22-31987R1

Cost-effectiveness of Repeat Delayed Imaging for Spontaneous Subarachnoid Hemorrhage

Dear Dr. Jin:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Alfred Pokmeng See

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Results of one-way sensitivity analysis.

    (PDF)

    Click here for additional data file. (376.9KB, pdf)
    S1 Table. Model input parameters.

    (DOCX)

    Click here for additional data file. (18.5KB, docx)
    Attachment

    Submitted filename: ONE-D-22-31987-recommendation.docx

    Click here for additional data file. (16.2KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (277.9KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

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