How to Choose Diseases for Newborn Screening by Tandem Mass Spectrometry Under the Nationally Recommended Program in Shenzhen, China Evidence From a Cost-Effectiveness Analysis

Mingren Yu School of Medicine and Health Management, Tongji Medical College of Huazhong University of Science and Technology Juan Xu (  xujuan@hust.edu.cn ) School of Medicine and Health Management, Tongji Medical College of Huazhong University of Science and Technology Xiaohong Song Department of Family Development and Maternal and Child Health, Shenzhen Municipal Health Commission Jiayue Du Department of Science and Education, the Fourth A liated Hospital of School of Medicine, Zhejiang University


Background Inborn Errors of Metabolism
Inborn errors of metabolism (IEMs) are a group of diseases caused by abnormal biochemical metabolic indicators which block the metabolic pathways in our bodies [1,2]. While most published studies have numbered IEMs in the 500-700 range [3][4][5], a recent article estimates the number to be more than 1015 [6], which suggests a high cumulative incidence of IEMs. There are many discrepancies in the prevalence of IEMs reported in these studies. Donald Waters et al. [7] estimated the global birth prevalence to be 50.9 per 100,000 live births based on a systematic literature review of birth prevalence and case fatality of IEMs globally. Other researches indicate prevalence is between 40 per 100,000 and 125 per 100000 [8,9]. In China, although epidemiological statistics are absent at the country level, regional data reveals an incidence of IEMs ranging from 35.3 per 100,000 to 136.4 per 100,000 [10][11][12]. Notwithstanding the actual incidence, it is now clear that IEMs affect a multitude of newborns and families all over the world.
Most IEMs are curable given early detection, but without prompt recognition can give rise to long-term disability and even death [13]. Since IEMs are ingravescent, and overlap in clinical manifestations, early symptoms may not be apparent or are challenging for differential diagnosis, if any [14]. The development of newborn screening (NBS) is now a critical tool in the prevention of primary diseases. IEMs can be detected via NBS in asymptomatic patients. In other words, medical intervention can be made quickly in the early stage to control disease progression [15]. Thus, morbidity and mortality associated with IEMs can be effectively reduced [16], and life-threatening or long-term sequelae prevented [17]. frames, incremental cost-effectiveness ratio (ICER) thresholds, etc. employed in studies. Nevertheless, what cannot be ignored is that economic evaluations prove MS/MS newborn screening to be economically e cient, and offer policymakers unequivocal scienti c evidence for the bene ts of NBS programs.
In China, to say nothing of Shenzhen province, any economic evaluation of MS/MS neonatal screening is yet to be carried out. In an effort to correct this situation, we have conducted this study to determine the costeffectiveness of MS/MS screening in the social and economic context of Shenzhen based on the diseases nominated by the national program. In doing so, we take into account the government budget and explore how to select the appropriate number of IEMs for detection.

Selection of IEMs
To guide applicants preparing the material of registration and application for amino acid, carnitine, and succinylacetone detection reagent (MS/MS), the Center for Medical Device Evaluation of National Medical Products Administration of China (NMPA) enacted "Guiding Principles for Amino Acid, Carnitine and Succinylacetone Detection Reagent Registration" in 2019 [59]. The guideline recommends 12 types of IEMs that are relatively common in China and suitable for screening by MS/MS (Table 1). Compared with the numbers of IEMs detected in other countries, it is a conservative recommendation based on China's actual situation, suiting a referable and applicable pilot program for Shenzhen.

Model Structure
We developed a decision-tree and Markov model to conduct the cost-effectiveness analysis of expanded newborn screening using the following assumptions: A child can have only one kind of disease; The progress of IEMs is divided into several independent Markov states (health states) according to the main sequelae. And in each cycle, a child can be in only one of the Markov states.
The states' future distribution depends only on current events, and not on those that occurred before.

Sensitivity and Speci city
The screening methods in Shenzhen include immuno uorescence for the current program while MS/MS only for expanded screening. As is showed in Table 2, the former sensitivity and speci city are 100% and 78.6%, and their counterparts are both 100%.  Table 3.
Because of the large numbers of people covered and the high maturity of widely used MS/MS, the incidence data is referable for Shenzhen. Data for the age-speci c mortality and incidence of sequelae of different IEMs between the screening and nonscreening groups remain scarce in China, leaving us no alternative but to refer to studies from other countries. In order to simulate the natural progress of diseases more accurately, the rate of death due to other causes was also added to the model as a parameter. This part of event probabilities is detailed in Additional le 1.

Costs
The cost of MS/MS screening includes direct costs and indirect costs from a social perspective. Direct costs include direct medical cost and direct non-medical cost. The former consists of expenditures for screening, transportation costs and the program cost. Indirect costs are due to the lost productivity of families during the con rmation, treatment, and follow-up stages of NBS. Since detection in newborns occurs within six days in the hospital, families do not need to go to any particular hospital, so transportation and lost productivity costs during the screening stage are not counted.
Cost inputs used in the model are shown in Table 4. The data were derived mainly from the eld investigation and estimation based on the Guidelines for the Treatment of Rare Diseases (2019) [62], drug prices at online pharmacies, and assumptions of this study. Also, we referred to published literature, government policies, and statistical yearbooks if parameters could not be directly obtained or estimated. Sunk costs a The calculation process of the treatment cost of the diseases is detailed in Additional le 2. b Schoen et al. [57] divide the cost of treatment into two parts at 5 years of age since, in some cases, additional care is needed for children with IEMs detected after symptoms manifest during their rst ve years. We also found discrepancies between different ages in the treatment and medication criteria for IEMs when referring to Guidelines for the Treatment of Rare Diseases (2019). Therefore, we did the same work to estimate the treatment cost by dividing patients into two groups at age 5.

Effectiveness
Quality-adjusted life-years (QALYs) were estimated through the Markov model, multiplying the length of time in different health states by the utility value for states. We also calculated the ICER between current screening and expanded screening programs. An ICER threshold set at 568.704 RMB, three times per capita GDP in Shenzhen, was used in this study. The utility parameters of health states are listed in Table 5, estimated mainly from data in published articles. We presumed the utility of "alive state" to be 1, which means healthy.

Sensitivity analysis
We carried out one-way sensitivity analysis and constructed tornado diagrams to assess the uncertainty in the model and the robustness of the results. One-way sensitivity analysis in this study evaluated the in uence of the discount rate in the range 0-10% (base value is 3%), with 1% as an interval of 10 categories. Tornado diagrams include factors like the incidence of IEMs, costs (e.g., the cost of screening, con rmation, transportation, etc.), and utility of health states. The incidence of IEMs was assumed to vary by 50% from their mean value, and costs were 10%. The value of utility being tested varied based on the upper/lower boundaries illustrated in published articles.

Budget impact analysis
Implementing MS/MS screening, the expansion of diseases screened, and the increase in costs will inevitably place a burden on health expenditure, making it necessary to conduct a budget impact analysis (BIA) of MS/MS screening from the standpoint of Shenzhen's government.
Health expenditure entailed in the frame of this study included the cost of screening, treatment, and follow-up, as well as the program cost. We assumed that these program costs remain unchanged between the expanded screening and the status quo. What should be noted is that children must receive continuous medical treatment

Results
Cost-effectiveness analysis and BIA Detecting 12 IEMs in the nationally recommended program  To specify the costs of the MS/MS newborn screening program, the results of BIA are detailed in

Detecting some types of IEMs selected from national recommendations
The results of the cost-effectiveness analysis of screening a single disease are shown in Table 8. ICERs of all screening programs are higher than the threshold, and diseases are ranked by ICER (from minimum to  According to the above ICER rankings of diseases, 11 screening strategies were nally devised. The ICER of each screening program is shown in Fig. 3, below. Only the ICER of the rst strategy (PKU and PCD) is higher than the threshold, at 748196 RMB per QALY. All other ICERs are below the threshold. As the number of diseases detected increases, the ICER gradually decreases and nally tends to stabilize.
The results of the BIA of the 11 screening strategies above are shown in Fig. 4. Although the screening program's budget grows with the increasing number of diseases detected, there is no signi cant difference between single program budgets. The budget for all screening programs holds steady, near 580 million RMB.

Sensitivity analysis
We conducted a one-way sensitivity analysis based on the nationally recommended program of 12 IEMs (Fig. 5 and Fig. 6). We discussed the discount rate and other parameters separately, since the former is remarkably in uential. It turns out that the ICER is less than three times per capita GDP when the discount rate is≤7% and, particularly when the discount rate is equivalent to 7%, the ICER is very close to the threshold. Also, the ICER is lower than one times per capita GDP (189,568RMB) as the discount rate is≤1.5%, which means the screening program is very cost-effective.
The top three in uential parameters are the incidences of PCD (P_PCD), the incidence of MMA (P_MMA), and the cost of screening by MS/MS (C_MSScr). As we can see, the incidence of diseases accounts for a large proportion of top in uential parameters, and the top three are the incidences of PCD, MMA, and MSUD. Apart from disease incidence, the cost of screening by MS/MS (C_MSScr), the utility of the state without sequelae (U_NS) and the cost of con rmation by IF (C_FACom) weigh heavily for the ICER. But, no matter how parameters change within the range, the ICER remains below the threshold at all times, clarifying that the results are robust.

Discussion
This study considered the cost-effectiveness of MS/MS newborn screening in Shenzhen, China. From a social perspective, we con rmed that it is cost-effective to implement the expanded screening, with some preconditions. First, it is not economically e cient to detect only one type of disease. Especially for PKU, the results illustrated IF to be a more cost-effective method currently. The factors contributing to this situation is that detecting a single disease cannot embody the advantages of MS/MS -"one blood sampling for multiple diseases" [72] but re ects that MS/MS is more expansive than IF. Second, MS/MS screening can be costeffective only if at least three diseases (PKU, PCD and MMA) are covered. The selection of detected IEMs is connected with the incidence of diseases. The higher the incidence is, the more QALYs can be saved and the more diseases detected, and the smaller ICER of the program will be. Moreover, when the screening program covers ve diseases (PKU, PCD, MMA, MSUD, IVA), the ICER closely approaches its critical value (since the ICER of the program covering six diseases accounts for more than 95% of the ICER of ve diseases).
The above points can explain why the number of NBS programs varies from region to region, and also reveal two policy ideas for selecting the number of diseases covered. One of the policy ideas, we call "ICER maximization idea". "One blood sampling for multiple diseases" allows an MS/MS screening program to cover more IEMs without additional cost. Therefore, screening more diseases leads to more QALYs saved, making the program more economically e cient. The rst policy idea nally can attain a maximal ICER as the decisionmaker adds more and more IEMs into the NBS program, which is perhaps the reason for the US and Canada setting their number of IEMs at 42. The ICER maximization policy idea signi cantly proposes the request to regions in terms of the development of social, economic and medical science. The other policy strategy is the "ICER validation idea". Screening IEMs with high regional incidence allows the ICER to access its critical value closely. Moreover, there exists the inevitable problem of how to treat these hard-to-cure diseases. Although various therapies have so far been developed [73], there are several factors such as the cost of treatment, the complexity and di culty of treatment, patient compliance, and so on [74,75], which constitute a huge challenge for medical treatment. Newborns detected positive can only, without appropriate medical treatments being available, cause families serious economic and emotional stress. It is therefore wise to include some IEMs with a high incidence and for which reasonable treatment is available in the screening program. And, in this case, the ICER of the program is already close to the minimum value. We believe that's why some countries, such as the UK, South Korea, and Germany, have limited detectable diseases to less than 20. In brief, for the initial implementation of MS/MS screening in Shenzhen, we would suggest utilizing the "ICER validation idea".
The results of this study are generally robust. One-way sensitivity analysis revealed that caution should be taken when the discount rate surpasses 7%. But, statistics indicate that China's annual in ation rate has remained at around 2% for the past decade (owing to COVID-19, the rate once approached 6%, but remained below 7%) [76]. That is to say, the implementation of MS/MS screening in Shenzhen will be cost-effective for some time to come and likely to be highly cost-effective, since in ation sometimes falls below 1.5%.
The ndings of the BIA performed demonstrate that no signi cant difference exists among different programs in the whole budget. As long as we choose a cost-effective screening program, in every year over the next decade budgets will all reach about 58.00 million RMB. Combining this with the ICER of a program detecting ve diseases which reaches the critical value, we can conclude that if the budget of the program covering ve diseases is affordable for the Shenzhen administration, it is better to screen for all twelve diseases as per the nationally recommended program. According to the Guidelines for the Treatment of Rare Diseases(2019), there are speci c and systematic treatments for these diseases.
Here, we also considered whether the Shenzhen government could bear the budget as proposed, and the answer is yes. According to the Department Final Report of the Health Commission of Shenzhen in 2018 [77], the budget for public health projects in NBS (including screening for hearing, for IEMs, and for trisomies 21, 18, and 13) was Another of our team's studies [79], to investigate patients' willingness to pay (WTP) for the MS/MS screening, revealed the average WTP value was 242 RMB, and that 68.71% (404/588) of families were willing to pay more than 200 RMB. So, the payment policy is truly exible when the WTP value is compared with 20% of the screening cost (average 60.98RMB-79.57RMB per year) that a family should currently be able to afford. And if policymakers are concerned about the risks of health expenditure, it is opportune to increase the proportion of out-of-pocket payment to relieve the high-cost burdens of government. Such a policy change would, however, need to be properly considered since the aim of "gradually providing the NBS program free of charge" was proposed in a recent provincial policy. Brie y, the series of data presented above makes the claim that the MS/MS newborn screening program is affordable for the Shenzhen government.
Due to the lack of epidemiological investigation in China and Shenzhen, the integral local database of IEMs is still extraordinarily wanting. So, in order to shorten the odyssey, key recommendations are for research that outlines top priorities to enhance epidemiological studies of IEMs, and advance the establishment of the IEMs database in China. Only in this way can we proceed with a cost-effectiveness analysis suiting China's circumstances and provide further empirical evidence for the NBS program.

Conclusion
We have attempted to put forward policy suggestions for choosing diseases for MS/MS screening in Shenzhen, conducting a cost-effectiveness analysis based on the 12 IEMs recommended by NMPA. This study has con rmed that MS/MS screening covering at least three diseases is cost-effective. The Shenzhen government is entirely able to undertake the budget for the screening program. This study also discussed two policy concepts for selecting IEMs for detection. One, the "ICER maximization idea", represents the strategy of choosing to maximize the ICER of the expanded program. The other, the "ICER validation idea", which considers the curability and affordability of the disease as the basis of healthcare decisions, and achieves a cost-effective ICER for the screening program. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interest
The authors declare that they have no competing interests.     One-way sensitivity analysis of discount rate in expanded screening