精準化新生兒聽力篩檢之機率性經濟效益評估

Abstract

背景介紹 新生兒聽力受損(聽損兒)是全球常見的健康議題。然而，使用儀器進行全面新生兒聽力篩檢，例如使用自動聽性腦幹反應(aABR; automated auditory brainstem reflex) 及瞬態誘發耳聲傳射(TE-OAE; transient evoked otoacoustic emission)，雖在經濟富裕的已開發國家已被證實提早確認聽損兒乃具備具成本效益，但從全球衛生角度來看，全面新生兒聽力篩檢仍有下列議題: 目前以儀器篩檢的方式並無法有效篩檢到遲發型及漸進增長型的聽損兒，以及經濟不富裕的國家並無法導入這套篩檢系統。前者解決方法可藉由精準醫療的發展應用於全面新生兒聽力篩檢，而後者可應用簡易的篩檢方法，例如COBRA風險評分法。儘管如此，若同時考慮成本及效益問題，針對綜合基因檢測、簡易篩檢法以及儀器篩檢法進行經濟評估是當務之急。在新生兒聽力篩檢中納入基因標記篩檢做為調適性設計，在全球不同情境中應是可被接受的。

研究目的 因此，本次研究的目標如下 (1)探討在經濟富裕國家中，儀器篩檢加上基因篩檢的不同搭配組合 ; (2)探討在非經濟富裕國家中，儀器篩檢加上以COBRA評分法為基礎的高危險群的不同搭配組合; (3)發展以風險為基礎的調適性篩檢，(1)儀器篩檢法及(2)COBRA評分法之後加基因標記篩檢 (4)發展一系列馬可夫經濟決策模型評估(1)-(3)的診斷績效,效益及早期發現的成本 (5)根據目標(4)結果發展個人化決策模型 (6)根據目標(4)及(5)結果執行經濟評估，發展一套最佳篩檢模型，可用於以族群為基礎的全面新生兒篩檢以及個人化新生兒篩檢。

材料與方法 本次理論研究，我們針對全面新生兒聽力篩檢進行經濟評估，篩檢策略包括(1)全面使用aABR及(2)COBRA評分法(3)aABR接續基因篩檢(4)基因篩檢接續aABR以及(5)基因篩檢接續COBRA評分法。新生兒聽損發生率、帶聽損基因的新生兒聽損惡化程度結果以及聽損兒的醫療成本，分別採用來自台灣的全面新生兒聽力篩檢資料庫、本土追蹤研究與健保資料庫。聽損惡化的四個程度(正常、輕微、中度及嚴重)採用4階段的馬可夫模型建立。診斷工具(aABR及COBRA score)的效能指標參數、就醫確診率以及醫療成本，特別是教育費用及生產力損失引用文獻探討資料。我們使用馬可夫決策樹分析不同篩檢策略的結果。研究時間為終身。採用社會觀點。以隨機成本效用方法分析比較不同策略相較於與無篩檢或相較於台灣目前採用aABR的結果。主要結果以遞增成本效用比值呈現。 結果 不論是儀器篩檢法、風險評分法或基因篩檢加上儀器篩檢法，所有篩檢策略皆優於無篩檢策略，亦即成本較低且效用較高。採用aABR及COBRA遞增成本效用比值分別為$-26177.8 與 $-28141。若假設支付意願為20,000元，則COBRA法具有成本效用的機率為100%。伴隨基因篩檢成本越低，基因篩檢搭配aABR或COBRA法俱有成本效益的機率則會越高。 若與aABR篩檢策略相較，aABR加上基因篩檢需要增加$90.5元，但可增加0.0001 QALYs。當基因篩檢成本為$100元，遞增成本效用比值為$905,000元，但當基因篩檢成本降為$50元，遞增成本效用比值降為$428,000元。 在假設支付意願為20,000元下，aABR加上基因篩檢與無篩檢相較，具有成本效益的機率為87.4%。若採基因篩檢加上aABR，則機率為86.2%。aABR加上基因篩檢與aABR相較，在支付意願為184,000時，則具有成本效益的機率為59%。 結論 針對新生兒聽力篩檢採用簡易篩檢法及儀器篩檢法納入基因篩檢法的經濟成效是可見的。使用COBRA簡易評分法可視為在非富裕國家的第一線篩檢工具。儀器分析法加上基因篩檢則仍需要耗費巨大成本預防聽損兒。基因篩檢加上以風險評估的調適性篩檢，則應該再進一步發展成個人化模式應用於聽力篩檢。

Introduction Hearing impairment in children is a common global health problem. While universal newborn hearing screening (UNHS) with instrument-based screening method like automated auditory brainstem reflex (a-ABR) and transient evoked otoacoustic emission (TE-OAE) has been proven cost-effective in highly economically developed countries to identify early cases of hearing loss there are still several concerns about UNHS from a global viewpoint. These include the efficacy of instrument-based screening method in the failure of early identifying children with late-onset or progressive sensorineural hearing impairment, and also the limited use of these instrument-based in low- and middle-income countries. The former issue may be tackled by using newborn genetic screening spurred by the recently developed precision medicine in hearing loss and the latter one may be coped with the administration of the simple screening method such as the COBRA risk score. However, the consideration of both effectiveness and cost aspects reveals the imperatives of doing economic appraisal of the combined genetic testing and the simple screening method with instrument-based methods. Allowing for using genetic-marker-based information for newborn hearing loss screening, cannot be overemphasized in different global scenarios. Aims The objectives of thesis are therefore (1)to envisage a series of screening modalities of newborn hearing screening using the combination of instrument-based screening method with genetic testing in highly economically-developed countries; (2)to envisage a series of screening modalities of newborn hearing screening using the combination of instrument-based screening method with high risk approach based on COBRA score in low and middle-income countries; (3)to develop risk-based screening design following genetic markers in (1) and COBRA score in (2); (4)to develop a series of Markov health economic decision models to evaluate the performance, effectiveness, and cost of early detection of hearing loss following (1)-(3); (5)to develop personalized decision mode for newborn hearing screening following (4); (6)to do economic appraisal of different screening strategies following (4) and (5) to identify the optimal screening modality at population level for UNHS and at individual level for personalized newborn hearing screening.

Material and Methods Economic evaluation of newborn hearing screening (NHS) was performed in the light of strategies under consideration including (1) universal screening with aABR, and (2) COBRA score, (3) aABR followed by genetic screening, (4) genetic screening followed by aABR, and (5) genetic screening followed by COBRA score. The status of carrying conclusive genotypes for hearing loss and its consequence after birth has been derived from a Taiwanese study. The four-state Markov model was built up for the progression of hearing loss from normal, mild, moderate, and severe hearing loss. Parameters of performance of screening tool (aABR, and COBRA score), compliance rate of hearing orthopraxy, and cost for medical care, special education program, and productivity loss were abstracted from literatures. We used the Markov decision tree analysis to construct the hearing loss related consequence given different strategies. The time horizon is lifetime. Societal perspective was taken. We also performed the probabilistic cost-utility analysis to compare different strategies against no screening and universal NHS with aABR, the current policy in Taiwan. The scattered plot and acceptability curves are also reported. Results Regardless of instrument-based screening methods, risk-score based screening or the combined genetic testing with instrument-based screening, all screening strategies dominated over no screening strategy, indicating less cost and more utility. The ICURs were $-26177.8 and $-28141 for aABR and COBRA score screening, respectively. The probability of COBRA score screening being cost-effective was 100% given on WTP of $20,000. The combined genetic testing with aABR or COBRA score strategies were more cost-effective when genetic testing cost was reduced. Compared with aABR strategy, the aABR followed by genetic test strategy required more $90.4, but gained more 0.0001 QALYs. The ICUR for this combined genetic testing with aABR strategy against aABR screening was $905,000 when genetic testing cost was $100. The ICUR reduced to $428,000 when genetic testing cost was lower to $50. Given $20,000 of WTP, the probability of being cost-effective of aABR followed by genetic screening against no screening was 87.4%. The corresponding figure for genetic screening followed by aABR against no screening was 86.2%. The probability of being cost-effective was 59% for aABR followed by genetic test strategy against aABR strategy when WTP was $184,000.

Conclusions The economic evaluation for newborn hearing screening with simple screening method and instrument-based method considering genetic information is demonstrated. The simple method using COBRA score should be considered as first-line screening strategy for low- and middle-income countries. The combined genetic test with instrument-based method still required the enormous cost for preventing deaf from the current findings. The screening strategy based on the risk-based adaptive screening design following genetic markers should be further developed to pursue personalized mode of newborn hearing screening.