WI State Public Health Lab Capacity for SCID Screening

描述(由申请人提供)： 项目概述/摘要该项目将进行研究，以开发、评估和/或改进针对各种形式的严重联合免疫缺陷(SCID)的常规新生儿血液斑点筛查试验。它将持续三年，这是一个全面整合的SCID试点计划，测试国家统计局计划内的所有威斯康星州新生儿。它将传播知识和专业知识，以促进和促进SCID-NBS测试。严重联合免疫缺陷(SCID)是一组威胁生命的遗传疾病，估计每66,000名活产中就有1名发生。造血干细胞移植(HSCT)是非常有效的(高达95%的存活率)，只有当SCID婴儿在生命早期，在获得严重感染之前被识别的话。SCID婴儿出生时看起来正常，通常没有家族病史。因此，大多数SCID婴儿直到被诊断为威胁生命的机会性感染时才被识别，导致大量发病率和总存活率下降50%-70%。因此，在感染之前发现新生儿的能力对人口健康具有巨大的影响。在胸腺T细胞发育过程中，T细胞受体正常的生产性重排产生T细胞受体切除环(TRECs)，存在于约70%的外周NAOVE T细胞(nn，nn)中。重要的是，所有已知的遗传SCID缺陷都会导致严重的NAOVE T细胞淋巴细胞减少症。在2006-2007年，我们进行了两项大规模研究，以确定使用干血斑点(DBS)定量TRECs来检测SCID新生儿的可行性。基于这些试点研究的成功，证明了检测盲性SCID样本的能力和~0.02%的低筛查阳性率，威斯康星州于2008年1月1日启动了预期新生儿SCID的试点筛查(nn，nn，nn)。基于这些早期的结果，我们假设，通过TREC分析进行SCID的NBS将是一种高度可靠、敏感和成本效益高的手段，可以在新生儿期内肯定地识别SCID。我们建议的方法不仅将证明常规NBS治疗SCID的可行性，而且将研究和建立a)书面测试方法，b)关键基线数据，即发病率、参考范围、质量保证方案、c)转诊做法等，以及d)展示完整的SCID计划-测试、诊断和治疗。“a-d”是验证测试方法的关键，但也是鼓励和促进其他州国家统计局项目采用SCID测试所必需的。当通过重复、重复的TRECs检测和2-肌动蛋白检测(均在最初的DBS上)确认后，第二个全血样本将通过流式细胞仪(CD3、CD4、CD8、CD19、CD56、CD45和CD45RO)进行评估；低计数需要立即转诊到CHW免疫缺陷诊所进行评估。“数据共享”、出版和与其他州国家统计局项目的一对一合作将自由传播知识和专业知识，并促进全国采用SCID测试。 公共卫生相关性： 项目说明-与公共卫生相关严重联合免疫缺陷(SCID)是一种无症状的隐匿性疾病，如果不治疗，是100%致命的；SCID可以通过常规新生儿筛查(NBS)检测到，这是一项重要的公共卫生计划，目前在所有50个州实施。如果治疗得当，在不到三个月的时间内进行骨髓移植，声称治愈率为95%。2007年美国医学会的数据显示，治疗5名临床诊断为SCID的婴儿和1名在一周内确诊的SCID婴儿的不同成本分别为2200,000美元和250,000美元；美国每年有40到160名SCID婴儿(真实发病率未知)出生。SCID的国家统计局符合2010年健康人(孕产妇、婴儿和健康)的要求，即“减少婴儿死亡”和“确保适当的新生儿血点筛查”。我们提出了一个具有双重目标的为期三年的项目：在威斯康星州公共卫生实验室的新生儿筛查计划中完全实施一个全面的试点测试计划(同时对其他47种情况进行测试)，并通过这样做不仅证明了国家统计局对SCID的有效性，而且还创建了一个模型，展示了在其他州的现有计划中增加SCID的可行性和要求。我们的SCID-NBS计划不仅将提供基本的基线数据(即目标人群中的发病率)，还将检测01至03年出生的患有SCID的新生儿。

DESCRIPTION (provided by applicant): Project Summary/Abstract The project will conduct research to develop, evaluate and/or improve routine newborn blood spot screening tests for forms of Severe Combined Immuno Deficiencies (SCID). It will continue for three years, a full scale-fully integrated, SCID pilot program testing all Wisconsin newborns within the NBS program. It will disseminate knowledge and expertise to promote and facilitate SCID-NBS testing. Severe combined immune deficiency (SCID) is a group of life-threatening genetic disorders that occur in an estimated 1 in 66,000 live births. Hematopoietic stem cell transplantation (HSCT) is highly curative (up to 95% survival) only if the SCID infants are recognized early in life, prior to the acquisition of severe infections. SCID infants appear normal at birth and often have no family history. Hence, most SCID infants are not recognized until diagnosed with life-threatening opportunistic infections, resulting in substantial morbidities and reduced overall survival of 50-70% Thus, the ability to detect newborns prior to the acquisition of infections has tremendous population health impact. During T cell development in the thymus, normal productive rearrangement of the T-cell receptor generates T-cell receptor excision circles (TRECs) which are present in ~70% of all peripheral naove T- cells(nn,nn). Importantly, all of the known genetic SCID defects lead to severe naove T-cell lymphopenia. In 2006-7, we performed two large-scale studies to determine the feasibility of quantitating TRECs using dried blood spots (DBS) to detect SCID newborns. Based on the success of these pilot studies, which demonstrated the ability to detect blinded SCID samples and a low screening positive rate of ~0.02%, the State of Wisconsin initiated a pilot, prospective newborn screening for SCID on January 1st 2008(nn,nn, nn). Based on these early results, we hypothesize that NBS for SCID by TREC analysis will be a highly robust, sensitive, and cost-effective means of positively identifying SCID within the newborn period. Our proposed approach will not only demonstrate the feasibility of routine NBS for SCID but will research and establish a) a documented testing methodology, b) critical baseline data, i.e. incidence rates, reference ranges, quality assurance protocols, c) referral practices, etc., and d) demonstrate a complete SCID program --- testing, diagnosis and treatment. "a-d" are critical to validating the test methodology but also needed to encourage and facilitate the adoption of SCID testing by other states' NBS programs. When confirmed by a repeat, duplicate TRECs assay and 2-actin measurement, (both on the initial DBS), a second whole blood specimen is assessed by flow cytometry (CD3, CD4, CD8, CD19, CD56, CD45 and CD45RO); low counts warrant immediate referral and assessment at the Immune Deficiency Clinic at CHW. "Data sharing," publication and one-on-one collaboration with other state NBS programs will freely disseminate knowledge and expertise and facilitate national adoption of SCID testing. PUBLIC HEALTH RELEVANCE: Project Narrative - relevance to public health Severe combined immunodeficiency (SCID) is an asymptomatic, insidious disease which, untreated, is 100% fatal; SCID can be detected by routine newborn screening (NBS), a vital public health program currently implemented in all 50 states. Properly treated, by bone marrow transplant at less than three months, cure rates of 95% are claimed. 2007 WI data shows the differential cost of treating 5 clinically diagnosed SCID babies and one diagnosed at one week is $2,200,000 each vs $250,000; between 40 and 160 SCID babies (true incidence is unknown) are born in the US each year. NBS for SCID meets the Healthy People 2010 (Maternal, infant and health) mandates to "reduce infant deaths" and "to ensure appropriate newborn blood spot screening." We propose a three year project with dual goals: to implement a full scale pilot testing program fully within the Wisconsin State Public Health Laboratory's Newborn Screening Program (concurrent with testing for 47 other conditions) and by doing so demonstrating not only the efficacy of NBS for SCID but also creating a model showing the feasibility of, and requirements for, adding SCID to existing programs in other states. Our SCID-NBS program will not only produce essential baseline data (i.e. incidence rates in the target population), it will detect SCID afflicted newborns born in year 01 through 03.