We screen newborns, don't we?: realizing the promise of public health genomics.
We screen newborns, don't we?: realizing the promise of public health genomics.
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DOI：
10.1038/gim.2013.11
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发表时间：
2013-05
期刊：
影响因子：
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通讯作者：
Rimer BK
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文献类型：
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作者：
Evans JP;Berg JS;Olshan AF;Magnuson T;Rimer BK
乍一看，从关注罕见疾病中获得公共卫生利益的概念似乎违反直觉。事实上，早期发现和管理相对罕见的具有患癌症等疾病的单基因风险的个体对总体癌症死亡率的影响可以忽略不计。然而，如果疾病的总发病率、检测高风险的实用性和干预能力都足够高，那么识别这些个体就会为许多人及其家庭成员带来巨大的好处。以新生儿筛查苯丙酮尿症等疾病为例。我们常规采用新生儿筛查的疾病都是罕见的。尽管如此，通过明智地将筛查应用于那些具有特定特征组合（严重后果、有效预防、无症状潜伏期和负担得起的检测）的疾病，它已成为成功的公共卫生干预的典范。14.现在是时候研究在成人中应用基因组分析的潜力了，其方式类似于使新生儿筛查在新生儿群体中如此成功的方式。我们在此敦促在基因组学和公共卫生界之间建立新的伙伴关系。该伙伴关系将把重点从单纯的常见疾病扩大到新开发的基因组学力量，以确定人口中携带高度渗透性突变的罕见（但总体上数量可观）个体，这些突变带来了可预防疾病的高风险。这项工作将使用负担得起的大规模平行测序技术来测序一小部分定义明确的基因，这些基因符合高突变率（突变时患病风险高）和有效的症状前干预的双重标准。可以选择许多候选基因座用于这种方法的初始试验。当然，与林奇综合征相关的主要基因（MSH2，MLH1和MSH6）和某些其他高度渗透的癌症易感基因（如APC、BRCA1、BRCA2、MYH、PTEN和VHL）是有希望的候选基因，与可预防的血管灾难高风险相关的基因也是如此（例如，FBN1，COL3A1，和MYH 11）大规模平行测序的成本已经大幅下降，目前估计在一个基因组中测序大约12个这样的基因，从唾液样品中以高度多重方式提取的样品的价格将是每个样品约200美元，这个数字在不久的将来可能会进一步下降。人们在声称通过应用新的医疗技术节省费用时必须谨慎，但治疗可以预防的疾病肯定是昂贵的，并且有可能通过精心设计的努力来识别和预防这些疾病，特别是如果使用风险分层策略，则可能证明具有成本效益。当然，要成功实施这样一个计划，尤其是大规模实施，必须克服许多障碍和挑战。筛选的基因的选择应首先集中在那些具有最高的遗传率，并与最有效和可接受的预防方式。最大限度地减少假阳性（相应地牺牲一定程度的灵敏度）是必要的，部分原因是
At first blush, the notion of deriving public health benefit from a focus on rare diseases seems counterintuitive. Indeed, early detection and management of the relatively rare individuals with monogenic risks to develop diseases such as cancer will have a negligible effect on overall cancer mortality. However, if aggregate incidence of disease, practicality of detecting high risk, and ability to intervene are all sufficiently high, identifying such individuals produces profound dividends for many people and their family members. Take the example of newborn screening for disorders such as phenylketonuria. The disorders for which we routinely employ newborn screening are uniformly rare. Nevertheless, by judiciously applying screening to those disorders for which a specific combination of features pertain (serious outcome, effective prevention, asymptomatic latent period, and an affordable assay), it has become an exemplar of successful public health intervention. 14 Now is the time to investigate the potential of applying genomic analysis in adults in a way similar to that which has made newborn screening so successful in the neonatal population. We urge here that a new partnership be forged between the genomics and public health communities. The partnership would expand the focus from solely common diseases and embrace the newly developed power of genomics to identify those rare (but, in aggregate, substantial number of) individuals in the population who carry highly penetrant mutations that confer a high risk of preventable diseases. This effort would use affordable, massively parallel sequencing technology to sequence a small, defined set of genes that meet the twin bars of high penetrance (high risk of disease when mutated) and effective presymptomatic intervention. A number of candidate loci could be selected for an initial trial of such an approach. Certainly, the major genes associated with Lynch syndrome (MSH2, MLH1, and MSH6) and certain other highly penetrant cancer predisposition genes (eg, APC, BRCA1, BRCA2, MYH, PTEN, and VHL) are promising candidates, as are genes associated with high risk for preventable vascular catastrophe (eg, FBN1, COL3A1, and MYH11) and possibly familial hypercholesterolemia.The cost of massively parallel sequencing has declined so dramatically that current estimates for sequencing roughly a dozen such genes in a highly multiplexed fashion from saliva samples would be~ $200 per sample, a number that is likely to decline further in the near future. One must be cautious in making claims of cost savings through the application of new medical technology, but treating diseases that could be prevented is certainly expensive, and it is possible that a well-designed effort to identify and prevent them could prove cost effective, especially if a risk-stratification strategy were used. Of course, many barriers and challenges must be overcome to implement such a program successfully, especially on a large scale. The selection of the genes to be screened should focus initially on those that have the highest penetrance and are associated with the most effective and acceptable preventive modalities. Minimizing false positives (with a corresponding sacrifice of some degree of sensitivity) is necessary, in part because no