Whittemore A S, Halpern J
Department of Health Research and Policy, Stanford University School of Medicine, California 94305.
Biometrics. 1994 Mar;50(1):118-27.
We describe a class of nonparametric tests for linkage between a marker and a gene assumed to exist and to govern susceptibility to a disease. The tests are formed by assigning a score to each possible pattern of marker allele sharing (identity-by-descent) among affected pedigree members, and then averaging the scores over all patterns compatible with the observed marker genotype and genealogical relationship of the affected members. Different score functions give different tests. One function, which examines marker allele similarity across pairs of affected pedigree members, gives a test similar to that of Fimmers et al. (1989, in Multipoint Mapping and Linkage Based on Affected Pedigree Members: Genetic Analysis Workshop, R. C. Elston, M. A. Spence, S. E. Hodge, and J. W. MacCluer (eds), 123-128; City: Alan R. Liss). A second function examines allele similarity across arbitrary subsets, not just pairs, of affected members. The resulting test can be more powerful than the one based solely on pairs of affected members. The approach has several advantages: it does not require knowledge of the mode of disease inheritance; it does not require unambiguous determination of identity-by-descent at the marker; it does not suffer from variability due to chance allele similarity among affected members who are unrelated, such as spouses; it allows marker genotypes of unaffected members to contribute information on allele sharing among the affected; it permits calculation of exact P-values. Computational requirements limit the tests to many pedigrees with few (< 16) affected members.
我们描述了一类用于检测标记与假定存在并控制疾病易感性的基因之间连锁关系的非参数检验方法。这些检验方法是通过为受影响家系成员中标记等位基因共享（同源性）的每种可能模式赋予一个分数，然后在与观察到的标记基因型以及受影响成员的系谱关系兼容的所有模式上对分数进行平均而形成的。不同的分数函数给出不同的检验。一种函数，它检查受影响家系成员对之间的标记等位基因相似性，给出的检验类似于Fimmers等人（1989年，《基于受影响家系成员的多点定位和连锁：遗传分析研讨会》，R.C.Elston、M.A.Spence、S.E.Hodge和J.W.MacCluer（编），第123 - 128页；城市：Alan R. Liss）的检验。第二种函数检查受影响成员的任意子集（而不仅仅是对）之间的等位基因相似性。由此产生的检验可能比仅基于受影响成员对的检验更具效力。该方法有几个优点：它不需要疾病遗传模式的知识；它不需要在标记处明确确定同源性；它不会因无关的受影响成员（如配偶）之间偶然的等位基因相似性而产生变异性；它允许未受影响成员的标记基因型为受影响成员之间的等位基因共享提供信息；它允许计算精确的P值。计算要求将这些检验限制在受影响成员较少（<16个）的许多家系中。
