Bias and efficiency in family-based gene-characterization studies: Conditional, prospective, retrospective, and joint likelihoods
Bias and efficiency in family-based gene-characterization studies: Conditional, prospective, retrospective, and joint likelihoods
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DOI：
10.1086/302808
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发表时间：
2000-03-01
影响因子：
9.8
通讯作者：
Thomas, DC
中科院分区：
文献类型：
--
作者：
Kraft, P;Thomas, DC
我们重新审视了层匹配病例对照研究的通常条件似然，并考虑了三种可能更适合于基于家族的基因表征研究的替代方案：第一，前瞻性似然，即Pr（D/G，A）;第二，回顾性似然，Pr（G/D）;第三，确定校正的联合似然，Pr（D，G/A）。这些可能性提供遗传相对风险参数的无偏估计，以及群体等位基因频率和基线风险。即使当确定方案不能被建模时，只要确定仅取决于家族的表型，基于回顾似然的参数估计仍然是无偏的。尽管需要估计额外的参数，但在估计遗传相对风险时，相对于条件似然，前瞻性、回顾性和联合似然可以导致效率的显著提高。如果可以假设基线风险和等位基因频率是同质的，这是正确的。然而，在存在异质性的情况下，假设同质性的参数估计值可能存在严重偏倚。我们讨论了这个问题的程度，并提出了一个混合模型的方法提供一致的参数估计时，基线风险和等位基因频率是异质性的。混合模型的前瞻性，回顾性和联合似然的效率增益相对于条件似然的效率在这里提出的情况下是小的。
We revisit the usual conditional likelihood for stratum-matched case-control studies and consider three alternatives that may be more appropriate for family-based gene-characterization studies: First, the prospective likelihood, that is, Pr (D/G, A); second, the retrospective likelihood, Pr (G/D); and third, the ascertainment-corrected joint likelihood, Pr (D, G/A). These likelihoods provide unbiased estimators of genetic relative risk parameters, as well as population allele frequencies and baseline risks. The parameter estimates based on the retrospective likelihood remain unbiased even when the ascertainment scheme cannot be modeled, as long as ascertainment only depends on families' phenotypes. Despite the need to estimate additional parameters, the prospective, retrospective, and joint likelihoods can lead to considerable gains in efficiency, relative to the conditional likelihood, when estimating genetic relative risk. This is true if baseline risks and allele frequencies can be assumed to be homogeneous. In the presence of heterogeneity, however, the parameter estimates assuming homogeneity can be seriously biased. We discuss the extent of this problem and present a mixed models approach for providing consistent parameter estimates when baseline risks and allele frequencies are heterogeneous. The efficiency gains of the mixed-model prospective, retrospective, and joint likelihoods relative to the efficiency of conditional likelihood are small in the situations presented here.