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On the identification of individual level pleiotropic, pure direct, and principal stratum direct effects without cross world assumptions.

ABSTRACT: The analysis of natural direct and principal stratum direct effects has a controversial history in statistics and causal inference as these effects are commonly identified with either untestable cross world independence or graphical assumptions. This article demonstrates that the presence of individual level natural direct and principal stratum direct effects can be identified without cross world independence assumptions. We also define a new type of causal effect, called pleiotropy, that is of interest in genomics, and provide empirical conditions to detect such an effect as well. Our results are applicable for all types of distributions concerning the mediator and outcome.

SUBMITTER: Zaidi JM

PROVIDER: S-EPMC10839820 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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On the identification of individual level pleiotropic, pure direct, and principal stratum direct effects without cross world assumptions.

Zaidi Jaffer M JM VanderWeele Tyler J TJ

Scandinavian journal of statistics, theory and applications 20200424 3

The analysis of natural direct and principal stratum direct effects has a controversial history in statistics and causal inference as these effects are commonly identified with either untestable cross world independence or graphical assumptions. This article demonstrates that the presence of individual level natural direct and principal stratum direct effects can be identified without cross world independence assumptions. We also define a new type of causal effect, called pleiotropy, that is of ...[more]

PMID: 38317823

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Project description:BackgroundComparative genomics aims to detect signals of evolutionary conservation as an indicator of functional constraint. Surprisingly, results of the ENCODE project revealed that about half of the experimentally verified functional elements found in non-coding DNA were classified as unconstrained by computational predictions. Following this observation, it has been hypothesized that this may be partly explained by biased estimates on neutral evolutionary rates used by existing sequence conservation metrics. All methods we are aware of rely on a comparison with the neutral rate and conservation is estimated by measuring the deviation of a particular genomic region from this rate. Consequently, it is a reasonable assumption that inaccurate neutral rate estimates may lead to biased conservation and constraint estimates.ResultsWe propose a conservation signal that is produced by local Maximum Likelihood estimation of evolutionary parameters using an optimized sliding window and present a Kullback-Leibler projection that allows multiple different estimated parameters to be transformed into a conservation measure. This conservation measure does not rely on assumptions about neutral evolutionary substitution rates and little a priori assumptions on the properties of the conserved regions are imposed. We show the accuracy of our approach (KuLCons) on synthetic data and compare it to the scores generated by state-of-the-art methods (phastCons, GERP, SCONE) in an ENCODE region. We find that KuLCons is most often in agreement with the conservation/constraint signatures detected by GERP and SCONE while qualitatively very different patterns from phastCons are observed. Opposed to standard methods KuLCons can be extended to more complex evolutionary models, e.g. taking insertion and deletion events into account and corresponding results show that scores obtained under this model can diverge significantly from scores using the simpler model.ConclusionOur results suggest that discriminating among the different degrees of conservation is possible without making assumptions about neutral rates. We find, however, that it cannot be expected to discover considerably different constraint regions than GERP and SCONE. Consequently, we conclude that the reported discrepancies between experimentally verified functional and computationally identified constraint elements are likely not to be explained by biased neutral rate estimates.

Dataset Information

On the identification of individual level pleiotropic, pure direct, and principal stratum direct effects without cross world assumptions.

Publications

On the identification of individual level pleiotropic, pure direct, and principal stratum direct effects without cross world assumptions.

Similar Datasets

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