Extreme sampling for genetic rare variant association analysis of dichotomous traits with focus on infectious disease susceptibility

As genomic sequencing becomes more accurate and less costly, large cohorts and consortiums of cohorts are providing high power for rare variant association studies for many conditions. When large sample sizes are not attainable and the phenotype under study is continuous, an extreme phenotypes design can provide high statistical power with a small to moderate sample size. We extend the extreme phenotypes design to the dichotomous infectious disease outcome by sampling on extremes of the pathogenic exposure instead of sampling on extremes of phenotype. We use a likelihood ratio test (LRT) to test the significance of association between infection status and presence of susceptibility rare variants. More than 10 billion simulations are studied to assess the method. The method results in high sample enrichment for rare variants affecting susceptibility. Greater than 90% power to detect rare variant associations is attained in reasonable scenarios. The ordinary case-control design requires orders of magnitude more samples to achieve the same power. The Type I error rate of the LRT is accurate even for p-values < 10 -7 . We find that erroroneous exposure assessment can lead to power loss more severe than excluding the observations with errors. Nevertheless, careful sampling on exposure extremes can make a study feasible by providing adequate statistical power. Limitations of this method are not unique to this design, and the power is never less than that of the ordinary case-control design. The method applies without modification to other dichotomous outcomes that have strong association with a continuous covariate.

Famine, Affluence, and Amorality

I argue that the debate concerning the nature of first-person moral judgment, namely, whether such moral judgments are inherently motivating (internalism) or whether moral judgments can be made in the absence of motivation (externalism), may be founded on a faulty assumption: that moral judgments form a distinct kind that must have some shared, essential features in regards to motivation to act. I argue that there is little reason to suppose that first-person moral judgments form a homogenous class in this respect by considering an ordinary case: student readers of Peter Singer’s “Famine, Affluence, and Morality”. Neither internalists nor externalists can provide a satisfying account as to why our students fail to act in this particular case, but are motivated to act by their moral judgments in most cases. I argue that the inability to provide a satisfying account is rooted in this shared assumption about the nature of moral judgments. Once we consider rejecting the notion that first-person moral decision- making forms a distinct kind in the way it is typically assumed, the internalist/externalist debate may be rendered moot.

Symbolic Top-k Planning

The objective of top-k planning is to determine a set of k different plans with lowest cost for a given planning task. In practice, such a set of best plans can be preferred to a single best plan generated by ordinary optimal planners, as it allows the user to choose between different alternatives and thus take into account preferences that may be difficult to model. In this paper we show that, in general, the decision problem version of top-k planning is PSPACE-complete, as is the decision problem version of ordinary classical planning. This does not hold for polynomially bounded plans for which the decision problem turns out to be PP-hard, while the ordinary case is NP-hard. We present a novel approach to top-k planning, called sym-k, which is based on symbolic search, and prove that sym-k is sound and complete. Our empirical analysis shows that sym-k exceeds the current state of the art for both small and large k.

Computing abelian varieties over finite fields isogenous to a power

In this paper we give a module-theoretic description of the isomorphism classes of abelian varieties A isogenous to $$B^r$$Br, where the characteristic polynomial g of Frobenius of B is an ordinary square-free q-Weil polynomial, for a power q of a prime p, or a square-free p-Weil polynomial with no real roots. Under some extra assumptions on the polynomial g we give an explicit description of all the isomorphism classes which can be computed in terms of fractional ideals of an order in a finite product of number fields. In the ordinary case, we also give a module-theoretic description of the polarizations of A.

Introduction

we know to tell many lies that sound like truth,but we know to sing reality, when we will.Hesiod, Theogony 27–28 (trans. M. L. West)Human cooperation and development are underwritten by a practice of information sharing. Given our limited lifespan and point of view, we are dependent on information acquired from others. Our limitations concern both the world and the minds of others. No one can investigate every corner of the universe, or even of their own neighborhood, and we cannot always tell what someone is thinking just by looking at their face. We depend on others to share information with us both about the world and their thoughts. By far, most of the information we acquire from others we acquire from testimony. Language is our best tool for sharing information. This system of using language to overcome our cognitive limitations relies fundamentally on sincerity. In the most ordinary case ...