Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score

Mendelian randomization (MR) is a method of exploiting genetic variation to unbiasedly estimate a causal effect in presence of unmeasured confounding. MR is being widely used in epidemiology and other related areas of population science. In this paper, we study statistical inference in the increasingly popular two-sample summary-data MR design. We show a linear model for the observed associations approximately holds in a wide variety of settings when all the genetic variants satisfy the exclusion restriction assumption, or in genetic terms, when there is no pleiotropy. In this scenario, we derive a maximum profile likelihood estimator with provable consistency and asymptotic normality. However, through analyzing real datasets, we find strong evidence of both systematic and idiosyncratic pleiotropy in MR, echoing the omnigenic model of complex traits that is recently proposed in genetics. We model the systematic pleiotropy by a random effects model, where no genetic variant satisfies the exclusion restriction condition exactly. In this case we propose a consistent and asymptotically normal estimator by adjusting the profile score. We then tackle the idiosyncratic pleiotropy by robustifying the adjusted profile score. We demonstrate the robustness and efficiency of the proposed methods using several simulated and real datasets.Comment: 59 pages, 5 figures, 6 table

Aggregating Dependent Signals with Heavy-Tailed Combination Tests

Combining dependent p-values to evaluate the global null hypothesis presents a longstanding challenge in statistical inference, particularly when aggregating results from diverse methods to boost signal detection. P-value combination tests using heavy-tailed distribution based transformations, such as the Cauchy combination test and the harmonic mean p-value, have recently garnered significant interest for their potential to efficiently handle arbitrary p-value dependencies. Despite their growing popularity in practical applications, there is a gap in comprehensive theoretical and empirical evaluations of these methods. This paper conducts an extensive investigation, revealing that, theoretically, while these combination tests are asymptotically valid for pairwise quasi-asymptotically independent test statistics, such as bivariate normal variables, they are also asymptotically equivalent to the Bonferroni test under the same conditions. However, extensive simulations unveil their practical utility, especially in scenarios where stringent type-I error control is not necessary and signals are dense. Both the heaviness of the distribution and its support substantially impact the tests' non-asymptotic validity and power, and we recommend using a truncated Cauchy distribution in practice. Moreover, we show that under the violation of quasi-asymptotic independence among test statistics, these tests remain valid and, in fact, can be considerably less conservative than the Bonferroni test. We also present two case studies in genetics and genomics, showcasing the potential of the combination tests to significantly enhance statistical power while effectively controlling type-I errors

Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways.

Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy

A Comparative Study of Z′^{\prime} mediated Charged Lepton Flavor Violation at future lepton colliders

Charged lepton flavor violation (CLFV) represents a transition between charged leptons of different generations that violates lepton flavor conservation, which is a clear signature of possible new physics beyond the standard model. By exploiting a typical example model of extra Z$^{\prime}$ gauge boson, we perform a detailed comparative study on CLFV searches at several future lepton colliders, including a 240 GeV electron-positron collider and a TeV scale muon collider. Based on detailed signal and background Monte-Carlo studies with fast detector simulations, we derive the potentials in searching for Z$^{\prime}$ mediated CLFV couplings with $e\mu$, $e\tau$ and $\mu\tau$ of different future colliders. The results are compared with the current limits set by either low-energy experiments or the high-energy LHC experiments. We find that the sensitivity of the $\tau$ related CLFV coupling strength at future lepton colliders will be significantly improved comparing with the current best constraints.Comment: 11 pages, 5 figure