Normalizing Flows for Knockoff-free Controlled Feature Selection

Controlled feature selection aims to discover the features a response depends on while limiting the false discovery rate (FDR) to a predefined level. Recently, multiple deep-learning-based methods have been proposed to perform controlled feature selection through the Model-X knockoff framework. We demonstrate, however, that these methods often fail to control the FDR for two reasons. First, these methods often learn inaccurate models of features. Second, the "swap" property, which is required for knockoffs to be valid, is often not well enforced. We propose a new procedure called FlowSelect that remedies both of these problems. To more accurately model the features, FlowSelect uses normalizing flows, the state-of-the-art method for density estimation. To circumvent the need to enforce the swap property, FlowSelect uses a novel MCMC-based procedure to calculate p-values for each feature directly. Asymptotically, FlowSelect computes valid p-values. Empirically, FlowSelect consistently controls the FDR on both synthetic and semi-synthetic benchmarks, whereas competing knockoff-based approaches do not. FlowSelect also demonstrates greater power on these benchmarks. Additionally, FlowSelect correctly infers the genetic variants associated with specific soybean traits from GWAS data.Comment: 20 pages, 9 figures, 3 table

Scalable Causal Structure Learning via Amortized Conditional Independence Testing

Controlling false positives (Type I errors) through statistical hypothesis testing is a foundation of modern scientific data analysis. Existing causal structure discovery algorithms either do not provide Type I error control or cannot scale to the size of modern scientific datasets. We consider a variant of the causal discovery problem with two sets of nodes, where the only edges of interest form a bipartite causal subgraph between the sets. We develop Scalable Causal Structure Learning (SCSL), a method for causal structure discovery on bipartite subgraphs that provides Type I error control. SCSL recasts the discovery problem as a simultaneous hypothesis testing problem and uses discrete optimization over the set of possible confounders to obtain an upper bound on the test statistic for each edge. Semi-synthetic simulations demonstrate that SCSL scales to handle graphs with hundreds of nodes while maintaining error control and good power. We demonstrate the practical applicability of the method by applying it to a cancer dataset to reveal connections between somatic gene mutations and metastases to different tissues.Comment: 10 figures, 24 page

Impact of the adherence to medical treatment on the main urinary metabolic disorders in patients with kidney stones

To assess the effect of the adherence to medical treatment on urinary parameters in the 24-h metabolic study of patients with kidney stones. A retrospective, longitudinal, descriptive, and observational study was carried out by reviewing the hospital electronic medical record from 2014 to 2018. The adherence to drug treatment was measured 6 months after its initiation, and the numerical values of the metabolic studies were compared. Wilcoxon tests were performed to compare the difference before and after treatment. Ninety patients were evaluated, with 73.3% of adherence. The 180-day overall adherence rate was 61.2% in patients treated with a single drug and 85.4% in patients treated with multiple drugs. There is a statistically significant increase in citrate levels in patients with good adherence in comparison with non-adherent patients (p =0.031 vs. p =0.528). Medical treatment and dietary measures in patients with kidney stones have an initial impact at 6 months on the values of the main urinary metabolic alterations that predispose to calculi formation; the most significant is seen in those patients with adherence to medical treatment for hypocitraturia

Formation of Ferroelectrically Defined Ag Nanoarray Patterns

In order to produce the most effective Ag nanoarrays for plasmon enhanced fluorescence and Raman scattering made using ferroelectric substrates, the optimum conditions for the creation of arrays must be identified. We study here Ag nanopattern arrays formed using ferroelectric lithography based on periodically proton exchanged (PPE) template methods. We examine different conditions in regard to deposition of Ag nanoparticles and analyze the plasmon enhanced signal from the resulting nanoarray. We apply FLIM (fluorescence lifetime imaging) to assess different Ag nanoarray preparation conditions on fluorescence emission from selected fluorphores. In addition, we apply Raman and luminescence spectroscopy with AFM (atomic force microscopy) to study the plasmon enhancement of luminescence and Raman from the Ag nanoarrays

Interface modulated currents in periodically proton exchanged Mg doped lithium niobate

Conductivity in Mg doped lithium niobate (Mg:LN) plays a key role in the reduction of photorefraction and is therefore widely exploited in optical devices. However, charge transport through Mg:LN and across interfaces such as electrodes also yields potential electronic applications in devices with switchable conductivity states. Furthermore, the introduction of proton exchanged (PE) phases in Mg:LN enhances ionic conductivity, thus providing tailorability of conduction mechanisms and functionality dependent on sample composition. To facilitate the construction and design of such multifunctional electronic devices based on periodically PE Mg:LN or similar ferroelectric semiconductors, fundamental understanding of charge transport in these materials, as well as the impact of internal and external interfaces, is essential. In order to gain insight into polarization and interface dependent conductivity due to band bending, UV illumination, and chemical reactivity, wedge shaped samples consisting of polar oriented Mg:LN and PE phases were investigated using conductive atomic force microscopy. In Mg:LN, three conductivity states (on/off/transient) were observed under UV illumination, controllable by the polarity of the sample and the externally applied electric field. Measurements of currents originating from electrochemical reactions at the metal electrode-PE phase interfaces demonstrate a memresistive and rectifying capability of the PE phase. Furthermore, internal interfaces such as domain walls and Mg:LN-PE phase boundaries were found to play a major role in the accumulation of charge carriers due to polarization gradients, which can lead to increased currents. The insight gained from these findings yield the potential for multifunctional applications such as switchable UV sensitive micro-and nanoelectronic devices and bistable memristors. (C) 2016 AIP Publishing LLC

Interface and thickness dependent domain switching and stability in Mg doped lithium niobate

Controlling ferroelectric switching in Mg doped lithium niobate (Mg: LN) is of fundamental importance for optical device and domain wall electronics applications that require precise domain patterns. Stable ferroelectric switching has been previously observed in undoped LN layers above proton exchanged (PE) phases that exhibit reduced polarization, whereas PE layers have been found to inhibit lateral domain growth. Here, Mg doping, which is known to significantly alter ferroelectric switching properties including coercive field and switching currents, is shown to inhibit domain nucleation and stability in Mg: LN above buried PE phases that allow for precise ferroelectric patterning via domain growth control. Furthermore, piezoresponse force microscopy (PFM) and switching spectroscopy PFM reveal that the voltage at which polarization switches from the \"up\" to the \"down\" state increases with increasing thickness in pure Mg: LN, whereas the voltage required for stable back switching to the original \"up\" state does not exhibit this thickness dependence. This behavior is consistent with the presence of an internal frozen defect field. The inhibition of domain nucleation above PE interfaces, observed in this study, is a phenomenon that occurs in Mg: LN but not in undoped samples and is mainly ascribed to a remaining frozen polarization in the PE phase that opposes polarization reversal. This reduced frozen depolarization field in the PE phase also influences the depolarization field of the Mg: LN layer above due to the presence of uncompensated polarization charge at the PE-Mg: LN boundary. These alterations in internal electric fields within the sample cause long-range lattice distortions in Mg: LN via electromechanical coupling, which were corroborated with complimentary Raman measurements. (C) 2015 AIP Publishing LLC

Thickness, humidity, and polarization dependent ferroelectric switching and conductivity in Mg doped lithium niobate

Mg doped lithium niobate (Mg:LN) exhibits several advantages over undoped LN such as resistance to photorefraction, lower coercive fields, and p-type conductivity that is particularly pronounced at domain walls and opens up a range of applications, e.g., in domain wall electronics. Engineering of precise domain patterns necessitates well founded knowledge of switching kinetics, which can differ significantly from that of undoped LN. In this work, the role of humidity and sample composition in polarization reversal has been investigated under application of the same voltage waveform. Control over domain sizes has been achieved by varying the sample thickness and initial polarization as well as atmospheric conditions. In addition, local introduction of proton exchanged phases allows for inhibition of domain nucleation or destabilization, which can be utilized to modify domain patterns. Polarization dependent current flow, attributed to charged domain walls and band bending, demonstrates the rectifying ability of Mg: LN in combination with suitable metal electrodes that allow for further tailoring of conductivity. (C) 2015 AIP Publishing LLC

Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens

12-Bis-THA Cl2 [12,12'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used

Using global remote camera data of a solitary species complex to evaluate the drivers of group formation

We would like to thank Megan Whatton, Belden Giman, Hongliang Bu, Dajun Wang, Fang Wang, Roland Kays, Jillian Kilborn, and New Hampshire Fish and Game for their roles in contributing data that was used in this analysis. Any use of trade, product, or firm names is for descriptive purposes only and does not imply endorsement by the US Government.Peer reviewe