Identification of countercurrent tubule-vessel arrangements in the early development of mouse kidney based on immunohistochemistry and computer-assisted 3D visualization.

Nephron loop-vessel countercurrent arrangement in the medulla provides the structural basis for the formation of concentrated urine. To date, the morphogenesis of it and relevant water and solutes transportation has not been fully elucidated. In this study, with immunohistochemistry for aquaporins (AQP) and Na-K-2Cl co-transporter (NKCC2), as well as 3D visualization, we noticed in embryonic day 14.5 kidneys that the countercurrent arrangement of two pairs of loop-vessel was established as soon as the loop and vessel both extended into the medulla. One pair happened between descending limb and ascending vasa recta, the other occurred between thick ascending limb and descending vasa recta. Meanwhile, the immunohistochemical results showed that the limb and vessel expressing AQP-1 such as descending thick and thin limb and descending vasa recta was always accompanied with AQP-1 negative ascending vasa recta or capillaries and thick ascending limb, respectively. Moreover, the thick ascending limb expressing NKCC2 closely contacted with descending vasa recta without expressing NKCC2. As kidney developed, an increasing number of loop-vessels in countercurrent arrangement extended into the interstitium of the medulla. In addition, we observed that the AQP-2 positive ureteric bud and their branches were separated from those pairs of tubule-vessels by a relatively large and thin-walled veins or capillaries. Thus, the present study reveals that the loop-vessel countercurrent arrangement is formed at the early stage of nephrogenesis, which facilitates the efficient transportation of water and electrolytes to maintain the medullary osmolality and to form a concentrated urine.

A magnesium phosphonate metal-organic framework showing excellent performance for lead(II) sensing and removal from aqueous solutions.

A hydrogen-bonded three-dimensional porous metal-organic framework [Mg(H2PCD)2(H2O)2]·2H2O (denoted as Mg-MOF·2H2O; H3PCD = 9-(2-(ethoxy(hydroxy)phosphonyl)ethyl)-9H-carbazole-3,6-dicarboxylic acid) was synthesized by the reactions of H3PCD and Mg(II) under solvothermal conditions. The free carboxylate group was maintained in the pore surface by adjusting the acidic reaction conditions. The highly stable Mg-MOF exhibits excellent performance for lead(II) sensing and removal from aqueous solutions.

A Hexanuclear Gadolinium(III)-Based Nanoprobe for Magnetic Resonance Imaging of Tumor Apoptosis.

Magnetic resonance imaging (MRI) is instrumental in the noninvasive evaluation of tumor tissues in patients subjected to chemotherapy, thereby yielding essential diagnostic data crucial for the prognosis of tumors and the formulation of therapeutic strategies. Currently, commercially available MRI contrast agents (CAs) predominantly consist of mononuclear gadolinium(III) complexes. Because there is only one Gd(III) atom per molecule, these CAs often require administration in high doses to achieve the desired contrast quality, which inevitably leads to some adverse events. Herein, we develop a six-nuclei, apoptosis-targeting T1 CA, Gd6-ZnDPA nanoprobe, which consists of a hexanuclear gadolinium nanocluster (Gd6) with an apoptosis-targeting group (ZnDPA). The amplification of Gd(III) by the hexanuclear structure generates its high longitudinal relaxivity (44.67 mM-1 s-1, 1T) and low r1/r2 ratio (0.68, 1T). Based on the Solomon-Bloembergen-Morgan (SBM) theory, this notable improvement is primarily ascribed to a long correlation tumbling time (τR). More importantly, the Gd6-ZnDPA nanoprobe shows excellent tumor apoptosis properties with an enhanced MR signal ratio (∼74%) and a long MRI imaging acquisition time window (∼48 h) in 4T1 tumor-bearing mice. This study introduces an experimental gadolinium-based CA for the potential imaging of tumor apoptosis in the context of MRI.

Design and Optimization of 3D-Printed Variable Cross-Section I-Beams Reinforced with Continuous and Short Fibers.

By integrating fiber-reinforced composites (FRCs) with Three-dimensional (3D) printing, the flexibility of lightweight structures was promoted while eliminating the mold's limitations. The design of the I-beam configuration was performed according to the equal-strength philosophy. Then, a multi-objective optimization analysis was conducted based on the NSGA-II algorithm. 3D printing was utilized to fabricate I-beams in three kinds of configurations and seven distinct materials. The flexural properties of the primitive (P-type), the designed (D-type), and the optimized (O-type) configurations were verified via three-point bending testing at a speed of 2 mm/min. Further, by combining different reinforcements, including continuous carbon fibers (CCFs), short carbon fibers (SCFs), and short glass fibers (SGFs) and distinct matrices, including polyamides (PAs), and polylactides (PLAs), the 3D-printed I-beams were studied experimentally. The results indicate that designed and optimized I-beams exhibit a 14.46% and 30.05% increase in the stiffness-to-mass ratio and a 7.83% and 40.59% increment in the load-to-mass ratio, respectively. The CCFs and SCFs result in an outstanding accretion in the flexural properties of 3D-printed I-beams, while the accretion is 2926% and 1070% in the stiffness-to-mass ratio and 656.7% and 344.4% in the load-to-mass ratio, respectively. For the matrix, PAs are a superior choice compared to PLAs for enhancing the positive impact of reinforcements.

Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.

OBJECTIVES: To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death. DESIGN: Multicentre, randomised, open label trial. SETTING: 106 hospitals in China between 13 June 2018 and 10 July 2022. PARTICIPANTS: 4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg. INTERVENTIONS: Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted. RESULTS: 2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups. CONCLUSIONS: Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03479554.

Effect of an Emergency Department Process Improvement Package on Suicide Prevention: The ED-SAFE 2 Cluster Randomized Clinical Trial.

Importance: Suicide is a leading cause of deaths in the US. Although the emergency department (ED) is an opportune setting, ED-initiated interventions remain underdeveloped and understudied. Objective: To determine if an ED process improvement package, with a subfocus on improving the implementation of collaborative safety planning, reduces subsequent suicide-related behaviors. Design, Setting, and Participants: The Emergency Department Safety Assessment and Follow-up Evaluation 2 (ED-SAFE 2) trial, a stepped-wedge cluster randomized clinical trial conducted in 8 EDs across the US, used an interrupted time series design with three 12-month sequential phases: baseline, implementation, and maintenance. A random sample of 25 patients per month per site 18 years and older who screened positive on the Patient Safety Screener, a validated suicide risk screener, were included. The primary analyses focused on those who were discharged from the ED, while secondary analyses focused on all patients who screened positive, regardless of disposition. Data were collected on patients who presented for care from January 2014 to April 2018, and data were analyzed from April to December 2022. Interventions: Each site received lean training and built a continuous quality improvement (CQI) team to evaluate the current suicide-related workflow in the ED, identify areas of improvement, and implement efforts to improve. Each site was expected to increase their universal suicide risk screening and implement collaborative safety planning for patients at risk of suicide who were discharged home from the ED. Site teams were centrally coached by engineers experienced in lean CQI and suicide prevention specialists. Main Outcomes and Measures: The primary outcome was a composite comprising death by suicide or suicide-related acute health care visits, measured over a 6-month follow-up window. Results: Across 3 phases, 2761 patient encounters were included in the analyses. Of these, 1391 (50.4%) were male, and the mean (SD) age was 37.4 (14.5) years. A total of 546 patients (19.8%) exhibited the suicide composite during the 6-month follow-up (9 [0.3%] died by suicide and 538 [19.5%] of a suicide-related acute health care visit). A significant difference was observed for the suicide composite outcome between the 3 phases (baseline, 216 of 1030 [21%]; implementation, 213 of 967 [22%]; maintenance, 117 of 764 [15.3%]; P = .001). The adjusted odds ratios of risk of the suicide composite during the maintenance phase was 0.57 (95% CI, 0.43-0.74) compared with baseline and 0.61 (0.46-0.79) compared with the implementation phase, which reflect a 43% and 39% reduction, respectively. Conclusions and Relevance: In this multisite randomized clinical trial, using CQI methods to implement a department-wide change in suicide-related practices, including the implementation of a safety plan intervention, yielded a significant decrease in suicide behaviors in the maintenance period of the study. Trial Registration: ClinicalTrials.gov Identifier: NCT02453243.

Design and enhanced anticorrosion performance of a Zn5Mo2O11·5H2O/h-BN nanocomposite with labyrinth of nanopores.

Zinc molybdate (ZMO) is a safe and effective grafting material for anticorrosion. Herein, we reported the synthesis of ZMO/h-BN with the labyrinth of capillary pores owing to the in situ growth of ZMO on flake hexagonal boron nitride (h-BN) using the hydrothermal method. The special morphological structure provided a tortuous path for aggressive species to the steel substrate, which extended and blocked the transmission of aggressive species, enhancing the physical corrosion barrier performance. In addition, the capillary pores of ZMO contributed to the competitive adsorption of Cl- in an electrolyte and reduced the diffusion of aggressive species, thus further delaying the corrosion process. Moreover, the capture of oxygen by forming a B-O bond with h-BN and the formation of a molybdate passive film are beneficial for the inhibition of cathodic and anodic reactions. As verified by electrochemical impedance spectroscopy (EIS), the anticorrosion performance of ZMO/h-BN coating increased by 49.58% and 130.72% compared with ZMO and epoxy resin (EP) coatings after immersing in a NaCl aqueous solution (3.50 wt%) for 72 h. This coating matrix provides an avenue for molybdate-based corrosion remediation.

Identification of Long Noncoding RNAs That Exert Transcriptional Regulation by Forming RNA-DNA Triplexes in Prostate Cancer.

Long noncoding RNAs (lncRNAs) are involved in transcriptional regulation, and their deregulation is associated with the development of various human cancers, including prostate cancer (PCa). However, their underlying mechanisms remain unclear. In this study, lncRNAs that interact with DNA and regulate mRNA transcription in PCa were screened and identified to promote PCa development. First, 4195 protein-coding genes (PCGs, mRNAs) were obtained from the The Cancer Genome Atlas (TCGA) database, in which 1148 lncRNAs were differentially expressed in PCa. Then, 44,270 pairs of co-expression relationships were calculated between 612 lncRNAs and 2742 mRNAs, of which 42,596 (96%) were positively correlated. Among the 612 lncRNAs, 392 had the potential to interact with the promoter region to form DNA:DNA:RNA triplexes, from which lncRNA AD000684.2(AC002128.1) was selected for further validation. AC002128.1 was highly expressed in PCa. Furthermore, AD000684.2 positively regulated the expression of the correlated genes. In addition, AD000684.2 formed RNA-DNA triplexes with the promoter region of the regulated genes. Functional assays also demonstrated that lncRNA AD000684.2 promotes cell proliferation and motility, as well as inhibits apoptosis, in PCa cell lines. The results suggest that AD000684.2 could positively regulate the transcription of target genes via triplex structures and serve as a candidate prognostic biomarker and target for new therapies in human PCa.

Sheet-like 2D Manganese(IV) Complex with High Photothermal Conversion Efficiency.

We report a stable, water-soluble, mononuclear manganese(IV) complex [MnIV(H2L)]·5H2O (Mn-HDCL) that acts as an efficient photothermal material. This system is based on a hexahydrazide clathrochelate ligand (L/HDCL) and is obtained via an efficient one-pot templated synthesis that avoids the need for harsh reaction conditions. Scanning tunneling microscopy images reveal that Mn-HDCL exists as a 2D sheet-like structure. In Mn-HDCL, the manganese(IV) ion is trapped within the cavity of the cage-like ligand. This effectively shields the Mn(IV) ion from the external environment while providing adequate water solubility. As a result of orbital transitions involving the coordinated manganese(IV) ion, as well as metal-to-ligand charge transfer effects, Mn-HDCL possesses a large extinction coefficient and displays a photothermal performance comparable to single-wall carbon nanotubes in the solid state. A high photothermal conversion efficiency (ca. 71%) was achieved in aqueous solution when subjected to near-infrared 730 nm laser photo-irradiation. Mn-HDCL is paramagnetic and provides a modest increase in the T1-weighted contrast of magnetic resonance images both in vitro and in vivo. Mn-HDCL was found to target tumors passively and allow tumor margins to be distinguished in vivo in a mouse model. In addition, it also exhibited an efficient laser-triggered photothermal therapy effect in vitro and in vivo. We thus propose that Mn-HDCL could have a role to play as a tumor-targeting photothermal sensitizer.

Mechanical Degradation and Failure Analysis of Different Glass/Basalt Hybrid Composite Configuration in Simulated Marine Condition.

This work aims to evaluate the failure mechanisms of plain glass and basalt fiber reinforced composites and a selected glass/basalt hybrid composite sequence subjected to artificial seawater conditions. Sets of plain and five hybrid composite configurations were fabricated by vacuum assisted resin injection technique (VARI), and subjected to seawater aged for 258 days at 30 °C and 70 °C followed by tensile, flexural and charpy impact testing, respectively. Failure analysis for dry and seawater-aged composites were undertaken using scanning electron microscopy (SEM). Results showed that some hybrid laminates with sandwich-like and alternating sequencing exhibited superior mechanical properties and ageing resistance than plain laminates. GB3 ([B2G2]S) type hybrid composite with basalt fiber outer plies retained 100% tensile strength and 86.6% flexural strength after ageing, which was the highest among all the laminates. However, GB4 ([BGBG]S) type specimen with alternating sequencing retained the highest residual impact strength after ageing. SEM analysis on the failed specimens showed fiber breaking, matrix cracking and debonding caused by fiber-matrix interface degradation due to seawater exposure. However different hybrid configurations to a considerable extent prevented crack propagation across specimens, hence altering the overall damage morphology among different specimens.

Delicate and Fast Photochemical Surface Modification of 2D Photoresponsive Organosilicon Metal-Organic Frameworks.

Photoresponsive arylsilanes have been fascinating molecules for decades because of their unique photophysical characteristics and surface chemistry. Here we report the synthesis and fabrication of a crystalline two-dimensional trisilyl metal-organic framework (TSiMOF) orderly installed with the classical photoresponsive hexamethyltrisilane groups on the surface. Irradiated by UV light under air in minutes the fluorescence of the TSiMOF is turned on simultaneously with an intriguing surface transformation from superhydrophobic to hydrophilic. Thus, multifarious luminescent and hydrophilic patterns including logos, characters and Quick Response codes, etc. with good resolution are readily generated on the facilely fabricated TSiMOF film. The mechanism of this transformation is revealed by control experiments that the superficial trimethylsilyl groups suffering photochemical oxidation have been converted to hydroxyl groups.

Design of a MOF based on octa-nuclear zinc clusters realizing both thermal stability and structural flexibility.

An octa-nuclear zinc (Zn8) cluster-based two-fold interpenetrated metal-organic framework (MOF) of [(CH3)2NH2]2[Zn8O3(FDC)6]·7DMF (denoted as Zn8-as; H2FDC = 9H-fluorene-2,7-dicarboxylic acid; DMF = N,N-dimethylformamide) was synthesized by the reaction of a hard base of a curved dicarboxylate ligand (H2FDC) with the borderline acid of Zn(II) under solvothermal conditions. Zn8-as shows significant crystal volume shrinkage upon heating, yielding a solvate-free framework of [(CH3)2NH2]2[Zn8O3(FDC)6] (Zn8-de). Zn8-de displays gated adsorption for C2H2 and type-I adsorption for CO2, attributed to the framework flexibility and the different interactions between the gas molecules and the host framework.

Numerical Study on the Progressive Damage Behavior of the Interfacial Debonding between Shape Memory Alloy and Polymer Matrix.

The shape memory alloy reinforced composites have promising application potential for aerospace, automotive and biomedical engineering, while the interfacial bonding performance between shape memory alloy and polymer matrix is crucial to the improvement on the mechanical properties. The interfacial bonding mechanical properties are not uniform on the interface between shape memory alloy and the polymer matrix due to the existence of internal defects. Based on the cohesive zone model, an innovative finite element model is proposed to simulate the progressive damage behavior of the interfacial debonding between shape memory alloy and polymer matrix. The good agreement between the numerical results and the available experimental results indicates the validation of the proposed model. The progressive damage and connection of different positions of the interface between shape memory alloy and polymer matrix result in the final interfacial debonding behavior. Further, the effects of the shape memory alloy length-diameter ratio and embedded depth on the interface performance between shape memory alloy and polymer matrix are investigated.

Improved Dynamic Compressive and Electro-Thermal Properties of Hybrid Nanocomposite Visa Physical Modification.

The current work studied the physical modification effects of non-covalent surfactant on the carbon-particle-filled nanocomposite. The selected surfactant named Triton™ X-100 was able to introduce the steric repelling force between the epoxy matrix and carbon fillers with the help of beneficial functional groups, improving their dispersibility and while maintaining the intrinsic conductivity of carbon particles. Subsequent results further demonstrated that the physically modified carbon nanotubes, together with graphene nanoplates, constructed an effective particulate network within the epoxy matrix, which simultaneously provided mechanical reinforcement and conductive improvement to the hybrid nanocomposite system. For example, the hybrid nanocomposite showed maximum enhancements of ~75.1% and ~82.5% for the quasi-static mode-I critical-stress-intensity factor and dynamic compressive strength, respectively, as compared to the neat epoxy counterpart. Additionally, the fine dispersion of modified fillers as a double-edged sword adversely influenced the electrical conductivity of the hybrid nanocomposite because of the decreased contact probability among particles. Even so, by adjusting the modified filler ratio, the conductivity of the hybrid nanocomposite went up to the maximum level of ~10-1-100 S/cm, endowing itself with excellent electro-thermal behavior.

Stabilization of radical active species in a MOF nanospace to exploit unique reaction pathways.

We synthesized a metal-organic framework (MOF) using a ligand bearing haloalkoxy chains as a radical precursor. The radicals generated in the MOF upon photoirradiation were stable even at 250 K or under an O2 atmosphere, despite radicals generated from the ligand decomposing at 200 K; thus, the regular arrangement of radicals effectively stabilized them. Moreover, a unique photoproduct was obtained only in the MOF, indicating that the confinement effect in the nanospace enabled a specific reaction that did not occur in the bulk state. We propose a new platform for exploring chemical reactions and materials based on reactive species.

Triplet Carbene with Highly Enhanced Thermal Stability in the Nanospace of a Metal-Organic Framework.

Triplet carbenes (TCs) are of great interest due to their magnetic properties and reactivity, which descend from TCs' unique electronic state. However, the reactivity and stability of TCs are usually a trade-off, and it is difficult to achieve both at the same time. In this work, we were able to enhance the thermal stability of a TC species while maintaining its reactivity by confining them in the nanospace of a metal-organic framework (MOF). We synthesized a new MOF using a TC precursor; subsequently, TCs were generated by photostimulation. The TCs generated in the MOF nanospace were detectable up to 170 K, whereas their non-MOF-confined counterparts (bare ligand) could not be detected above 100 K. In addition, the reactivity of TC generated in MOF with O2 was drastically improved compared to that of bare ligand. Our approach is generally applicable to the stabilization of highly reactive species, whose reactivity needs to be preserved.

Molecular motion in the nanospace of MOFs upon gas adsorption investigated by in situ Raman spectroscopy.

Molecular motions taking place in the nanospace of metal-organic frameworks (MOFs) are an interesting research subject, although not yet fully investigated. In this work, we utilized in situ Raman spectroscopy in the ultralow-frequency region to investigate the libration motion (including the rotational motion of phenylene rings) of MOFs, in particular [Cu2(bdc)2(dabco)] (Cu-JAST-1), where bdc = 1,4-benzenedicarboxylate and dabco = 1,4-diazabicyclo[2.2.2]octane. The libration mode of Cu-JAST-1 was found to be significantly suppressed by the adsorption of various guest molecules, such as CO2, Ar, and N2. In addition, an appreciable correlation between the libration mode and adsorption equilibrium time was identified, which provides useful novel tools in the design of MOFs acting as molecular adsorption and separation materials.

Trapping and Releasing of Oxygen in Liquid by Metal-Organic Framework with Light and Heat.

Nanoporous materials can adsorb small molecules into their nanospaces. However, the trapping of light gas molecules dissolved in solvents suffers from low concentration and poor adsorption affinity. Here, the reversible trapping and releasing of dissolved oxygen are shown through integrating photosensitization and chemical capturing abilities into a metal-organic framework (MOF), MOMF-1. 9,10-Di(4-pyridyl)anthracene (dpa) ligands in MOMF-1 generates singlet oxygen from triplet oxygen under photoirradiation without additional photosensitizers, and successively reacts with it to produce anthracene endoperoxide, forming MOMF-2, which is proved crystallographically. The reverse reaction also proceeds quantitatively by heating MOMF-2. Moreover, MOMF-1 exhibits excellent water resistance, and completely removes oxygen of ppm order concentrations in water. The new material shown in this report allows controlling of the amount of dissolved oxygen, which can be applicable in various fields relating to numerous oxidation phenomena.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Patients With Child-Pugh B or C Cirrhosis.

PURPOSE: Our purpose was to report outcomes in patients with Child-Pugh B or C (CP B/C) hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Patients with HCC suitable for SBRT were prospectively enrolled in the study from 2012 to 2018. Outcomes in patients with CP B/C were analyzed. Cox proportional hazard models were used to compare survival outcomes between baseline CP score and post-SBRT CP score. RESULTS: Twenty-three patients with CP B/C with a total of 29 HCC tumors were treated with SBRT. Eighty-seven percent of patients were CP B8-C10. Median tumor size was 3.1 cm (range, 1-10 cm). Median dose delivered was 40 Gy in a median of 5 fractions. Eighteen of 23 patients (78.3%) had been previously treated with transarterial chemoembolization. Median follow-up was 14.5 months. Rates of 6- and 12-month local control were 100% and 92.3%, respectively. Six- and 12-month survival rates were 73.9% and 56.5%, respectively. Median survival was 14.5 months overall and 9.2, 22.5, 14.5, and 14.4 months for patients with CP B7, B8, B9, and C10, respectively. No patients exhibited symptoms of classic radiation-induced liver disease. However, 10 patients had CP score progression, with 4 patients (17%) having a ≥2-point increase in CP score by 6 months (or time of censor). There were 7 liver-related deaths, and based on independent review by a hepatologist, 1 of these deaths may have been attributable to SBRT-related liver injury. Fifteen of 23 patients were listed for liver transplant (LT) at the time of SBRT and 9 went on to receive LT with a pathologic complete response rate of 63.6%. Median survival, excluding patients who received LT, was 7.3 months. CONCLUSIONS: SBRT is a reasonable treatment option for carefully selected patients with CP B7-C10. In our small cohort, there was no detectable difference between local control or overall survival and baseline CP score.

Bayesian variable selection for high dimensional predictors and self-reported outcomes.

BACKGROUND: The onset of silent diseases such as type 2 diabetes is often registered through self-report in large prospective cohorts. Self-reported outcomes are cost-effective; however, they are subject to error. Diagnosis of silent events may also occur through the use of imperfect laboratory-based diagnostic tests. In this paper, we describe an approach for variable selection in high dimensional datasets for settings in which the outcome is observed with error. METHODS: We adapt the spike and slab Bayesian Variable Selection approach in the context of error-prone, self-reported outcomes. The performance of the proposed approach is studied through simulation studies. An illustrative application is included using data from the Women's Health Initiative SNP Health Association Resource, which includes extensive genotypic (>900,000 SNPs) and phenotypic data on 9,873 African American and Hispanic American women. RESULTS: Simulation studies show improved sensitivity of our proposed method when compared to a naive approach that ignores error in the self-reported outcomes. Application of the proposed method resulted in discovery of several single nucleotide polymorphisms (SNPs) that are associated with risk of type 2 diabetes in a dataset of 9,873 African American and Hispanic participants in the Women's Health Initiative. There was little overlap among the top ranking SNPs associated with type 2 diabetes risk between the racial groups, adding support to previous observations in the literature of disease associated genetic loci that are often not generalizable across race/ethnicity populations. The adapted Bayesian variable selection algorithm is implemented in R. The source code for the simulations are available in the Supplement. CONCLUSIONS: Variable selection accuracy is reduced when the outcome is ascertained by error-prone self-reports. For this setting, our proposed algorithm has improved variable selection performance when compared to approaches that neglect to account for the error-prone nature of self-reports.