Doppler ultrasound is more accurate than pulse oximeter plethysmography in the measurement of systolic arterial pressure from the median caudal artery in anesthetized dogs.

OBJECTIVE: To compare the accuracy of doppler ultrasound (DOP) and pulse oximeter plethysmography (POP) in the measurement of systolic arterial pressure (SAP) to invasive blood pressure (IBP) in anesthetized dogs. ANIMALS: 40 client-owned healthy dogs > 10 kg. METHODS: Dogs were anesthetized for surgical procedures in dorsal recumbency. Invasive blood pressure was measured from a dorsal pedal artery. DOP and POP device probes were placed over the median caudal artery with a flow-occluding cuff for noninvasive blood pressure measurement. Systolic arterial pressure measured by DOP, loss of pulse oximeter plethysmograph (POPL), and return of pulse oximeter plethysmograph (POPR) were compared to SAP measured by IBP. A linear mixed model was used to determine correlation. Bland-Altman analyses were performed to determine bias, SD, and limits of agreement. The accuracy of DOP and POP was compared to IBP across different tensive states. RESULTS: Conditional R2 values for DOP, POPL, and POPR versus IBP were 0.92, 0.85, and 0.87, respectively (all P < .001). The biases for DOP, POPL, and POPR compared to IBP were +7.6 ± 13.1, +3.9 ± 14.4, and +8.6 ± 15.2 mm Hg (bias ± SD), respectively. Limits of agreement (lower, upper) were (-18.1, +33.3), (-24.3, +32.1), and (-21.2, +38.4) mm Hg for DOP, POPL, and POPR, respectively. DOP and POP overestimated SAP during hypotension (SAP < 90 mm Hg), DOP to a lesser magnitude. CLINICAL RELEVANCE: DOP measured from the median caudal artery may be acceptable for SAP measurement in dorsally recumbent, healthy anesthetized dogs > 10 kg. POP was determined an unacceptable method.

Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure.

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

Using genetic association data to guide drug discovery and development: Review of methods and applications.

Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.

Incidence, morbidity, mortality and disparities in dementia: A population linked electronic health records study of 4.3 million individuals.

INTRODUCTION: We report dementia incidence, comorbidities, reasons for health-care visits, mortality, causes of death, and examined dementia patterns by relative deprivation in the UK. METHOD: A longitudinal cohort analysis of linked electronic health records from 4.3 million people in the UK was conducted to investigate dementia incidence and mortality. Reasons for hospitalization and causes of death were compared in individuals with and without dementia. RESULTS: From 1998 to 2016 we observed 145,319 (3.1%) individuals with incident dementia. Repeated hospitalizations among senior adults for infection, unknown morbidity, and multiple primary care visits for chronic pain were observed prior to dementia diagnosis. Multiple long-term conditions are present in half of the individuals at the time of diagnosis. Individuals living in high deprivation areas had higher dementia incidence and high fatality. DISCUSSION: There is a considerable disparity of dementia that informs priorities of prevention and provision of patient care.

The survivorship of revision total hip replacement with severe proximal bone deficiency using a modular taper fluted prosthesis.

Contemporary uncemented femoral revision hip systems have become commonly used over the past decade and have enabled the reconstruction of leg length, offset and anteversion as independent variables through the use of modular junctions. Modular junction failures between the proximal body and distal stem have been described with revision systems, although this is rare. We sought to identify the survivorship of one revision system in a salvage arthroplasty scenario where no host bone support of the modular junction was present. From a series of 136 patients, 15 patients (16 hips) were identified without host bone support of the modular junction with a mean radiological follow up of over 6 years (76 months +/- 35 months). There have been no cases of prosthetic fracture over the follow-up duration, with two revisions performed for reasons of aseptic loosening and infection. The mean BMI of the study group was 30.2 with 78% of the cohort classified as overweight or obese. It is well recognised that, host bone support of the modular junction is preferable, however the satisfactory outcomes over the midterm in these complex patients suggests that modular revision systems remain an option.

A three-portal laparoscopic hysterectomy in a chimpanzee (Pan troglodytes) with a uterine manipulator and vessel sealing device.

OBJECTIVE: To report the treatment and outcome of a a captive chimpanzee (Pan troglodytes) undergoing 3-portal laparoscopic hysterectomy. Additionally, the technique used for successful urinary catheterization is described. ANIMALS: A 29-year-old female intact chimpanzee with uterine bleeding. STUDY DESIGN: Clinical case report. METHODS: Uterine changes consistent with adenomyosis and/or endometriosis were noted on abdominal ultrasonographic and computed tomographic examinations. A urinary catheter was placed before a 3-portal laparoscopic hysterectomy with a uterine manipulator (VCare) and a vessel sealer (Ligasure). The uterus was submitted for histopathology. RESULTS: Preoperative urinary catheterization was achieved with several modifications and prevented bladder protrusion into the surgical field. Laparoscopy provided excellent visualization of the pelvic structures and VCare effectively maneuvered the uterus for a safe and efficient dissection. The use of the vessel sealer was effective, and bleeding was minimal. Anesthesia and surgery lasted 240 and 150 minutes, respectively. No complications were encountered. Histopathological changes of the uterus were consistent with adenomyosis and myometrial hyperplasia. The chimpanzee recovered uneventfully and returned to normal behavior with no recurrence of uterine bleeding 5 months after surgery. CONCLUSION: The 3-portal laparoscopic technique reported here allowed hysterectomy without complication in this chimpanzee. Urinary catheterization was technically challenging but successful.

Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic.

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.

BACKGROUND: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. METHODS: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. RESULTS: Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3-4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2-5.4) in solid-organ cancers and 2.6 months (95%CI 1.2-5.6) in lymphomas. HR23B status did not predict response. CONCLUSIONS: CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.

Exome sequencing and characterization of 49,960 individuals in the UK Biobank.

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Saccharomyces cerevisiae Fermentation Products That Mitigate Foodborne Salmonella in Cattle and Poultry.

Prior studies revealed that yeast fermentation products, specifically XPC™ and related products (Diamond V, Cedar Rapids, IA), serve as viable food safety tools across multiple food animal species including cattle and poultry. Providing this supplement in feed leads to reduced prevalence, load, virulence, and antibiotic resistance of foodborne pathogens such as Salmonella and Escherichia coli O157:H7. These findings are worthy of further study, especially when coupled with the enhanced growth and performance observed with these products. Mechanistically, XPC appears to modulate these effects through the immune system and gut microbiome. Herein we further investigated this product and demonstrate that XPC mediates an enhancement of immunocyte killing of Salmonella in calves fed the product. Additionally, these studies reveal that XPC reduces the lymph node infiltration, invasiveness, and antibiotic resistance of Salmonella in dairy calves fed the product-consistent with findings observed in poultry and adult beef cattle. Furthermore, the reduction in invasiveness does not lead to a rebound hyperinvasive phenotype in Salmonella obtained from XPC-fed animals. In summary, these studies suggest that XPC reduces the invasion of Salmonella and may alter various phenotypic characteristics of the pathogen.

Polymorphisms in Natural Killer Cell Receptor Protein 2D (NKG2D) as a Risk Factor for Cholangiocarcinoma.

BACKGROUND AND AIMS: Understanding of the significant genetic risk factors for Cholangiocarcinoma (CC) remains limited. Polymorphisms in the natural killer cell receptor G2D (NKG2D) gene have been shown to increase risk of CC transformation in patients with Primary Sclerosing Cholangitis (PSC). We present a validation study of NKG2D polymorphisms in CC patients without PSC. METHODS: Seven common Single Nucleotide Polymorphisms (SNPs) of the NKG2D gene were genotyped in 164 non-PSC related CC subjects and 257 controls with HaploView. The two SNPs that were positively identified in the previous Scandinavian study, rs11053781 and rs2617167, were included. RESULTS: The seven genotyped SNPs were not associated with risk of CC. Furthermore, haplotype analysis revealed that there was no evidence to suggest that any haplotype differs in frequency between cases and controls (P > 0.1). CONCLUSION: The common genetic variation in NKG2D does not correlate significantly with sporadic CC risk. This is in contrast to the previous positive findings in the Scandinavian study with PSC-patients. The failure to reproduce the association may reflect an important difference between the pathogenesis of sporadic CC and that of PSC-related CC. Given that genetic susceptibility is likely to be multifaceted and complex, further validation studies that include both sporadic and PSC-related CC are required.

A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer.

BACKGROUND: In the current study, the authors sought to determine the maximum tolerated dose (MTD) of the novel class 1 selective histone deacetylase inhibitor CXD101 in a dose escalation study in patients with advanced solid tumors or recurrent/refractory lymphoma. METHODS: The authors escalated the dose of CXD101 from 1 mg twice daily orally for 5 days in a 21-day cycle (3+3 design). RESULTS: A total of 39 patients were enrolled, 36 of whom received CXD101. Of the 30 patients in the escalation cohort, 29 were evaluable for determination of the dose-limiting toxicity (DLT). DLTs were noted at doses of 16 mg twice daily (1 of 6 patients), 20 mg twice daily (1 of 6 patients), and 24/25 mg twice daily (2 of 5 patients, both of whom developed neutropenic fever). The MTD was 20 mg twice daily, which achieved maximal plasma concentrations (±standard deviation) of 231±76 nM to 342±126 nM, which was within the biologically active range. Six patients received 20 mg twice daily in an expansion cohort. The most frequent adverse events were fatigue, nausea, and reversible cytopenia. Key grade 3 to 4 adverse events (according to Common Terminology Criteria for Adverse Events criteria [version 4.03]) included thrombocytopenia (11%), neutropenia (17%), and neutropenic fever (2%) across the 133 CXD101 cycles given. The toxicity profile was similar to that of licensing studies with other histone deacetylase inhibitors. In 22 evaluable patients receiving a dose of ≥16 mg twice daily (17 of whom had lymphoma and 5 of whom had solid tumors), 3 partial responses (2 in patients with classic Hodgkin lymphoma after allogenic stem cell transplantation and 1 in a patient with angioimmunoblastic T-cell lymphoma) and 1 complete response (in a patient with follicular lymphoma) were noted (overall response rate of 18%) in addition to 9 patients who achieved durable stable disease. Responses were noted predominantly among patients with lymphoma (tumor reduction noted in 63% of patients on standard computed tomography). CONCLUSIONS: The MTD in the current study was found to be 20 mg twice daily. Encouraging and durable activity was observed in patients with Hodgkin lymphoma, T-cell lymphoma, and follicular lymphoma.

Learning curve with a new primary total knee arthroplasty implant: a multicenter perspective with more than 2000 patients.

BACKGROUND: This study provides an example for evaluating learning curve when introducing a new knee system. METHODS: Thirty-five investigators across 22 sites prospectively implanted 843 subjects with currently available products (group A). Seventy-seven investigators across 48 sites prospectively implanted 2330 subjects with the ATTUNE Knee System; in which the first 10 subjects for each surgeon were the learning curve cases (group B, N = 611), and the later subjects were designated as group C (N = 1719). Surgical time, rates of intraoperative and early postoperative complications, and patient-reported outcome measures (PROMs) at a minimum of 1 year were compared. RESULTS: Mean (standard deviation) surgical time was 72.0 (21.6) minutes for group A, 83.0 (24.2) for group B, and 72.1 (24.1) for group C (P < .001 for group B vs group C; P = .955 for group C vs group A). Intraoperative, early (<90 day) complication rates, and PROMs were similar for all groups. CONCLUSIONS: The new knee system learning curve was characterized by a slightly longer surgical time with no negative impact on complications or PROMs. LEVEL OF EVIDENCE: III.

A Hierarchical Model To Understand the Processing of Polysaccharides/Protein-Based Films in Ionic Liquids.

In recent years, biomaterials from abundant and renewable sources have shown potential in medicine and materials science alike. In this study, we combine theoretical modeling, molecular dynamics simulations, and several experimental techniques to understand the regeneration of cellulose/silk-, chitin/silk-, and chitosan/silk-based biocomposites after dissolution in ionic liquid and regeneration in water. We propose a novel theoretical model that correlates the composite's microscopic structure to its bulk properties. We rely on modeling non-cross-linked biopolymers that present layer-like structures such as ß-sheets and we successfully predict structural, thermal, and mechanical properties of a mixture of these biomolecules. Our model and experiments show that the solubility of the pure substance in the chosen solvent can be used to modulate the amount of crystallinity of the biopolymer blend, as measured by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). Thermogravimetric analysis (TGA) shows that the decomposition temperature of the blended biocomposites compared to their pure counterparts is reduced in accordance with our theoretical predictions. The morphology of the material is further characterized through scanning electron microscopy (SEM) and shows differently exposed surface area depending on the blend. Finally, differential scanning calorimetry (DSC) is performed to characterize the residual water content in the material, essential for explaining the regeneration process in water. As a final test of the model, we compare our model's prediction of the Young's modulus with existing data in the literature. The model correctly reproduces experimental trends observed in the Young's modulus due to varying the concentration of silk in the biopolymer blend.

One- and two-stage surgical revision of peri-prosthetic joint infection of the hip: a pooled individual participant data analysis of 44 cohort studies.

One-stage and two-stage revision strategies are the two main options for treating established chronic peri-prosthetic joint infection (PJI) of the hip; however, there is uncertainty regarding which is the best treatment option. We aimed to compare the risk of re-infection between the two revision strategies using pooled individual participant data (IPD). Observational cohort studies with PJI of the hip treated exclusively by one- or two-stage revision and reporting re-infection outcomes were retrieved by searching MEDLINE, EMBASE, Web of Science, The Cochrane Library, and the WHO International Clinical Trials Registry Platform; as well as email contact with investigators. We analysed IPD of 1856 participants with PJI of the hip from 44 cohorts across four continents. The primary outcome was re-infection (recurrence of infection by the same organism(s) and/or re-infection with a new organism(s)). Hazard ratios (HRs) for re-infection were calculated using Cox proportional frailty hazards models. After a median follow-up of 3.7 years, 222 re-infections were recorded. Re-infection rates per 1000 person-years of follow-up were 16.8 (95% CI 13.6-20.7) and 32.3 (95% CI 27.3-38.3) for one-stage and two-stage strategies respectively. The age- and sex-adjusted HR of re-infection for two-stage revision was 1.70 (0.58-5.00) when compared with one-stage revision. The association remained consistently absent after further adjustment for potential confounders. The HRs did not vary importantly in clinically relevant subgroups. Analysis of pooled individual patient data suggest that a one-stage revision strategy may be as effective as a two-stage revision strategy in treating PJI of the hip.

Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference.

Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

Computational and experimental analysis of short peptide motifs for enzyme inhibition.

The metabolism of living systems involves many enzymes that play key roles as catalysts and are essential to biological function. Searching ligands with the ability to modulate enzyme activities is central to diagnosis and therapeutics. Peptides represent a promising class of potential enzyme modulators due to the large chemical diversity, and well-established methods for library synthesis. Peptides and their derivatives are found to play critical roles in modulating enzymes and mediating cellular uptakes, which are increasingly valuable in therapeutics. We present a methodology that uses molecular dynamics (MD) and point-variant screening to identify short peptide motifs that are critical for inhibiting ß-galactosidase (ß-Gal). MD was used to simulate the conformations of peptides and to suggest short motifs that were most populated in simulated conformations. The function of the simulated motifs was further validated by the experimental point-variant screening as critical segments for inhibiting the enzyme. Based on the validated motifs, we eventually identified a 7-mer short peptide for inhibiting an enzyme with low µM IC50. The advantage of our methodology is the relatively simplified simulation that is informative enough to identify the critical sequence of a peptide inhibitor, with a precision comparable to truncation and alanine scanning experiments. Our combined experimental and computational approach does not rely on a detailed understanding of mechanistic and structural details. The MD simulation suggests the populated motifs that are consistent with the results of the experimental alanine and truncation scanning. This approach appears to be applicable to both natural and artificial peptides. With more discovered short motifs in the future, they could be exploited for modulating biocatalysis, and developing new medicine.

Impact of Phosphorylation and Pseudophosphorylation on the Early Stages of Aggregation of the Microtubule-Associated Protein Tau.

The microtubule-associated protein tau regulates the stability of microtubules within neurons in the central nervous system. In turn, microtubules are responsible for the remodeling of the cytoskeleton that ultimately leads to the formation or pruning of new connections among neurons. As a consequence, dysfunction of tau is associated with many forms of dementia as well as Alzheimer's disease. In the brain, tau activity is regulated by its phosphorylation state. Phosphorylation is a post-translational modification of proteins that adds a phosphate group to the side chain of an amino acid. Phosphorylation at key locations in the tau sequence leads to a higher or lower affinity for microtubules. In Alzheimer's disease, tau is present in an abnormal phosphorylation state. However, studying the effect of phosphorylation experimentally has been extremely challenging as there is no viable way of exactly selecting the location and the number of phosphorylated sites. For this reason, researchers have turned to pseudophosphorylation. In this technique, actual phosphorylation is mimicked by mutating the selected amino acid into glutamate or aspartate. Whether this methodology is equivalent to actual phosphorylation is still open to debate. In this study, we will show that phosphorylation and pseudophosphorylation are not exactly equivalent. Although for larger aggregates the two techniques lead to similar structures, the kinetics of the process may be altered. In addition, very little is known about the impact that this may have on the early stages of aggregation, such as nucleation and conformational rearrangement. In this study, we show that the two methods may produce a similar ensemble of conformations, even though the kinetic and chemical details that lead to it are quite different.

Mendelian Randomisation study of the influence of eGFR on coronary heart disease.

Impaired kidney function, as measured by reduced estimated glomerular filtration rate (eGFR), has been associated with increased risk of coronary heart disease (CHD) in observational studies, but it is unclear whether this association is causal or the result of confounding or reverse causation. In this study we applied Mendelian randomisation analysis using 17 genetic variants previously associated with eGFR to investigate the causal role of kidney function on CHD. We used 13,145 participants from the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium and 194,427 participants from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease (CARDIoGRAMplusC4D) consortium. We observed significant association of an unweighted gene score with CHD risk (odds ratio = 0.983 per additional eGFR-increasing allele, 95% CI = 0.970-0.996, p = 0.008). However, using weights calculated from UCLEB, the gene score was not associated with disease risk (p = 0.11). These conflicting results could be explained by a single SNP, rs653178, which was not associated with eGFR in the UCLEB sample, but has known pleiotropic effects that prevent us from drawing a causal conclusion. The observational association between low eGFR and increased CHD risk was not explained by potential confounders, and there was no evidence of reverse causation, therefore leaving the remaining unexplained association as an open question.

Selecting instruments for Mendelian randomization in the wake of genome-wide association studies.

Mendelian randomization (MR) studies typically assess the pathogenic relevance of environmental exposures or disease biomarkers, using genetic variants that instrument these exposures. The approach is gaining popularity-our systematic review reveals a greater than 10-fold increase in MR studies published between 2004 and 2015. When the MR paradigm was first proposed, few biomarker- or exposure-related genetic variants were known, most having been identified by candidate gene studies. However, genome-wide association studies (GWAS) are now providing a rich source of potential instruments for MR analysis. Many early reviews covering the concept, applications and analytical aspects of the MR technique preceded the surge in GWAS, and thus the question of how best to select instruments for MR studies from the now extensive pool of available variants has received insufficient attention. Here we focus on the most common category of MR studies-those concerning disease biomarkers. We consider how the selection of instruments for MR analysis from GWAS requires consideration of: the assumptions underlying the MR approach; the biology of the biomarker; the genome-wide distribution, frequency and effect size of biomarker-associated variants (the genetic architecture); and the specificity of the genetic associations. Based on this, we develop guidance that may help investigators to plan and readers interpret MR studies.