Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Highly porous tantalum acetabular components without ancillary screws have similar migration to porous titanium acetabular components with screws at 2 years: a randomized controlled trial

Background: It is proposed that highly porous coatings on acetabular components, such as a porous tantalum coating, provide adequate fixation without ancillary screw fixation in primary total hip arthroplasty (THA). However, tantalum acetabular components have been associated with higher rates of revision than other uncemented components in national registries. The aim of this randomized controlled trial is to determine whether the early migration of a solid-backed tantalum acetabular component was no greater than that of a titanium acetabular component with ancillary screw fixation that has proven good clinical results. Methods: Sixty-six patients aged 40 to 64 years, with osteoarthritis and Charnley grade A or B activity grade and who underwent primary THA, were recruited into the trial. Patients were randomized intraoperatively to receive either the tantalum or titanium acetabular component. All patients received the same cemented polished tapered femoral stem, 28-mm cobalt-chromium femoral head, and highly cross-linked polyethylene liner. Acetabular component migration was measured using radiostereometric analysis at 4-6 days postoperatively and at 6 weeks, 3 months, 1 and 2 years following THA. Results: The mean proximal migration at 2 years for the tantalum cohort was 0.17 mm (95% confidence interval, 0.09-0.24) which was no greater than that of the titanium cohort which was 0.19 mm (0.07-0.32). Harris hip scores and functional activity scores were similar between groups. Conclusion: These results demonstrate that early stability can be achieved without ancillary screw fixation through the use of a highly porous high friction coating on a solid-backed modular acetabular component. Level of Evidence: Level I.Donald W. Howie, Oksana T. Holubowycz, Stuart A. Callary, Thomas S. Robertson, Lucian B. Solomo

Does cup-cage reconstruction with oversized cups provide initial stability in THA for osteoporotic acetabular fractures?

Background The incidence of acetabular fractures in osteoporotic patients is increasing. Immediate total hip arthroplasty (THA) has potential advantages, but achieving acetabular component stability is challenging and, at early followup, reported revision rates for loosening are high. Questions/purposes This study measured acetabular component stability and the initial surface contact achieved between the acetabular component and unfractured region of the pelvis after THA using an oversized acetabular component and cup-cage reconstruction. Methods Between November 2011 and November 2013, we treated 40 acute acetabular fractures in patients older than 70 years of age. Of these, 12 (30%) underwent immediate THA using an oversized acetabular component with screws inserted only into the ilium and a cup-cage construct. Postoperatively all patients were mobilized without weightbearing restrictions. Indications for immediate THA after acetabular fractures were displaced articular comminution deemed unreducible. Eleven of the 12 were prospectively studied to evaluate the initial stability of the reconstructions using radiostereometric analysis. One of the patients died of a pulmonary embolism after surgery, and the remaining 10 (median age, 81 years; range, 72–86 years) were studied. Of these, five were analyzed at 1 year and five were analyzed at 2 years. Acetabular component migration was defined as acceptable if less than the limits for primary THA that predict later loosening (1.76 mm of proximal migration and 2.53 of sagittal rotation). The contact surface between the acetabular component and ilium in direct continuity with the sacroiliac joint, and the ischium and pubis in direct continuity with the symphysis pubis, was measured on postoperative CT scans. Results At 1 year the median proximal migration was 0.83 mm (range, 0.09–5.13 mm) and sagittal rotation was 1.3° (range, 0.1°–7.4°). Three of the 10 components had migration above the suggested limits for primary THA at 1 year postoperatively. The contact surface achieved at surgery between the acetabular component and pelvis ranged from 11 to 17 cm2 (15%–27% of each component). Conclusions The majority of acetabular components in this cohort were stable despite the small contact surface achieved between the component and pelvic bone. Three of 10 migrated in excess of the limits that predict later loosening in primary THA but it remains to be seen whether these limits apply to this selected group of frail osteoporotic patients. We continue to use this technique routinely to treat patients with the same indications, but since the analysis of these data we have added screw fixation of the acetabular component to the ischial tuberosity and the superior pubic ramus. Level of Evidence Level IV, therapeutic study.Lucian B. Solomon, Patrick Studer, John M. Abrahams, Stuart A. Callary, Caroline R. Moran, Roumen B. Stamenkov, Donald W. Howi

The variation in hip stability measurements between supine and standing radiographs of dysplastic hips

AIMS: The aims of this study were to compare clinically relevant measurements of hip dysplasia on radiographs taken in the supine and standing position, and to compare Hip2Norm software and Picture Archiving and Communication System (PACS)-derived digital radiological measurements. METHODS: Preoperative supine and standing radiographs of 36 consecutive patients (43 hips) who underwent periacetabular osteotomy surgery were retrospectively analyzed from a single-centre, two-surgeon cohort. Anterior coverage (AC), posterior coverage (PC), lateral centre-edge angle (LCEA), acetabular inclination (AI), sharp angle (SA), pelvic tilt (PT), retroversion index (RI), femoroepiphyseal acetabular roof (FEAR) index, femoroepiphyseal horizontal angle (FEHA), leg length discrepancy (LLD), and pelvic obliquity (PO) were analyzed using both Hip2Norm software and PACS-derived measurements where applicable. RESULTS: Analysis of supine and standing radiographs resulted in significant variation for measurements of PT (p < 0.001) and AC (p = 0.005). The variation in PT correlated with the variation in AC in a limited number of patients (R2 = 0.378; p = 0.012). CONCLUSION: The significant variation in PT and AC between supine and standing radiographs suggests that it may benefit surgeons to have both radiographs when planning surgical correction of hip dysplasia. We also recommend using PACS-derived measurements of AI and SA due to the poor interobserver error on Hip2Norm.Ameya Bhanushali, Mukai Chimutengwende-Gordon, Martin Beck, Stuart Adam Callary, Kerry Costi, Donald W. Howie, Lucian Bogdan Solomo