Identifying rare genetic variants in 21 highly multiplex autism families: the role of diagnosis and autistic traits.

Autism is a highly heritable, heterogeneous, neurodevelopmental condition. Large-scale genetic studies, predominantly focussing on simplex families and clinical diagnoses of autism have identified hundreds of genes associated with autism. Yet, the contribution of these classes of genes to multiplex families and autistic traits still warrants investigation. Here, we conducted whole-genome sequencing of 21 highly multiplex autism families, with at least three autistic individuals in each family, to prioritise genes associated with autism. Using a combination of both autistic traits and clinical diagnosis of autism, we identify rare variants in genes associated with autism, and related neurodevelopmental conditions in multiple families. We identify a modest excess of these variants in autistic individuals compared to individuals without an autism diagnosis. Finally, we identify a convergence of the genes identified in molecular pathways related to development and neurogenesis. In sum, our analysis provides initial evidence to demonstrate the value of integrating autism diagnosis and autistic traits to prioritise genes.

Podoscopic classification of second toe deformities.

BACKGROUND: The AFCP (French Association of Foot Surgery) classification was recently introduced as a reliable and quick visual method for the assessment of sagittal plane deformities of the second toe. The aim of this study was four-fold: (1) to describe a new toe-ground area score (TAS) as an additional dynamic tool of such classification, (2) to verify whether all second toe deformities could be classified, (3) to assess the TAS intra- and inter-observer reliability and (4) to evaluate the TAS learning curve. METHODS: In this retrospective study 52 s toes were evaluated using a podoscope. Ten foot and ankle surgeons assessed independently standardised videos of each case acquired in a blinded fashion. Assessment was repeated three times, 15 days apart. Intra- (Intraclass Correlation Coefficient or ICC) and inter-observer reliability (Fleiss' Kappa coefficient) were calculated. Mean time to assess a deformity was also recorded. RESULTS: All the 522 observations (52 feet assessed by 10 surgeons) were successfully rated using the TAS. Intra- and inter-observer reliability were substantial for the first round (ICC: 0.79; Kappa: 0.76) and excellent for the second (ICC: 0.88; Kappa: 0.8) and third round (ICC: 0.84; Kappa: 0.81). Mean assessment time ± standard deviation was 22 ± 11 s per case for the last two rounds. CONCLUSIONS: The TAS has been proven reliable and quick in the assessment of second toe deformities. When combined with a static segmentary classification of the toe (such as the AFCP classification) it might provide further dynamic informations about the ability of the toe to engage the ground. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.

Intra- and inter-observer reliability of the AFCP classification for sagittal plane deformities of the second toe.

BACKGROUND: The French Association of Foot Surgery (AFCP) recently proposed a morphological classification of lesser toe deformities, describing the position of each joint (metatarsophalangeal or MTP, proximal interphalangeal or PIP and distal interphalangeal or DIP) in relation to their anatomic position in the sagittal plane. A study was designed to test its reliability for assessment of sagittal plane deformities of the second toe. METHODS: In this retrospective study 55 toes (55 feet, 50 patients) were evaluated. Eleven foot and ankle surgeons assessed independently standardized photographs of each case acquired in a blinded fashion. Assessment was repeated three times, each 15 days apart. Intra- (Intraclass Correlation Coefficient or ICC) and inter-observer reliability (Fleiss' Kappa coefficient) were calculated for each joint. RESULTS: Intra- and inter-observer reliability were moderate for the MTP joint (ICC range, 0.54-0.61) (Kappa range, 0.53-0.61) and substantial for the PIP (ICC range, 0.60-0.71) (Kappa range, 0.68-0.75) and DIP joints (ICC range, 0.69-0.78) (Kappa range, 0.74-0.78). Mean assessment time±standard deviation was 35±10s per case. CONCLUSIONS: The AFCP classification proved itself reliable in the assessment of sagittal plane defomities of the second toe among eleven foot and ankle surgeons. It is based only on a visual description of the deformity, and does not provide informations on either the clinical reducibility of the deformity and the radiographic joint status. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.

lme4qtl: linear mixed models with flexible covariance structure for genetic studies of related individuals.

BACKGROUND: Quantitative trait locus (QTL) mapping in genetic data often involves analysis of correlated observations, which need to be accounted for to avoid false association signals. This is commonly performed by modeling such correlations as random effects in linear mixed models (LMMs). The R package lme4 is a well-established tool that implements major LMM features using sparse matrix methods; however, it is not fully adapted for QTL mapping association and linkage studies. In particular, two LMM features are lacking in the base version of lme4: the definition of random effects by custom covariance matrices; and parameter constraints, which are essential in advanced QTL models. Apart from applications in linkage studies of related individuals, such functionalities are of high interest for association studies in situations where multiple covariance matrices need to be modeled, a scenario not covered by many genome-wide association study (GWAS) software. RESULTS: To address the aforementioned limitations, we developed a new R package lme4qtl as an extension of lme4. First, lme4qtl contributes new models for genetic studies within a single tool integrated with lme4 and its companion packages. Second, lme4qtl offers a flexible framework for scenarios with multiple levels of relatedness and becomes efficient when covariance matrices are sparse. We showed the value of our package using real family-based data in the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT2) project. CONCLUSIONS: Our software lme4qtl enables QTL mapping models with a versatile structure of random effects and efficient computation for sparse covariances. lme4qtl is available at https://github.com/variani/lme4qtl .

solarius: an R interface to SOLAR for variance component analysis in pedigrees.

UNLABELLED: : The open source environment R is one of the most widely used software for statistical computing. It provides a variety of applications including statistical genetics. Most of the powerful tools for quantitative genetic analyses are stand-alone free programs developed by researchers in academia. SOLAR is one of the standard software programs to perform linkage and association mappings of the quantitative trait loci (QTLs) in pedigrees of arbitrary size and complexity. solarius allows the user to exploit the variance component methods implemented in SOLAR. It automates such routine operations as formatting pedigree and phenotype data. It parses also the model output and contains summary and plotting functions for exploration of the results. In addition, solarius enables parallel computing of the linkage and association analyses that makes the calculation of genome-wide scans more efficient. AVAILABILITY AND IMPLEMENTATION: solarius is available on CRAN and on GitHub https://github.com/ugcd/solarius CONTACT: : aziyatdinov@santpau.cat.

Influence of Skin Marker Positioning and Their Combinations on Hip Joint Center Estimation Using the Functional Method.

Accurate estimation of hip joint center (HJC) position is crucial during gait analysis. HJC is obtained with predictive or functional methods. But in the functional method, there is no consensus on where to place the skin markers and which combination to use. The objective of this study was to analyze how different combinations of skin markers affect the estimation of HJC position relative to predictive methods. Forty-one healthy volunteers were included in this study; thirteen markers were placed on the pelvis and hip of each subject's lower limbs. Various marker combinations were used to determine the HJC position based on ten calibration movement trials, captured by a motion capture system. The estimated HJC position for each combination was evaluated by focusing on the range and standard deviation of the mean norm values of HJC and the mean X, Y, Z coordinates of HJC for each limb. The combinations that produced the best estimates incorporated the markers on the pelvis and on proximal and easily identifiable muscles, with results close to predictive methods. The combination that excluded the markers on the pelvis was not robust in estimating the HJC position.

Reliability of a new computerized equinometer based on Silfverskiöld test to measure gastrocnemius tightness.

BACKGROUND: Several tools exist to measure tightness of the gastrocnemius muscles; however, few of them are reliable enough to be used routinely in the clinic. The primary objective of this study was to evaluate the intra- and inter-rater reliability of a new equinometer. The secondary objective was to determine the load to apply on the plantar surface of the metatarsal heads to achieve the highest reliability when measuring gastrocnemius tightness. METHODS: The equinometer consisted of a goniometer and an electronic dynamometer, hooked up to a computer. Three raters carried out three trials of passive dorsiflexion by applying controlled pressure to the metatarsal heads of both ankles in 29 healthy subjects under two experimental conditions: knee extended (KE) and knee flexed at 30 degrees (KF). The equinometer continuously recorded the ankle dorsiflexion values (in °) corresponding to each 1 N interval of plantar pressure between 4 N and 20 N. The intra- and inter-rater reliability of the ankle dorsiflexion were evaluated through the intra-class correlation (ICC) coefficients in each of the pressure intervals. RESULTS: The intra-rater ICC in KE and KF was between 0.84 and 0.98. The inter-rater ICC in KE and KF was between 0.59 and 0.92. The pressure interval between 14 N and 15 N had the highest intra-rater (ICC = 1) and inter-rater reliability (0.87≤ICC≤0.99). A more refined analysis of this interval found that a load of 14.5 N yielded the best reliability. CONCLUSIONS: This compact equinometer has excellent intra-rater reliability and moderate to good inter-rater reliability. Since this reliability is optimal in the 14-15 N range, this load should be used going forward in clinical practice, especially when aiming to define a pathological threshold for tightness of the gastrocnemius muscles.

Gait analysis after total hip arthroplasty by direct minimally invasive anterolateral approach: A controlled study.

INTRODUCTION: Clinical and functional improvement after minimally invasive total hip arthroplasty (THA) has become increasingly controversial. The minimally invasive anterolateral approach (MIALA) allows rapid recovery resulting in a reduced need for rehabilitation. Alterations in muscle and static balance have previously been demonstrated. Results in the context of quantified gait analysis (QGA) and MIALA compared to an asymptomatic population remain unknown beyond one year postoperatively. Thus, the main objective of this controlled study was to compare the spatiotemporal parameters of gait, obtained using a QGA, beyond one year postoperatively in subjects operated on for THA by MIALA, with a group of asymptomatic subjects of the same age. The secondary objectives of the study were to compare the other QGA and EMG data acquired in operated subjects with asymptomatic subjects. HYPOTHESIS: We hypothesized that QGA and EMG parameters would not normalize beyond one year postoperatively. PATIENTS AND METHODS: Thirty-one subjects were recruited, including 16 patients (68 years old; IQR: 65-70) who underwent MIALA, at 15.5 months postoperatively (IQR: 13-17) and 15 asymptomatic subjects (62 years old; IQR: 61-71). Subjects underwent QGA and maximal isometric muscle force tests on the gluteus medius, gluteus maximus, Tensor Fascia Lata (TFL) and Sartorius muscles. Spatiotemporal gait parameters were the primary endpoint. The other QGA parameters: kinetics (characteristic values of vertical ground reaction forces, peak hip moments) and kinematics (hip joint amplitudes and pelvic mobility in the frontal and sagittal plane) constituted the secondary criteria. RESULTS: Five subjects were excluded for unrestored offset. Walking speed was lower in operated patients (1.03m/s versus 1.18m/s, p=0.005). Maximal isometric muscle force moments were lower in patients operated on for the gluteus maximus and medius as well as the TFL (p<0.005). The vertical ground reaction forces were lower for the operated patients for the loading phase (FzFCmax, p=0.001), the single stance phase (FzSPmin, p=5.05.10-2) and the swing phase (FzTOmax, p=0.0002). The moments were lower in the sagittal plane for the operated patients (0.6N.m for the operated versus 1.1N.m for the asymptomatic, p=0.02). The pelvic amplitudes in the sagittal plane were lower for operated patients (3.3° versus 7.2°, p=0.05). DISCUSSION: Our hypothesis appears to be validated. Gait deficits persisted beyond one year postoperatively after THA with MIALA. A decrease in walking speed, maximal isometric muscle force of the gluteus medius and gluteus maximus and TFL was observed, as well as a decrease in propulsive force and peak hip moment. Functionally, these results could signify muscle damage following surgery, requiring rehabilitation for improved muscle function. LEVEL OF PROOF: III: Non-randomized controlled trial.

MRI assessment of minimally invasive anterolateral approaches in total hip arthroplasty.

INTRODUCTION: Total hip arthroplasty (THA) on a minimally invasive anterolateral (MIAL) approach frequently leads to gluteus minimus and gluteus medius lesions, and sometimes to tensor fasciae latae (TFL) denervation. We therefore developed compensatory strategies, which we assessed on pre- and post-operative MRI: 1) to assess gluteus minimus and gluteus medius fatty infiltration (FI), 2) to assess TFL FI, and 3) to assess FI in the other periarticular muscles. HYPOTHESIS: The modified MIAL approach reduces the rate of gluteus minimus and gluteus medius lesion. MATERIALS AND METHODS: A continuous prospective single-surgeon series of THA using a MIAL approach included 25 patients. Femoral implantation was performed with the hip in extension so as to distance the proximal femur from the gluteals, avoiding muscle trauma. The superior gluteal nerve branch in the space between the gluteus medius and TFL, running toward the TFL, was systematically released and protected. MRI was performed preoperatively and at 3 months and 1 year post-surgery. FI was analyzed according to the Goutallier classification in all periarticular muscles. RESULTS: One patient lacked preoperative MRI and was excluded, leaving 24 patients, for 72 MRIs. In 10/24 patients (41.7%) the gluteus minimus and in 8/24 patients (33.3%) the anterior third of the gluteus medius showed ≥2 grade increase in FI between preoperative and 1-year MRI, with significant increases in both at 3 months (p<0.001) and 1 year (p<0.001). At least a 2 grade increase in FI at 1 year was seen in 1 patient (4.2%) in the TFL, in 2 (8.3%) in the piriformis, and in 1 (4.2%) in the obturator internus. There were no significant differences in FI between preoperative, 3-month or 1-year MRI in any other periarticular muscles. CONCLUSION: Femoral implantation in hip extension did not reduce the rate of gluteal lesions, which remained frequent. In contrast, release of the superior gluteal nerve branch could be effective in conserving TFL innervation. Some rare lesions of the proximal part of the pelvi-trochanteric muscles were also observed. LEVEL OF EVIDENCE: IV, Prospective case series.

Comparative MRI assessment of three minimally invasive approaches in total hip arthroplasty.

INTRODUCTION: Minimally invasive approaches (direct anterior approach: DAA; minimally invasive anterolateral: MIAL; piriformis-sparing posterior approach: PSPA) are widely used for total hip arthroplasty (THA), with a muscle-sparing objective. There are no published comparative studies of muscle damage secondary to these approaches. The aim of the present study was to compare fatty infiltration (FI) on MRI induced by DAA, MIAL and PSPA in THA 1) in the tensor fasciae latae (TFL) and sartorius muscles, 2) in the gluteal muscles, and 3) in the pelvitrochanteric muscles. HYPOTHESIS: Greater FI is induced by DAA in anterior muscles, by MIAL in gluteal muscles and by PSPA in pelvitrochanteric muscles. MATERIALS AND METHODS: Three continuous prospective series of THA by DAA, MIAL and PSPA included 25 patients each. MRI was performed preoperatively and at 1 year postoperatively. FI was graded on the Goutallier classification in all periarticular hip muscles. Muscles showing ≥2 grade aggravation at 1 year were considered damaged. RESULTS: Nine patients whose preoperative MRI was uninterpretable were excluded. In all, 66 patients (21 DAA, 24 MIAL and 21 PSPA) with 132 MRI scans were analyzed. TFL was damaged in 2/21 DAA patients (9.5%), 1/24 MIAL patients (4.2%) and 0/21 PSPA patients (0%). There were no sartorius lesions. The anterior third of the gluteus medius was damaged in 8/24 MIAL patients (33.3%) and the gluteus minimus in 10/24 (41.7%), compared to 1/21 DAA patients (4.8%) and 0/21 PSPA patients (0%). The mid and posterior thirds of the gluteus medius and the gluteus maximus were never damaged. The piriformis muscle was damaged in 3/21 DAA patients (14.3%), 2/24 MIAL patients (8.3%) and 2/21 PSPA patients (9.5%). The obturator internus was damaged in 4/21 DAA patients (19%), 1/24 MIAL patients (4.2%) and 16/21 PSPA patients (76.2%). The obturator externus and quadratus femoris were mainly damaged in PSPA patients: respectively, 5/21 (23.8%) and 4/21 patients (19%)). CONCLUSION: The muscle-sparing properties of minimally invasive hip approaches are only theoretical. In the present series, there were rare TFL lesions with DAA and MIAL. Gluteus medius and minimus lesions were frequent in MIAL. Pelvitrochanteric muscles lesions were more frequent in PSPA, but found in all 3 approaches. These findings should help guide surgeons in their choice of approach and in informing patients about the damage these minimally invasive approaches can cause. LEVEL OF EVIDENCE: III, prospective comparative study.

Remote Assessment of Quality of Life and Functional Exercise Capacity in a Cohort of COVID-19 Patients One Year after Hospitalization (TELECOVID).

Studies have reported persistent symptoms in patients hospitalized for COVID-19 up to 6 months post-discharge; however, sequalae beyond 6 months are unknown. This study aimed to investigate the clinical status of COVID-19 patients one year after hospital discharge and describe the factors related to poor outcomes. We conducted a single-center, prospective, cohort study of patients in Le Havre hospital (France) between 1 March 2020 and 11 May 2020. Baseline characteristics were collected from medical charts (including KATZ index and Clinical Frailty scale (CFS)), and a remote assessment was conducted 12 months after discharge. The main outcomes were the scores of the physical and mental components (PCS and MCS) of the Short-Form 36 (SF-36) and performance on the one-minute sit-to-stand test (STST1'). Scores <50% of the predicted values were considered as poor, and univariate and multivariate analyses were undertaken to investigate factors related to poor outcomes. Remote assessment was performed for 128 of the 157 (82%) eligible patients. Twenty-two patients were admitted to the intensive care unit (ICU), 45 to the intermediate care unit (IU), and 61 to the general ward (GW). Patients who spent time in ICU were more independent and younger. A large proportion of the sample had poor physical (30%) and mental health (27%) and a poor functional exercise capacity (33%) at the remote assessment. Higher levels of frailty at admission and hospital discharge were, respectively, associated with a higher risk of poor functional exercise capacity (StdOR 3.64 (95%CI 1.39-10.72); p = 0.01) and a higher risk of poor mental health (StdOR 2.81 (95%CI 1.17-7.45); p = 0.03). Long-term outcomes following hospitalization for COVID-19 infection may be negative for at least one year after discharge. Remote follow-up assessment could be highly beneficial for COVID-19 patients.

Stabilometric assessments of two rehabilitation protocols on postural parameters after posterior total hip arthroplasty: A prospective randomized comparative study.

INTRODUCTION: After total hip arthroplasty (THA), patients continue to have muscular, functional and postural deficits. The literature seems to support the use of postoperative rehabilitation, especially self-directed programs. However, there is no set protocol for the management of postural disorders. Therefore, the purpose of this study was to compare postural parameters of a group of patients who underwent posterior THA followed by 2 different types of rehabilitation (stabilometric platform (SP) and home-based self-directed protocols) with a control group of operated patients who did not undergo rehabilitation and a control group of age-matched asymptomatic subjects. HYPOTHESIS: We hypothesized that rehabilitation would normalize the stabilometric parameters. PATIENTS AND METHODS: A total of 67 subjects were enrolled in this study (mean age 67.85±1.22years) and divided into 4 groups. Forty-one of these subjects had undergone a posterior THA were randomly assigned between D10 and D21 to one of the following 3 groups: no rehabilitation control group (THACG=14), supervised rehabilitation with a stabilometric platform group (RSPG=16), and a self-directed home-based rehabilitation group (SDHRG=11). The 4th group was a control group made up of 26 age-matched asymptomatic nonoperated subjects (CG55-80). These rehabilitation protocols lasted 3weeks. At the end of the 3weeks, the groups performed the same stabilometric single leg and double leg stance tests (considering lower limb dominance) on an SP. RESULTS: No significant differences were observed between groups in the bipedal stance, except between the CG55-80 and the THACG, where a higher energy expenditure was observed in the THACG during the static stance with eyes open (EO) and eyes closed (EC): increase in the path length (Plength) covered by the center of pressure (COP) (EO: p=01; EC: p=03) and the average velocity (Vavg) of the COP (EO: p=01; EC: p=03). These differences were not observed in the SDHRG and RSPG whether they were compared with one another or with both control groups. In the unipedal stance, subjects in the RSPG and SDHRG showed greater muscle activity in the anterior and posterior chains and hip abductors, and used less energy to maintain the stance than those in the CG55-80, regardless of lower limb dominance: decrease in the mediolateral range of COP displacement (Xrange) (hip abductor muscles) (p=02) and anteroposterior range of COP displacement (Yrange) (anterior and posterior chains) (p=3.49.10-3), 95% confidence ellipse area (Earea) of COP data (p=1.47.10-3), Plength (p=04) and Vavg (p=04). The RSPG had a smaller Earea than the SDHRG (p=04), demonstrating a better postural stability during the unipedal stance performed on the dominant operated leg. DISCUSSION: Our results were consistent with the literature on the benefits of rehabilitation after THA, thus confirming our hypothesis that rehabilitation normalized stabilometric parameters between D31-D45, depending on the subjects. These results provide new information regarding rehabilitation techniques to be implemented postoperatively after a THA. A home-based self-directed rehabilitation program is just as effective as an SP program in managing postural disorders. LEVEL OF EVIDENCE: II; randomized controlled trial with low statistical power.

Quantitative gait analysis after total hip arthroplasty through a minimally invasive direct anterior approach: A case control study.

INTRODUCTION: Total Hip Arthroplasty (THA) leads to excellent clinical and functional results. The Minimally Invasive Anterior Approach (MIAA) theoretically allows rapid recovery and a reduction in the need for rehabilitation, but alterations in muscle and static balance have previously been demonstrated. Kinetic, kinematic and muscular alterations have been shown to persist up to 1year postoperatively but data beyond 1year postoperatively is lacking. Thus, the objective of this study was to compare the data from Quantitative Gait Analysis (QGA) coupled with electromyography (EMG), of patients one year postoperatively with THA through MIAA, compared to an asymptomatic control group. HYPOTHESIS: We hypothesized that QGA and EMG parameters would not normalize beyond one year postoperatively. PATIENTS AND METHODS: Twenty-seven patients were recruited, including 15 subjects (64.6±6.6years) operated on by MIAA, who at 15.9±3.1months postoperatively, along with 12 asymptomatic control subjects (68.9±9.7years), who underwent QGA and maximal isometric muscle strength tests, coupled with EMG on the gluteus medius and maximus, Tensor Fascia Lata (TFL) and Sartorius muscles. The spatiotemporal parameters of walking (step length, walking speed, cadence, single leg support time), kinetics (vertical ground reaction forces, hip moments in the 3 planes) and kinematics (coxofemoral and pelvic amplitudes) were analyzed. RESULTS: The walking speed was lower on the non-operated side of the experimental subjects (0.96ms-1 compared to 1.13ms-1 for asymptomatic [p=0.018]), as was the step length on the operated side (0.53m compared to 0.60m for asymptomatic [p=0.042]). Maximal isometric muscle strength was lower in subjects operated on for the gluteus maximus and medius (p=0.004), compared to asymptomatic subjects. Moments were lower in the subjects operated on in extension (0.72Nm on the operated side, 0.75Nm on the non-operated side compared to 1.06Nm for asymptomatic [p=0.007 and p=0.024]) and lateral rotation (0.09Nm on the operated side, 0.05Nm on the non-operated side compared to 0.16Nm for asymptomatic subjects [p=0.009 and p=0.0005]). Hip adduction amplitudes were lower on the operated side compared to asymptomatic subjects (3.93° versus 9.14° for asymptomatic [p=0.005]). Pelvic amplitudes in the frontal plane were lower amongst operated subjects (0.44° against 1.97° for asymptomatic [p=0.041]). Pelvic amplitudes in the sagittal plane were higher in the operated subjects (15.74° on the operated side, 15.43° on the non-operated side compared to 9.65° for asymptomatic [p=0.041 and p=0.032]). DISCUSSION: Our initial hypothesis was validated, since walking deficits persisted beyond one year postoperatively after THA through MIAA. A decrease in maximal isometric muscle strength of the gluteus medius and gluteus maximus was observed, as well as an alteration of kinetic and kinematic parameters in the sagittal and frontal planes. The results were in agreement with the literature and reflected the establishment of compensatory mechanisms to overcome alterations in joint strength and range more than one year postoperatively. These results would allow rehabilitation programs to be more specific and would justify a study on the other approaches for THA. LEVEL OF EVIDENCE: III; non-randomized control trial.

MISS: a non-linear methodology based on mutual information for genetic association studies in both population and sib-pairs analysis.

MOTIVATION: Finding association between genetic variants and phenotypes related to disease has become an important vehicle for the study of complex disorders. In this context, multi-loci genetic association might unravel additional information when compared with single loci search. The main goal of this work is to propose a non-linear methodology based on information theory for finding combinatorial association between multi-SNPs and a given phenotype. RESULTS: The proposed methodology, called MISS (mutual information statistical significance), has been integrated jointly with a feature selection algorithm and has been tested on a synthetic dataset with a controlled phenotype and in the particular case of the F7 gene. The MISS methodology has been contrasted with a multiple linear regression (MLR) method used for genetic association in both, a population-based study and a sib-pairs analysis and with the maximum entropy conditional probability modelling (MECPM) method, which searches for predictive multi-locus interactions. Several sets of SNPs within the F7 gene region have been found to show a significant correlation with the FVII levels in blood. The proposed multi-site approach unveils combinations of SNPs that explain more significant information of the phenotype than their individual polymorphisms. MISS is able to find more correlations between SNPs and the phenotype than MLR and MECPM. Most of the marked SNPs appear in the literature as functional variants with real effect on the protein FVII levels in blood. AVAILABILITY: The code is available at http://sisbio.recerca.upc.edu/R/MISS_0.2.tar.gz

MRI assessment of piriformis-sparing posterior approach in total hip arthroplasty.

INTRODUCTION: In total hip arthroplasty (THA), the posterior approach is the most common throughout the world. Dislocation is one of the main complications incurred, but the risk may be reduced by sparing posterior structures. Thus, piriformis-sparing posterior approaches (PSPA) were described, and satisfactory conservation of the muscle was reported. On the other hand, a recent cadaver study reported occult intrapelvic piriformis lesions in 91% of cases. In the light of this discordance, we performed pre- and postoperative MRI in THA by PSPA: 1) to assess the fatty infiltration of the piriformis induced by the approach, with particular attention to intrapelvic lesions; and 2) to assess fatty infiltration of the other periarticular muscles. HYPOTHESIS: The piriformis muscle will show little fatty infiltration following PSPA. MATERIALS AND METHODS: A continuous prospective single-surgeon series of THA by PSPA included 25 patients. MRI was performed preoperatively and at 3 months and 1 year postoperatively. Fatty infiltration was assessed on the Goutallier classification in all periarticular muscles. RESULTS: Preoperative MRI was lacking in 4 patients, who were excluded from analysis; 21 patients with MRI were thus analyzed. In the piriformis muscle, there was no significant change in fatty infiltration between preoperative and 3-month (p=0.29) or 1-year (p=0.41) MRI. Two of the 21 patients (9.5%) showed grade 3 or 4 fatty infiltration at 1 year, compared to 0/21 (0%) preoperatively; both showed sacral avulsion of the piriformis. Significant differences between preoperative and 1-year MRI were found for the obturator internus and externus, with grade 3 or 4 infiltration at 1 year in 14 cases for the obturator internus (14/21: 66.7%), in 3/21 for the obturator externus (14.3%) and in 6/21 for the quadratus femoris (28.6%), compared to respectively 0/21 (0%), 0/21 (0%) and 3/21 (14.3%) preoperatively. There were no significant differences for any of the other periarticular muscles. CONCLUSION: PSPA in THA ensured good conservation of the piriformis. There may, however, be rare and irreversible sacral lesions invisible intraoperatively. LEVEL OF EVIDENCE: IV; prospective case series.

Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits.

Previous studies have identified differences in DNA methylation in autistic individuals compared to neurotypical individuals. Yet, it is unclear if this extends to autistic traits-subclinical manifestation of autism features in the general population. Here, we investigate the association between DNA methylation at birth (cord blood), and scores on the Social and Communication Disorders Checklist (SCDC), a measure of autistic traits, in 701 8-year-olds, by conducting a methylome-wide association study (MWAS). We did not identify significant CpGs associated with SCDC. The most significant CpG site was cg14379490, on chromosome 9 (MWAS beta = - 1.78 ± 0.35, p value = 5.34 × 10 -7 ). Using methylation data for autism in peripheral tissues, we did not identify a significant concordance in effect direction of CpGs with p value < 10-4 in the SCDC MWAS (binomial sign test, p value > 0.5). In contrast, using methylation data for autism from post-mortem brain tissues, we identify a significant concordance in effect direction of CpGs with a p value < 10-4 in the SCDC MWAS (binomial sign test, p value = 0.004). Supporting this, we observe an enrichment for genes that are dysregulated in the post-mortem autism brain (one-sided Wilcoxon rank-sum test, p value = 6.22 × 10-5). Finally, integrating genome-wide association study (GWAS) data for autism (n = 46,350) with mQTL maps from cord-blood (n = 771), we demonstrate that mQTLs of CpGs associated with SCDC scores at p value thresholds of 0.01 and 0.005 are significantly shifted toward lower p values in the GWAS for autism (p < 5 × 10-3). We provide additional support for this using a GWAS of SCDC, and demonstrate a lack of enrichment in a GWAS of Alzheimer's disease. Our results highlight the shared cross-tissue methylation architecture of autism and autistic traits, and demonstrate that mQTLs associated with differences in DNA methylation associated with childhood autistic traits are enriched for common genetic variants associated with autism and autistic traits.

Electromyographic study of hip muscles involved in total hip arthroplasty: Surprising results using the direct anterior minimally invasive approach.

BACKGROUND: The functional and clinical benefit of minimally invasive total hip arthroplasty (THA) is well-known, but the literature reports impaired gait and posture parameters as compared to the general population, especially following use of the anterior minimally invasive approach, which has more severe impact on posture than the posterior approach. The reasons for this impairment, however, remain unexplained. We therefore conducted a surface electromyography (sEMG) study of the hip muscles liable to be affected by arthroplasty surgery: gluteus maximus (GMax), gluteus medius (GMed), tensor fasciae latae (TFL), and sartorius (S). The study addressed the following questions: (1) Is bipodal and unipodal GMed activity greater following anterior THA than in asymptomatic subjects? (2) Is a single manual test sufficient to assess maximal voluntary contraction (MVC) in hip abductors (GMax, GMed, TFL) and flexors (TFL, S)? HYPOTHESIS: Bipodal and unipodal GMed activity is greater following anterior THA than in asymptomatic subjects. METHOD: Eleven patients with anterior THA and 11 asymptomatic subjects, matched for age, gender and body-mass index, were included. Subjects underwent 3 postural tests: bipodal, eyes closed (BEC), unipodal on the operated side (UOP), and unipodal on the non-operated side (UnOP), with unipodal results averaged between both sides in the asymptomatic subjects. Data were recorded from 4-channel EMG and a force plate. EMG test activity was normalized as a ratio of MVC activity. RESULTS: Postural parameters (mean center of pressure displacement speed) were poorer and sEMG activity higher in anterior THA than asymptomatic subjects (p<0.005). On the BEC test, GMax and GMed activity was higher on both operated and non-operated sides than in asymptomatic controls (respectively, 0.15±0.12 and 0.12±0.6 versus 0.07±0.06 for GMax, and 0.13±0.08 and 0.13±0.08 versus 0.08±0.05 for GMed; p<0.05). On unipodal tests, both UOP and UnOP GMed activities were higher than in controls (respectively, 0.51±0.3 and 0.48±0.27 versus 0.28±0.13; p<0.04); GMax and TFL activities were higher than in controls only on the UOP tests (respectively, 0.49±0.43 versus 0.24±0.18, and 0.23±0.17 versus 0.12±0.16; p<0.05). DISCUSSION: sEMG activity in the hip abductors, which are the main stabilizing muscles for the pelvis, is increased following anterior THA, in parallel with impaired postural parameters. This finding may be due to intraoperative TFL and S neuromuscular spindle lesion. The present preliminary study is to be followed up by a comparison of all 3 common minimally invasive approaches (anterior, anterolateral and posterior) using the same study protocol. LEVEL OF EVIDENCE: III, prospective case-control study.

Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis.

Venous thromboembolism is a complex disease with a high heritability. There are significant associations among Factor XI (FXI) levels and SNPs in the KNG1 and F11 loci. Our aim was to identify the genetic variation of KNG1 and F11 that might account for the variability of FXI levels. The KNG1 and F11 loci were sequenced completely in 110 unrelated individuals from the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) Project using Next Generation Sequencing on an Illumina MiSeq. The GAIT-2 Project is a study of 935 individuals in 35 extended Spanish families selected through a proband with idiopathic thrombophilia. Among the 110 individuals, a subset of 40 individuals was chosen as a discovery sample for identifying variants. A total of 762 genetic variants were detected. Several significant associations were established among common variants and low-frequency variants sets in KNG1 and F11 with FXI levels using the PLINK and SKAT packages. Among these associations, those of rs710446 and five low-frequency variant sets in KNG1 with FXI level variation were significant after multiple testing correction and permutation. Also, two putative pathogenic mutations related to high and low FXI levels were identified by data filtering and in silico predictions. This study of KNG1 and F11 loci should help to understand the connection between genotypic variation and variation in FXI levels. The functional genetic variants should be useful as markers of thromboembolic risk.

The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway-Related Traits: Exploring Metaphenotypes.

Traditional genetic studies of single traits may be unable to detect the pleiotropic effects involved in complex diseases. To detect the correlation that exists between several phenotypes involved in the same biological process, we introduce an original methodology to analyze sets of correlated phenotypes involved in the coagulation cascade in genome-wide association studies. The methodology consists of a two-stage process. First, we define new phenotypic meta-variables (linear combinations of the original phenotypes), named metaphenotypes, by applying Independent Component Analysis for the multivariate analysis of correlated phenotypes (i.e. the levels of coagulation pathway-related proteins). The resulting metaphenotypes integrate the information regarding the underlying biological process (i.e. thrombus/clot formation). Secondly, we take advantage of a family based Genome Wide Association Study to identify genetic elements influencing these metaphenotypes and consequently thrombosis risk. Our study utilized data from the GAIT Project (Genetic Analysis of Idiopathic Thrombophilia). We obtained 15 metaphenotypes, which showed significant heritabilities, ranging from 0.2 to 0.7. These results indicate the importance of genetic factors in the variability of these traits. We found 4 metaphenotypes that showed significant associations with SNPs. The most relevant were those mapped in a region near the HRG, FETUB and KNG1 genes. Our results are provocative since they show that the KNG1 locus plays a central role as a genetic determinant of the entire coagulation pathway and thrombus/clot formation. Integrating data from multiple correlated measurements through metaphenotypes is a promising approach to elucidate the hidden genetic mechanisms underlying complex diseases.

Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project.

BACKGROUND: Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE. OBJECTIVES: To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE. PATIENTS/METHODS: Lag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes. RESULTS: The results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed. CONCLUSIONS: The thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results.