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| 2. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 3. |
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| 4. |
- de Jong, S, et al.
(författare)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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| 5. |
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| 6. |
- Romagnoni, A, et al.
(författare)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Tidskriftsartikel (refereegranskat)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 9. |
- Loza, M. J., et al.
(författare)
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Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study
- 2016
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. Trial registration:NCT01274507(ADEPT), registered October 28, 2010 and NCT01982162(U-BIOPRED), registered October 30, 2013.
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| 12. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 13. |
- Dadoo, Sahil, et al.
(författare)
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Low-Volume Surgeons Use Allograft in Younger Patients and Show Greater Rates of Revision Following Primary Allograft Anterior Cruciate Ligament Reconstruction Compared With High-Volume Surgeons.
- 2023
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Ingår i: Arthroscopy, sports medicine, and rehabilitation. - 2666-061X. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- To determine whether surgeon volume affects revision rate following primary anterior cruciate ligament reconstruction (ACLR) with allograft and to determine whether surgeon volume impacts allograft tissue type used.All patients aged 14 years or older who underwent primary allograft ACLR at a large hospital system between January 2015 to December 2019 with minimum 2-year follow-up were included. Patients with double-bundle ACLR, multiligament reconstruction, and absent allograft type data were excluded. Surgeon volume was categorized as 35 or more ACLR/year for high-volume surgeons and less than 35 ACLR/year for low-volume surgeons. Revision was defined as subsequent ipsilateral ACLR. Patient characteristics, operative details, allograft type, and revision ACLR rates were retrospectively collected. Revision rate and allograft type were analyzed based on surgeon volume.A total of 457 primary allograft ACLR cases (mean age: 38.8 ± 12.3 years) were included. Low-volume surgeons experienced greater revision rates (10% vs 5%, P= .04) and used allograft in a younger population (37.6 vs 40.0 years old, P= .03) than high-volume surgeons. Subgroup analysis of the total cohort identified a significantly increased failure rate in patients <25 years old compared with ≥25 years old (30% vs 4%, P < .001). Allograft type selection varied significantly between surgeon volume groups, with low-volume surgeons using more bone-patellar tendon-bone (P < .001) and less semitendinosus allograft (P= .01) than high-volume surgeons. No differences in revision rate were observed based on allograft type (P= .71).There was a greater revision rate following primary allograft ACLR among low-volume surgeons compared with high-volume surgeons. Low-volume surgeons also used allograft in a younger population than did high-volume surgeons.Level III, retrospective comparative prognostic trial.
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| 14. |
- Engler, Ian D, et al.
(författare)
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Revision Rates After Primary Allograft ACL Reconstruction by Allograft Tissue Type in Older Patients.
- 2023
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Ingår i: Orthopaedic journal of sports medicine. - 2325-9671. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- While there is extensive literature on the use of allograft versus autograft in anterior cruciate ligament (ACL) reconstruction, there is limited clinical evidence to guide the surgeon in choice of allograft tissue type.To assess the revision rate after primary ACL reconstruction with allograft and to compare revision rates based on allograft tissue type and characteristics.Cohort study; Level of evidence, 3.Patients who underwent primary allograft ACL reconstructions at a single academic institution between 2015 and 2019 and who had minimum 2-year follow-up were included. Exclusion criteria were missing surgical or allograft tissue type data. Demographics, operative details, and subsequent surgical procedures were collected. Allograft details included graft tissue type (Achilles, bone-patellar tendon-bone [BTB], tibialis anterior or posterior, semitendinosus, unspecified soft tissue), allograft category (all-soft tissue vs bone block), donor age, irradiation duration and intensity, and chemical cleansing process. Revision rates were calculated and compared by allograft characteristics.Included were 418 patients (age, 39 ± 12years; body mass index, 30 ± 9kg/m2). The revision rate was 3% (11/418) at a mean follow-up of 4.9 ± 1.4years. There were no differences in revision rate according to allograft tissue type across Achilles tendon (3%; 3/95), BTB (5%; 3/58), tibialis anterior or posterior (3%; 5/162), semitendinosus (0%; 0/46), or unspecified soft tissue (0%; 0/57) (P = .35). There was no difference in revision rate between all-soft tissue versus bone block allograft (6/283 [2%] vs 5/135 [4%], respectively; P = .34). Of the 51% of grafts with irradiation data, all grafts were irradiated, with levels varying from 1.5 to 2.7 Mrad and 82% of grafts having levels of <2.0 Mrad. There was no difference in revision rate between the low-dose and medium-to high-dose irradiation cohorts (4% vs 6%, respectively; P = .64).Similarly low (0%-6%) revision rates after primary ACL reconstruction were seen regardless of allograft tissue type, bone block versus all-soft tissue allograft, and sterilization technique in 418 patients with mean age of 39 years. Surgeons may consider appropriately processed allograft tissue with or without bone block when indicating ACL reconstruction in older patients.
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| 15. |
- Greiner, Justin J., et al.
(författare)
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Factors Associated With Knee Extension Strength Symmetry After Anterior Cruciate Ligament Reconstruction With Quadriceps Tendon Autograft
- 2024
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Ingår i: ORTHOPAEDIC JOURNAL OF SPORTS MEDICINE. - 2325-9671. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diminished postoperative knee extension strength may occur after anterior cruciate ligament reconstruction (ACLR) with quadriceps tendon (QT) autograft. Factors influencing the restoration of knee extensor strength after ACLR with QT autograft remain undefined. Purpose: To identify factors that influence knee extensor strength after ACLR with QT autograft. Study Design: Case-control study; Level of evidence, 3. Methods: The authors performed a retrospective review of patients who underwent primary ACLR with QT autograft at a single institution between 2010 and 2021. Patients were included if they completed electromechanical dynamometer testing at least 6 months after surgery. Exclusion criteria consisted of revision ACLR, <6 months of follow-up, concomitant procedure (osteotomy, cartilage restoration), and concomitant ligamentous injury requiring surgery. Knee extension limb symmetry index (LSI) was obtained by comparing the peak torque of the operated and nonoperated extremities. Univariable and multivariable analyses were performed to identify factors associated with knee extension LSI in the patient, injury, rehabilitation, and preoperative patient-reported outcomes score domains. Results: A total of 107 patients (58 male; mean age, 22.8 years) were included. Mean knee extension LSI of the overall cohort was 0.82 +/- 0.18 at 7.5 +/- 2.0 months; 35 patients (33%) had a value of >= 0.90. Multivariable analysis demonstrated significant negative associations between knee extension LSI and female sex (-0.12; P < .001), increased age at the time of surgery (-0.01; P = .018), and larger QT graft width (-0.049; P = .053). Conclusion: Factors influencing knee extensor LSI after ACLR with QT autograft in this study population spanned patient and surgical factors, including female sex, older age at the time of surgery, and wider graft harvest. Surgeons should consider the association between these factors and lower postoperative knee extensor LSI to optimize patient outcomes.
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| 16. |
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| 17. |
- Kaarre, Janina, 1996, et al.
(författare)
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Strength symmetry after autograft anterior cruciate ligament reconstruction.
- 2024
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Ingår i: Journal of ISAKOS : joint disorders & orthopaedic sports medicine. - 2059-7762. ; 9:1, s. 3-8
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Tidskriftsartikel (refereegranskat)abstract
- To compare postoperative isometric quadriceps strength indices (QI%) and hamstring strength limb symmetry indices (HI%) between partial thickness quadriceps tendon (pQT), full thickness quadriceps tendon (fQT), and bone-patellar-tendon bone (BPTB) autograft anterior cruciate ligament reconstruction (ACLR).Patients with primary ACLR with pQT, fQT, or BPTB autograft with the documentation of quantitative postoperative strength assessments between 2016 and 2021 were included. Isometric Biodex data, including QI% and HI% (calculated as the percentage of involved to uninvolved limb strength) were collected between 5 and 8 months and between 9 and 15 months postoperatively.In total, 124 and 51 patients had 5-8- and 9-15-month follow-up strength data, respectively. No significant difference was detected between groups for sex. However, patients undergoing fQT were found to be older than those undergoing BPTB (24.6±7 vs 20.2±5;p = 0.01). There were no significant differences in the number of concomitant meniscus repairs between the groups (pQT vs. fQT vs. BPTB). No significant differences were detected in median (min-max) QI% between pQT, fQT, and BPTB 5-8 months [87% (44%-130%), 84% (44%-110%), 82% (37%-110%) or 9-15 months [89% (50%-110%), 89% (67%-110%), and 90% (74%-140%)] postoperatively. Similarly, no differences were detected in median HI% between the groups 5-8 months or 9-15 months postoperatively.The study was unable to detect differences in the recovery of quadriceps strength between patients undergoing ACLR with pQT, fQT, and BPTB autografts at 5-8 months and 9-15-months postoperatively.III.
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| 18. |
- Lian, Jayson, et al.
(författare)
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Rotatory Knee Laxity Exists on a Continuum in Anterior Cruciate Ligament Injury.
- 2020
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Ingår i: The Journal of bone and joint surgery. American volume. - 1535-1386. ; 102:3, s. 213-220
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this investigation was to compare the magnitude of rotatory knee laxity in patients with a partial anterior cruciate ligament (ACL) tear, those with a complete ACL tear, and those who had undergone a failed ACL reconstruction. It was hypothesized that rotatory knee laxity would increase with increasing injury grade, with knees with partial ACL tears demonstrating the lowest rotatory laxity and knees that had undergone failed ACL reconstruction demonstrating the highest rotatory laxity.A prospective multicenter study cohort of 354 patients who had undergone ACL reconstruction between 2012 and 2018 was examined. All patients had both injured and contralateral healthy knees evaluated using standardized, preoperative quantitative pivot shift testing, determined by a validated, image-based tablet software application and a surface-mounted accelerometer. Quantitative pivot shift was compared with the contralateral healthy knee in 20 patients with partial ACL tears, 257 patients with complete ACL tears, and 27 patients who had undergone a failed ACL reconstruction. Comparisons were made using 1-way analysis of variance (ANOVA) with post hoc 2-sample t tests with Bonferroni correction. Significance was set at p < 0.05.There were stepwise increases in side-to-side differences in quantitative pivot shift in terms of lateral knee compartment translation for patients with partial ACL tears (mean [and standard deviation], 1.4 ± 1.5 mm), those with complete ACL tears (2.5 ± 2.1 mm), and those who had undergone failed ACL reconstruction (3.3 ± 1.9 mm) (p = 0.01) and increases in terms of lateral compartment acceleration for patients with partial ACL tears (0.7 ± 1.4 m/s), those with complete ACL tears (2.3 ± 3.1 m/s), and those who had undergone failed ACL reconstruction (2.4 ± 5.5 m/s) (p = 0.01). A significant difference in lateral knee compartment translation was found when comparing patients with partial ACL tears and those with complete ACL tears (1.2 ± 2.1 mm [95% confidence interval (CI), 0.2 to 2.1 mm]; p = 0.02) and patients with partial ACL tears and those who had undergone failed ACL reconstruction (1.9 ± 1.7 mm [95% CI, 0.8 to 2.9 mm]; p = 0.001), but not when comparing patients with complete ACL tears and those who had undergone failed ACL reconstruction (0.8 ± 2.1 [95% CI, -0.1 to 1.6 mm]; p = 0.09). Increased lateral compartment acceleration was found when comparing patients with partial ACL tears and those with complete ACL tears (1.5 ± 3.0 m/s [95% CI, 0.8 to 2.3 m/s]; p = 0.0002), but not when comparing patients with complete ACL tears and those who had undergone failed ACL reconstruction (0.1 ± 3.4 m/s [95% CI, -2.2 to 2.4 m/s]; p = 0.93) or patients with partial ACL tears and those who had undergone failed ACL reconstruction (1.7 ± 4.2 m/s [95% CI, -0.7 to 4.0 m/s]; p = 0.16). An increasing lateral compartment translation of the contralateral, ACL-healthy knee was found in patients with partial ACL tears (0.8 mm), those with complete ACL tears (1.2 mm), and those who had undergone failed ACL reconstruction (1.7 mm) (p < 0.05).A progressive increase in rotatory knee laxity, defined by side-to-side differences in quantitative pivot shift, was observed in patients with partial ACL tears, those with complete ACL tears, and those who had undergone failed ACL reconstruction. These results may be helpful when assessing outcomes and considering indications for the management of high-grade rotatory knee laxity.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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