Multiple sclerosis (MS) is a prevalent inflammatory disease of the central nervous system that often leads to disability in young adults. Treatment options are limited and often only partly ...effective. The disease is likely caused by a complex interaction between multiple genes and environmental factors, leading to inflammatory‐mediated central nervous system deterioration. A series of genomic studies have confirmed a central role for the immune system in the development of MS, including genetic association studies that have now dramatically expanded the roster of MS susceptibility genes beyond the longstanding human leukocyte antigen (HLA) association in MS first identified nearly 40 years ago. Advances in technology together with novel models for collaboration across research groups have enabled the discovery of more than 50 non‐HLA genetic risk factors associated with MS. However, with a large proportion of the disease heritability still unaccounted for, current studies are now geared towards identification of causal alleles, associated pathways, epigenetic mechanisms, and gene–environment interactions. This article reviews recent efforts in addressing the genetics of MS and the challenges posed by an ever increasing amount of analyzable data, which is spearheading development of novel statistical methods necessary to cope with such complexity.
Among the tools of regenerative medicine, induced pluripotent stem cells (iPSCs) are interesting because the donor genotype can be selected. The construction of banks of iPSC cell lines selected from ...human leukocyte antigen (HLA) homozygous donors has been proposed to be an effective way to match a maximal number of patients receiving cell therapy from iPSC lines. However, what effort would be required to constitute such a bank for a worldwide application has remained unexplored. We developed a probabilistic model to compute the number of donors to screen for constituting banks of best‐chosen iPSC lines with homozygous HLA haplotypes (haplobanks) in four ancestry backgrounds. We estimated what percentage of the patients would be provided with single HLA haplotype matched cell lines. Genetic diversity leads to different outcomes for the four sets in all terms. A bank comprising iPSC lines representing the 20 most frequent haplotypes in each population would request quite different number of donors to screen, between 26,000 for European Americans and 110,000 for African Americans. It would also match different fractions of the recipient population, namely, more than 50% of the European Americans and 22% of African Americans. Conversely, a bank comprising the 100 iPSC lines with the most frequent HLA in each population would leave out only 22% of the European Americans, but 37% of the Asians, 48% of the Hispanics, and 55% of the African Americans. The constitution of a haplobank of iPSC lines is achievable through a large‐scale concerted worldwide collaboration. STEM CELLS 2012; 30:180–186.
To understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases.
Certain basic epidemiological ...parameters of MS (e.g., population-prevalence of MS, recurrence-risks for MS in siblings and twins, proportion of women among MS patients, and the time-dependent changes in the sex-ratio) are well-established. In addition, more than 233 genetic-loci have now been identified as being unequivocally MS-associated, including 32 loci within the major histocompatibility complex (MHC), and one locus on the X chromosome. Despite this recent explosion in genetic associations, however, the association of MS with the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 (H+) haplotype has been known for decades.
We define the "genetically-susceptible" subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive "non-susceptible" subset (G-). Using these well-established epidemiological parameters, we analyze, mathematically, the implications that these observations have regarding the genetic-susceptibility to MS. In addition, we use the sex-ratio change (observed over a 35-year interval in Canada), to derive the relationship between MS-probability and an increasing likelihood of a sufficient environmental exposure.
We demonstrate that genetic-susceptibitly is confined to less than 7.3% of populations throughout Europe and North America. Consequently, more than 92.7% of individuals in these populations have no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, far fewer than 32% can possibly be members the (G) subset. Also, despite the current preponderance of women among MS patients, women are less likely to be in the susceptible (G) subset and have a higher environmental threshold for developing MS compared to men. Nevertheless, the penetrance of MS in susceptible women is considerably greater than it is in men. Moreover, the response-curves for MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these environmental response-curves plateau at under 50% for women and at a significantly lower level for men.
The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population (< 7.3%) and requires specific combinations of non-additive genetic risk-factors. For example, only a minority of carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype are even in the (G) subset and, thus, genetic-susceptibility to MS in these carriers must result from the combined effect this haplotype together with the effects of certain other (as yet, unidentified) genetic factors. By itself, this haplotype poses no MS-risk. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the fact that environmental response-curves plateau well below 50% (especially in men), indicates that disease pathogenesis is partly stochastic. By extension, other diseases, for which monozygotic-twin recurrence-risks greatly exceed the disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent approaches in gait analysis involve the use of wearable motion sensors to extract spatio‐temporal parameters that characterize multiple aspects of an individual's gait. In particular, the ...medical community could largely benefit from this type of devices as they could provide the clinicians with a valuable tool for assessing gait impairment. Motion sensor data are however complex and there is an urgent unmet need to develop sound statistical methods for analyzing such data and extracting clinically relevant information. In this article, we measure gait by following the hip rotation over time and the resulting statistical unit is a time series of unit quaternions. We explore the possibility to form groups of patients with similar walking impairment by taking into account their walking data and their global decease severity with semi‐supervised clustering. We generalize a compromise‐based method named hclustcompro to unit quaternion time series by combining it with the proper dissimilarity quaternion dynamic time warping. We apply this method on patients diagnosed with multiple sclerosis to form groups of patients with similar walking deficiencies while accounting for the clinical assessment of their overall disability. We also compare the compromise‐based clustering approach with the method mergeTrees that falls into a sub‐class of ensemble clustering named collaborative clustering. The results provide a first proof of both the interest of using wearable motion sensors for assessing gait impairment and the use of prior knowledge to guide the clustering process. It also demonstrates that compromise‐based clustering is a more appropriate approach in this context.
To explore and describe the basis and implications of genetic and environmental susceptibility to multiple sclerosis (MS) using the Canadian population-based data.
Certain parameters of ...MS-epidemiology are directly observable (e.g., the recurrence-risk of MS in siblings and twins, the proportion of women among MS patients, the population-prevalence of MS, and the time-dependent changes in the sex-ratio). By contrast, other parameters can only be inferred from the observed parameters (e.g., the proportion of the population that is "genetically susceptible", the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment "sufficient" to cause MS, and if they do, the probability that they will develop the disease).
The "genetically susceptible" subset (G) of the population (Z) is defined to include everyone with any non-zero life-time chance of developing MS under some environmental conditions. The value for each observed and non-observed epidemiological parameter is assigned a "plausible" range. Using both a Cross-sectional Model and a Longitudinal Model, together with established parameter relationships, we explore, iteratively, trillions of potential parameter combinations and determine those combinations (i.e., solutions) that fall within the acceptable range for both the observed and non-observed parameters.
Both Models and all analyses intersect and converge to demonstrate that probability of genetic-susceptibitly, P(G), is limited to only a fraction of the population {i.e., P(G) ≤ 0.52)} and an even smaller fraction of women {i.e., P(G│F) < 0.32)}. Consequently, most individuals (particularly women) have no chance whatsoever of developing MS, regardless of their environmental exposure. However, for any susceptible individual to develop MS, requires that they also experience a "sufficient" environment. We use the Canadian data to derive, separately, the exponential response-curves for men and women that relate the increasing likelihood of developing MS to an increasing probability that a susceptible individual experiences an environment "sufficient" to cause MS. As the probability of a "sufficient" exposure increases, we define, separately, the limiting probability of developing MS in men (c) and women (d). These Canadian data strongly suggest that: (c < d ≤ 1). If so, this observation establishes both that there must be a "truly" random factor involved in MS pathogenesis and that it is this difference, rather than any difference in genetic or environmental factors, which primarily accounts for the penetrance difference between women and men.
The development of MS (in an individual) requires both that they have an appropriate genotype (which is uncommon in the population) and that they have an environmental exposure "sufficient" to cause MS given their genotype. Nevertheless, the two principal findings of this study are that: P(G) ≤ 0.52)} and: (c < d ≤ 1). Threfore, even when the necessary genetic and environmental factors, "sufficient" for MS pathogenesis, co-occur for an individual, they still may or may not develop MS. Consequently, disease pathogenesis, even in this circumstance, seems to involve an important element of chance. Moreover, the conclusion that the macroscopic process of disease development for MS includes a "truly" random element, if replicated (either for MS or for other complex diseases), provides empiric evidence that our universe is non-deterministic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genome‐wide associations studies have repeatedly identified the major histocompatibility complex genomic region (6p21.3) as key in immune pathologies. Researchers have also aimed to extend the ...biological interpretation of associations by focusing directly on human leukocyte antigen (HLA) polymorphisms and their combination as haplotypes. To circumvent the effort and high costs of HLA typing, statistical solutions have been developed to infer HLA alleles from single‐nucleotide polymorphism (SNP) genotyping data. Though HLA imputation methods have been developed, no unified effort has yet been undertaken to share large and diverse imputation models, or to improve methods. By training the HIBAG software on SNP + HLA data generated by the Consortium on Asthma among African‐ancestry Populations in the Americas (CAAPA) to create reference panels, we highlighted the importance of (a) the number of individuals in reference panels, with a twofold increase in accuracy (from 10 to 100 individuals) and (b) the number of SNPs, with a 1.5‐fold increase in accuracy (from 500 to 24,504 SNPs). Results showed improved accuracy with CAAPA compared to the African American models available in HIBAG, highlighting the need for precise population‐matching. The SNP‐HLA Reference Consortium is an international endeavor to gather data, enhance HLA imputation and broaden access to highly accurate imputation models for the immunogenomics community.
Risk stratification of sudden cardiac arrest (SCA) in Brugada syndrome (Brs) remains the main challenge for physicians. Several scores have been suggested to improve risk stratification but never ...replicated. We aim to investigate the accuracy of the Brs risk scores.
A total of 1613 patients mean age 45 ± 15 years, 69% male, 323 (20%) symptomatic were prospectively enrolled from 1993 to 2016 in a multicentric database. All data described in the risk score were double reviewed for the study. Among them, all patients were evaluated with Shanghai score and 461 (29%) with Sieira score. After a mean follow-up of 6.5 ± 4.7 years, an arrhythmic event occurred in 75 (5%) patients including 16 SCA, 11 symptomatic ventricular arrhythmia, and 48 appropriate therapies. Predictive capacity of the Shanghai score (n = 1613) and the Sieira (n = 461) score was, respectively, estimated by an area under the curve of 0.73 (0.67-0.79) and 0.71 (0.61-0.81). Considering Sieira score, the event rate at 10 years was significantly higher with a score of 5 (26.4%) than with a score of 0 (0.9%) or 1 (1.1%) (P < 0.01). No statistical difference was found in intermediate-risk patients (score 2-4). The Shanghai score does not allow to better stratify the risk of SCA.
In the largest cohort of Brs patient ever described, risk scores do not allow stratifying the risk of arrhythmic event in intermediate-risk patient.
According to a meta-analysis of randomized clinical trials, paclitaxel-coated devices (PCDs) for lower limb endovascular revascularization may be associated with increased risk of late mortality.
The ...purpose of this study was to determine whether PCDs are associated with all-cause mortality in a real-world setting.
DETECT is a nationwide, exhaustive retrospective cohort study using medico-administrative data from the French National Healthcare System representing >99% of the population. The main selection criterion was the first procedure of interest: endovascular revascularization for lower limb peripheral artery disease involving ≥1 balloon and/or stent performed between October 1, 2011, and December 31, 2019. Patients with or without PCDs were compared for all-cause mortality until December 31, 2021.
A total of 259,137 patients were analyzed, with 20,083 (7.7%) treated with ≥1 PCD. After a median follow-up of 4.1 years (Q1-Q3: 2.3-6.4 years), a total of 5,385 deaths/73,923 person-years (PY) (7.3/100 PY) and 109,844 deaths/1,060,513 PY (10.4/100 PY) were observed in the PCD and control groups, respectively. After adjustment for confounding factors, PCD treatment was associated with a lower risk of mortality in multivariable Cox analyses (HR: 0.86; 95% CI: 0.84-0.89; P < 0.001). Similar results were observed using propensity score matching approaches based on either nearest-neighbor or exact matching.
In a nationwide analysis based on large-scale real-world data, exposure to PCDs was not associated with a higher risk of mortality in patients undergoing endovascular revascularization for lower limb peripheral artery disease. (The DETECT Project; NCT05254106)
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Objective:
We sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast‐enhancing lesions on brain magnetic resonance imaging (MRI) in relapsing multiple ...sclerosis (MS).
Methods:
EPIC is a 5‐year longitudinal MS cohort study at the University of California at San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. From the overall cohort, we evaluated patients with clinically isolated syndrome or relapsing–remitting MS at baseline. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking, and MS treatments) repeated measures analyses, annual 25‐hydroxyvitamin D levels were evaluated for their association with subsequent new T2‐weighted and gadolinium‐enhancing T1‐weighted lesions on brain MRI, clinical relapses, and disability (Expanded Disability Status Scale EDSS).
Results:
A total of 2,362 3T brain MRI scans were acquired from 469 subjects. In multivariate analyses, each 10ng/ml higher 25‐hydroxyvitamin D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio IRR, 0.85; 95% confidence interval CI, 0.76–0.95; p = 0.004) and a 32% lower risk of a gadolinium‐enhancing lesion (IRR, 0.68; 95% CI, 0.53–0.87; p = 0.002). Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (−0.047; 95% CI, −0.091 to −0.003; p = 0.037). Higher vitamin D levels were associated with lower, but not statistically significant, relapse risk. Except for the EDSS model, all associations were stronger when the within‐person change in vitamin D level was the predictor.
Interpretation:
Vitamin D levels are inversely associated with MS activity on brain MRI. These results provide further support for a randomized trial of vitamin D supplementation. ANN NEUROL 2012;72:234–240.
Acute rejection (AR) of corneal transplants (CT) has a profound effect on subsequent graft survival but detailed immunological studies in human CT recipients are lacking. In this multi‐site, ...cross‐sectional study, clinical details and blood samples were collected from adults with clinically diagnosed AR of full‐thickness (FT)‐CT (n = 35) and posterior lamellar (PL)‐CT (n = 21) along with Stable CT recipients (n = 177) and adults with non‐transplanted corneal disease (n = 40). For those with AR, additional samples were collected 3 months later. Immune cell analysis was performed by whole‐genome microarrays (whole blood) and high‐dimensional multi‐color flow cytometry (peripheral blood mononuclear cells). For both, no activation signature was identified within the B cell and T cell repertoire at the time of AR diagnosis. Nonetheless, in FT‐ but not PL‐CT recipients, AR was associated with differences in B cell maturity and regulatory CD4+ T cell frequency compared to stable allografts. These data suggest that circulating B cell and T cell subpopulations may provide insights into the regulation of anti‐donor immune response in human CT recipients with differing AR risk. Our results suggest that, in contrast to solid organ transplants, genetic or cellular assays of peripheral blood are unlikely to be clinically exploitable for prediction or diagnosis of AR.
This multi‐site study comparing the blood lymphocyte repertoire of patients with acutely rejecting corneal transplants, with stable corneal transplants, and with native corneal disease reveals no evidence of immune activation in rejection but differences in B cell maturation and regulatory T cell frequency
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