Estimating parameters in genetic diseases requires efficient algorithms to compute likelihood of genetic models in pedigrees. The Elston-Stewart algorithm allows to compute pedigree likelihoods with ...a complexity O(n x gtw) where n is the number of individuals, g is the number of genotypes, tw is the tree-width of the pedigree (tw = 3 to 5 for standard families). Computing first and second derivatives of the likelihood function is of great interest both to maximise the likelihood more efficiently, and to obtain confidence intervals on parameters. These derivatives can be computed numerically but this approach is slow and might lead to unstable computations. In this work, we present an extension of the Elston-Stewart algorithm combining Mendelian laws and polynomial arithmetic in order to obtain exact derivatives of the likelihood function. For a univariate model (one parameter to estimate) our algorithm computes derivatives up to the dth order with a multiplicative complexity factor of (d+1)(d+2)/2=O(d2 ) (3 for d = 1, 6 for d = 2). For a multivariate model with p parameters, we obtain the likelihood, the gradient, and the Hessian with a complexity factor of O(p2). We illustrate the interest of our algorithm with two classical models in genetic epidemiology: 1) in segregation analysis, order 2 multivariate likelihood derivatives allows to compute confidence interval jointly for penetrance parameters and disease allele frequencies; 2) for two-point linkage we establish the distribution of recombination rate estimates and derive pointwise confidence intervals for LOD scores.
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Background: Most of the BRCA1/2 and PALB2 analyses performed in patients with a personal and familial history (FH) of breast/ovarian cancer are negative. In this context, there ...is no targeted analysis available to identify relatives at high risk (carrier of the causal hypothetical mutated gene). Thus, the recommendations of surveillance to all relatives are based only on the FH of cancer. At the Institut Curie we assess the degree of severity of the FH by calculating the probability of carrying a single autosomal dominant susceptibility gene without taking into account genotyping results but using the LINKAGE software with the parameters of the Claus-Easton model (1993). This reliable but old tool has a slow console interactive interface (roughly 15 min of clinicians time for each assessed family). Methods: We rewrite the model as a Bayesian network combining Mendelian genetics with classical survival analysis. All probabilistic computations are performed through belief propagation (sum-product algorithm) over real numbers or polynomials. The programming language is C++. Results: pCarrier is a modern and efficient implementation of the Claus-Easton model for clinicians with the following features: 1) fast non-interactive command line ( < 1s to process a previously registered family) combined with a graphical user-friendly interface; 2) computations dealing with monozygotic twins or loops without any human intervention (ex: loop breaking); 3) choice between the original discretized model (individual FH into 14 classes) and its continuous version (piecewise constant hazard); 4) marginal individual carrier distribution for all individuals in the pedigree; 5) joint distribution of the number of carriers among any group of individuals (ex: in the entire family, among the living only). Conclusions: pCarrier is experimented since January 2017 in the Institut Curie as a replacement of the existing tool and appears so far to be dramatically faster and easier to use for the clinicians, highly reliable (consistence with the existing tool), and able to provide new useful decision-making probabilities using the distribution of the number of carriers.
Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that ...additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95% CI: 1.01-5.06, p value = 0.04). Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
When considering a genetic disease with variable age at onset (e.g., familial amyloid neuropathy, cancers), computing the individual risk of the disease based on family history (FH) is of critical ...interest for both clinicians and patients. Such a risk is very challenging to compute because 1 the genotype X of the individual of interest is in general unknown, 2 the posterior distribution PX∣FH,T>t changes with t (T is the age at disease onset for the targeted individual), and 3 the competing risk of death is not negligible. In this work, we present modeling of this problem using a Bayesian network mixed with (right-censored) survival outcomes where hazard rates only depend on the genotype of each individual. We explain how belief propagation can be used to obtain posterior distribution of genotypes given the FH and how to obtain a time-dependent posterior hazard rate for any individual in the pedigree. Finally, we use this posterior hazard rate to compute individual risk, with or without the competing risk of death. Our method is illustrated using the Claus-Easton model for breast cancer. The competing risk of death is derived from the national French registry.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Complex regional pain syndrome (CRPS) is a rare neuropathic pain condition characterized by sensory, motor and autonomic alterations. Previous investigations have shown that transcranial direct ...current stimulation (tDCS) and transcutaneous electrical nerve stimulation (TENS) can alleviate pain in various populations, and that a combination of these treatments could provide greater hypoalgesic effects. In the present case report, we describe the effect of tDCS and TENS treatment on pain intensity and unpleasantness in a patient suffering from chronic CRPS.
The patient was a 37-year-old woman, suffering from left lower limb CRPS (type I) for more than 5 years. Despite medication (pregabalin, tapentadol, duloxetine), rehabilitation treatments (sensorimotor retraining, graded motor imagery) and spinal cord stimulation (SCS), the participant reported moderate to severe pain. Treatments of tDCS alone (performed with SCS turned off during tDCS application, 1 session/day, for 5 consecutive days) did not significantly decrease pain. Combining tDCS with TENS (SCS temporarily turned off during tDCS, 1 session/day, for 5 consecutive days) slightly reduced pain intensity and unpleasantness.
Our results suggest that combining tDCS and TENS could be a therapeutic strategy worth investigating further to relieve pain in chronic CRPS patients. Future studies should examine the efficacy of combined tDCS and TENS treatments in CRPS patients, and other chronic pain conditions, with special attention to the cumulative and long-term effects and its effect on function and quality of life.
Doctorat en psychologie (D. Ps)--Université du Québec à Trois-Rivières, 2005.
Comprend des réf. bibliogr.: f. 159-162. Également disponible en format microfiche et PDF.
PURPOSEComplex regional pain syndrome (CRPS) is a rare neuropathic pain condition characterized by sensory, motor and autonomic alterations. Previous investigations have shown that transcranial ...direct current stimulation (tDCS) and transcutaneous electrical nerve stimulation (TENS) can alleviate pain in various populations, and that a combination of these treatments could provide greater hypoalgesic effects. In the present case report, we describe the effect of tDCS and TENS treatment on pain intensity and unpleasantness in a patient suffering from chronic CRPS.RESULTSThe patient was a 37-year-old woman, suffering from left lower limb CRPS (type I) for more than 5 years. Despite medication (pregabalin, tapentadol, duloxetine), rehabilitation treatments (sensorimotor retraining, graded motor imagery) and spinal cord stimulation (SCS), the participant reported moderate to severe pain. Treatments of tDCS alone (performed with SCS turned off during tDCS application, 1 session/day, for 5 consecutive days) did not significantly decrease pain. Combining tDCS with TENS (SCS temporarily turned off during tDCS, 1 session/day, for 5 consecutive days) slightly reduced pain intensity and unpleasantness.DISCUSSIONOur results suggest that combining tDCS and TENS could be a therapeutic strategy worth investigating further to relieve pain in chronic CRPS patients. Future studies should examine the efficacy of combined tDCS and TENS treatments in CRPS patients, and other chronic pain conditions, with special attention to the cumulative and long-term effects and its effect on function and quality of life.
Digital Social Networks and Health CRAIG LEFEBVRE, R; BORNKESSEL, Alexandra S
Circulation (New York, N.Y.),
04/2013, Volume:
127, Issue:
17
Journal Article
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