Weakly Supervised Learning by a Confusion Matrix of Contexts

© 2019, Springer Nature Switzerland AG. Context consideration can help provide more background and related information for weakly supervised learning. The inclusion of less documented historical and environmental context in researching diabetes amongst Pima Indians uncovered reasons which were more likely to explain why some Pima Indians had much higher rates of diabetes than Caucasians, primarily due to historical, environmental and social causes rather than their specific genetic patterns or ethnicity as suggested by many medical studies. If historical and environmental factors are considered as external contexts when not included as part of a dataset for research, some forms of internal contexts may also exist inside the dataset without being declared. This paper discusses a context construction model that transforms a confusion matrix into a matrix of categorical, incremental and correlational context to emulate a kind of internal context to search for more informative patterns in order to improve weakly supervised learning from limited labeled samples for unlabeled data. When the negative and positive labeled samples and misclassification errors are compared to “happy families” and “unhappy families”, the contexts constructed by this model in the classification experiments reflected the Anna Karenina principle well - “Happy families are all alike; every unhappy family is unhappy in its own way”, an encouraging sign to further explore contexts associated with harmonizing patterns and divisive causes for knowledge discovery in a world of uncertainty

Is Lamarckian evolution relevant to medicine?

BACKGROUND: 200 years have now passed since Darwin was born and scientists around the world are celebrating this important anniversary of the birth of an evolutionary visionary. However, the theories of his colleague Lamarck are treated with considerably less acclaim. These theories centre on the tendency for complexity to increase in organisms over time and the direct transmission of phenotypic traits from parents to offspring. DISCUSSION: Lamarckian concepts, long thought of no relevance to modern evolutionary theory, are enjoying a quiet resurgence with the increasing complexity of epigenetic theories of inheritance. There is evidence that epigenetic alterations, including DNA methylation and histone modifications, are transmitted transgenerationally, thus providing a potential mechanism for environmental influences to be passed from parents to offspring: Lamarckian evolution. Furthermore, evidence is accumulating that epigenetics plays an important role in many common medical conditions. SUMMARY: Epigenetics allows the peaceful co-existence of Darwinian and Lamarckian evolution. Further efforts should be exerted on studying the mechanisms by which this occurs so that public health measures can be undertaken to reverse or prevent epigenetic changes important in disease susceptibility. Perhaps in 2059 we will be celebrating the anniversary of both Darwin and Lamarck

Nonuniform Cardiac Denervation Observed by 11C-meta-Hydroxyephedrine PET in 6-OHDA-Treated Monkeys

Parkinson's disease presents nonmotor complications such as autonomic dysfunction that do not respond to traditional anti-parkinsonian therapies. The lack of established preclinical monkey models of Parkinson's disease with cardiac dysfunction hampers development and testing of new treatments to alleviate or prevent this feature. This study aimed to assess the feasibility of developing a model of cardiac dysautonomia in nonhuman primates and preclinical evaluations tools. Five rhesus monkeys received intravenous injections of 6-hydroxydopamine (total dose: 50 mg/kg). The animals were evaluated before and after with a battery of tests, including positron emission tomography with the norepinephrine analog 11C-meta-hydroxyephedrine. Imaging 1 week after neurotoxin treatment revealed nearly complete loss of specific radioligand uptake. Partial progressive recovery of cardiac uptake found between 1 and 10 weeks remained stable between 10 and 14 weeks. In all five animals, examination of the pattern of uptake (using Logan plot analysis to create distribution volume maps) revealed a persistent region-specific significant loss in the inferior wall of the left ventricle at 10 (P<0.001) and 14 weeks (P<0.01) relative to the anterior wall. Blood levels of dopamine, norepinephrine (P<0.05), epinephrine, and 3,4-dihydroxyphenylacetic acid (P<0.01) were notably decreased after 6-hydroxydopamine at all time points. These results demonstrate that systemic injection of 6-hydroxydopamine in nonhuman primates creates a nonuniform but reproducible pattern of cardiac denervation as well as a persistent loss of circulating catecholamines, supporting the use of this method to further develop a monkey model of cardiac dysautonomia

Ideal timing to transfer from an acute care hospital to an interdisciplinary inpatient rehabilitation program following a stroke: an exploratory study

BACKGROUND: Timely accessibility to organized inpatient stroke rehabilitation services may become compromised since the demand for rehabilitation services following stroke is rapidly growing with no promise of additional resources. This often leads to prolonged lengths of stays in acute care facilities for individuals surviving a stroke. It is believed that this delay spent in acute care facilities may inhibit the crucial motor recovery process taking place shortly after a stroke. It is important to document the ideal timing to initiate intensive inpatient stroke rehabilitation after the neurological event. Therefore, the objective of this study was to examine the specific influence of short, moderate and long onset-admission intervals (OAI) on rehabilitation outcomes across homogeneous subgroups of patients who were admitted to a standardized interdisciplinary inpatient stroke rehabilitation program. METHODS: A total of 418 patients discharged from the inpatient neurological rehabilitation program at the Montreal Rehabilitation Hospital Network after a first stroke (79% of all cases reviewed) were included in this retrospective study. After conducting a matching procedure across these patients based on the degree of disability, gender, and age, a total of 40 homogeneous triads (n = 120) were formed according to the three OAI subgroups: short (less than 20 days), moderate (between 20 and 40 days) or long (over 40 days; maximum of 70 days) OAI subgroups. The rehabilitation outcomes (admission and discharge Functional Independence Measure scores (FIM), absolute and relative FIM gain scores, rehabilitation length of stay, efficiency scores) were evaluated to test for differences between the three OAI subgroups. RESULTS: Analysis revealed that the three OAI subgroups were comparable for all rehabilitation outcomes studied. No statistical difference was found for admission (P = 0.305–0.972) and discharge (P = 0.083–0.367) FIM scores, absolute (P = 0.533–0.647) and relative (P = 0.496–0.812) FIM gain scores, rehabilitation length of stay (P = 0.096), and efficiency scores (P = 0.103–0.674). CONCLUSION: OAI does not seem to affect significantly inpatient stroke rehabilitation outcomes of patients referred from acute care facilities where rehabilitation services are rapidly initiated after the onset of the stroke and offered throughout their stay. However, other studies considering factors such as the type and intensity of the rehabilitation are required to support those results

A computational approach to identify point mutations associated with occult hepatitis B: significant mutations affect coding regions but not regulative elements of HBV

<p>Abstract</p> <p>Background</p> <p>Occult Hepatitis B Infection (OBI) is characterized by absence of serum HBsAg and persistence of HBV-DNA in liver tissue, with low to undetectable serum HBV-DNA. The mechanisms underlying OBI remain to be clarified. To evaluate if specific point mutations of HBV genome may be associated with OBI, we applied an approach based on bioinformatics analysis of complete genome HBV sequences. In addition, the feasibility of bioinformatics prediction models to classify HBV infections into OBI and non-OBI by molecular data was evaluated.</p> <p>Methods</p> <p>41 OBI and 162 non-OBI complete genome sequences were retrieved from GenBank, aligned and subjected to univariable analysis including statistical evaluation. Their S coding region was analyzed for Stop codon mutations too, while S amino acid variability could be evaluated for genotype D only, due to the too small number of available complete genome OBI sequences from other genotypes.</p> <p>Prediction models were derived by multivariable analysis using Logistic Regression, Rule Induction and Random Forest approaches, with extra-sample error estimation by Multiple ten-fold Cross-Validation (MCV). Models were compared by t-test on the Area Under the Receiver Operating Characteristic curve (AUC) distributions obtained from the MCV runs for each model against the best-performing model.</p> <p>Results</p> <p>Variations in seven nucleotide positions were significantly associated with OBI, and occurred in 11 out of 41 OBI sequences (26.8%): likely, other mutations did not reach statistical significance due to the small size of OBI dataset. All variations affected at least one HBV coding region, but none of them mapped to regulative elements. All viral proteins, with the only exception of the X, were affected. Stop codons in the S, that might account for absence of serum HBsAg, were not significantly enriched in OBI sequences. In genotype D, amino acid variability in the S was higher in OBI than non-OBI, particularly in the immunodominant region. A Random Forest prediction model showed the best performance, but all models were not satisfactory in terms of specificity, due to the small sample size of OBIs; however results are promising in the perspective of a broader dataset of complete genome OBI sequences.</p> <p>Conclusions</p> <p>Data suggest that point mutations rarely occur in regulative elements of HBV, if ever, and contribute to OBI by affecting different viral proteins, suggesting heterogeneous mechanisms may be responsible for OBI, including, at least in genotype D, an escape mutation mechanism due to imperfect immune control. It appears possible to derive prediction models based on molecular data when a larger set of complete genome OBI sequences will become available.</p

Backward walking training improves balance in school-aged boys

<p>Abstract</p> <p>Background</p> <p>Falls remain a major cause of childhood morbidity and mortality. It is suggested that backward walking (BW) may offer some benefits especially in balance and motor control ability beyond those experienced through forward walking (FW), and may be a potential intervention for prevention of falls. The objective of this study was to investigate the effects of BW on balance in boys.</p> <p>Methods</p> <p>Sixteen healthy boys (age: 7.19 ± 0.40 y) were randomly assigned to either an experimental or a control group. The experimental group participated in a BW training program (12-week, 2 times weekly, and 25-min each time) but not the control group. Both groups had five dynamic balance assessments with a Biodex Stability System (anterior/posterior, medial/lateral, and overall balance index) before, during and after the training (week- 0, 4, 8, 12, 24). Six control and six experimental boys participated in a study comparing kinematics of lower limbs between FW and BW after the training (week-12).</p> <p>Results</p> <p>The balance of experimental group was better than that of control group after 8 weeks of training (<it>P </it>< 0.01), and was still better than that of control group (<it>P </it>< 0.05), when the BW training program had finished for 12 weeks. The kinematic analysis indicated that there was no difference between control and experimental groups in the kinematics of both FW and BW gaits after the BW training (<it>P </it>> 0.05). Compared to FW, the duration of stance phase of BW tended to be longer, while the swing phase, stride length, walking speed, and moving ranges of the thigh, calf and foot of BW decreased (<it>P </it>< 0.01).</p> <p>Conclusion</p> <p>Backward walking training in school-aged boys can improve balance.</p

Genetic background determines response to hemostasis and thrombosis

BACKGROUND: Thrombosis is the fatal and disabling consequence of cardiovascular diseases, the leading cause of mortality and morbidity in Western countries. Two inbred mouse strains, C57BL/6J and A/J, have marked differences in susceptibility to obesity, atherosclerosis, and vessel remodeling. However, it is unclear how these diverse genetic backgrounds influence pathways known to regulate thrombosis and hemostasis. The objective of this study was to evaluate thrombosis and hemostasis in these two inbred strains and determine the phenotypic response of A/J chromosomes in the C57BL/6J background. METHODS: A/J and C57Bl/6J mice were evaluated for differences in thrombosis and hemostasis. A thrombus was induced in the carotid artery by application of the exposed carotid to ferric chloride and blood flow measured until the vessel occluded. Bleeding and rebleeding times, as surrogate markers for thrombosis and hemostasis, were determined after clipping the tail and placing in warm saline. Twenty-one chromosome substitution strains, A/J chromosomes in a C57BL/6J background, were screened for response to the tail bleeding assay. RESULTS: Thrombus occlusion time was markedly decreased in the A/J mice compared to C57BL/6J mice. Tail bleeding time was similar in the two strains, but rebleeding time was markedly increased in the A/J mice compared to C57BL/6J mice. Coagulation times and tail morphology were similar, but tail collagen content was higher in A/J than C57BL/6J mice. Three chromosome substitution strains, B6-Chr5(A/J), B6-Chr11(A/J), and B6-Chr17(A/J), were identified with increased rebleeding time, a phenotype similar to A/J mice. Mice heterosomic for chromosomes 5 or 17 had rebleeding times similar to C57BL/6J mice, but when these two chromosome substitution strains, B6-Chr5(A/J )and B6-Chr17(A/J), were crossed, the A/J phenotype was restored in these doubly heterosomic progeny. CONCLUSION: These results indicate that susceptibility to arterial thrombosis and haemostasis is remarkably different in C57BL/and A/J mice. Three A/J chromosome substitution strains were identified that expressed a phenotype similar to A/J for rebleeding, the C57Bl/6J background could modify the A/J phenotype, and the combination of two A/J QTL could restore the phenotype. The diverse genetic backgrounds and differences in response to vascular injury induced thrombosis and the tail bleeding assay, suggest the potential for identifying novel genetic determinants of thrombotic risk

A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history.

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS

Tipping points in the dynamics of speciation.

Speciation can be gradual or sudden and involve few or many genetic changes. Inferring the processes generating such patterns is difficult, and may require consideration of emergent and non-linear properties of speciation, such as when small changes at tipping points have large effects on differentiation. Tipping points involve positive feedback and indirect selection stemming from associations between genomic regions, bi-stability due to effects of initial conditions and evolutionary history, and dependence on modularity of system components. These features are associated with sudden 'regime shifts' in other cellular, ecological, and societal systems. Thus, tools used to understand other complex systems could be fruitfully applied in speciation research