Empirical, free of genetic model, estimation of recurrence risks in multifactorial diseases: conditional probability approach]

Conditional probability approach in estimation of recurrence risks in sibships of different parental phenotypic matings with the different set of affected and normal siblings is considered. The formulae are presented for calculation of recurrence risks in cases of equal and different susceptibility of two sexes under different ways of sampling of family data: direct selection of offsprings through the parents; indirect selection of offsprings through affected siblings--the probands, under different ascertainment probability--from pi = 1.0 ("exhaustive selection") up to pi----0 ("single selection"); for the case of different susceptibility of the two sexes a possibility of the differences in the ascertainment probabilities of men (pi m) and of women (pi w) is allowed, unlike "independent ascertainment model", which requires the constancy of pi. The case of multiple incompatible subforms is considered for estimation of the recurrence risks of the specified subforms. The methods of the risks estimation proposed are free of genetic models being universal both for classical mendelian traits (with the constant risks) and for multifactorial ones (with variable risks).     

A likelihood approach to calculating risk support intervals.

Genetic risks are usually computed under the assumption that genetic parameters, such as the recombination fraction, are known without error. Uncertainty in the estimates of these parameters must translate into uncertainty regarding the risk. To allow for uncertainties in parameter values, one may employ Bayesian techniques or, in a maximum-likelihood framework, construct a support interval (SI) for the risk. Here we have implemented the latter approach. The SI for the risk is based on the SIs of parameters involved in the pedigree likelihood. As an empirical example, the SI for the risk was calculated for probands who are members of chronic spinal muscular atrophy kindreds. In order to evaluate the accuracy of a risk in genetic counseling situations, we advocate that, in addition to a point estimate, an SI for the risk should be calculated.     

Cardiovascular risk management of hypertension and hypercholesterolaemia in the Netherlands: from unifactorial to multifactorial approach

About 30?years ago, the first Dutch unifactorial guidelines on hypertension and hypercholesterolaemia were developed. These guidelines have been revised several times, often after publication of landmark studies on new generations of drugs. In 1978, cut-off points for pharmacological treatment of hypertension were based on diastolic blood pressure values ≥115?mmHg, and in 2000 they were lowered to >100?mmHg. From 1997 onwards, cut-off points for systolic blood pressure values >180?mmHg were introduced, which became leading. In 1987, cut-offs for hypercholesterolaemia of ≥8?mmol/l were set and from 2006 pharmacological treatment was based on a total/HDL cholesterol ratio >8. Around 2000, treatment decisions for hypertension and/or hypercholesterolaemia were no longer based on high levels of individual risk factors, but on a multifactorial approach based on total risk of cardiovascular diseases (CVD), determined by a risk function. In the 2006 multidisciplinary guideline on cardiovascular risk management, the Framingham risk tables were replaced by European SCORE risk charts. A cut-off point of 10% CVD mortality was set in the Netherlands. In 2011, this cut-off point changed to 20% fatal plus nonfatal CVD risk. Nowadays, 'the lower the risk factors, the lower the absolute risk' is the leading paradigm in CVD prevention.     

On the genetic contribution to selected multifactorial diseases with autoimmune characteristics.

The genetics of multifactorial diseases characterized by autoimmune phenomena are elusive so far. Yet, it is clear that the genetic contribution to a given clinically defined autoimmune disease entity is mostly variable and highly complex. On the basis of two basically different model diseases, Wegener's Granulomatosis and multiple sclerosis, approaches are discussed to unravel at least certain genetic predisposition factors. Major difficulties in these analyses arise from (in)exact definition of the clinical phenotype (disease entity), the vast number of potential candidate genes, the small to modest contribution of each genetic variation to disease risk and the combinatorial possibilities.     

CIDeR: multifactorial interaction networks in human diseases

ABSTRACT: The pathobiology of common diseases is influenced by heterogeneous factors interacting in complex networks. CIDeR http://mips.helmholtz-muenchen.de/cider/ is a publicly available, manually curated, integrative database of metabolic and neurological disorders. The resource provides structured information on 18,813 experimentally validated interactions between molecules, bioprocesses and environmental factors extracted from the scientific literature. Systematic annotation and interactive graphical representation of disease networks make CIDeR a versatile knowledge base for biologists, analysis of large-scale data and systems biology approaches.     

DNA polymorphism analysis in families with recurrence of free trisomy 21

We used DNA polymorphic markers on the long arm of human chromosome 21 in order to determine the parental and meiotic origin of the extra chromosome 21 in families with recurrent free trisomy 21. A total of 22 families were studied, 13 in which the individuals with trisomy 21 were siblings (category 1), four families in which the individuals with trisomy 21 were second-degree relatives (category 2), and five families in which the individuals with trisomy 21 were third-degree relatives, that is, their parents were siblings (category 3). In five category 1 families, parental mosaicism was detected, while in the remaining eight families, the origin of nondisjunction was maternal. In two of the four families of category 2 the nondisjunctions originated in individuals who were related. In only one of five category 3 families, the nondisjunctions originated in related individuals. These results suggest that parental mosaicism is an important etiologic factor in recurrent free trisomy 21 (5 of 22 families) and that chance alone can explain the recurrent trisomy 21 in many of the remaining families (14 of 22 families). However, in a small number of families (3 of 22), a familial predisposing factor or undetected mosaicism cannot be excluded.     

Assessment of the risk of recurrence isolated cases of dominantly inherited diseases with incomplete penetrance and age-related dependence

A modification of the method for risk estimation in isolated cases of autosomal dominant disorders with reduced penetrance is presented. It is based on the Bayesian theorem and considers such parameters as fitness, age-specific expressivity of the gene and the effect of parental age on mutation rate. The definite expression of the risk estimation is proposed. Using hereditary polyposis as an example, possible risks are proposed. The table of risks, depending on the parental age, is given.     

Laboratory approach to mitochondrial diseases

Dysfunction in mitochondrial processes has been related to several pathologies. In these disorders, the cell suffers oxidative imbalance that is mostly due to defects in pyruvate metabolism, mitochondrial fatty acids oxidation, the citric acid cycle or electron transport by the mitochondrial respiratory chain. These metabolic alterations produce mitochondrial diseases that have been related to inherited syndromes, such as MERRF or MELAS. The main affected organs are brain, skeletal muscle, kidney, heart and liver, because of the high energetic demand and the oxidative metabolism. Moreover, the relationship between mitochondrial dysfunction and neurodegenerative processes, such as Parkinson disease or Alzheimer disease, as well as ageing, has been shown. Because mitochondrias are the target of several xenobiotics, such as aspirin, AZT or alcohol consumption, motochondrial impairment has also been proposed as a mechanism of toxicity. Most laboratory tests that are available in the diagnosis of mitochondrial illness are assayed in tissue biopsies and are usually difficult to interpret. Recently, it has been shown that non-invasive techniques, such as nuclear magnetic resonance or the 2-keto [1-¹³C] isocaproic acid breath test, may be useful to assess mitochondrial function. This article attempts to show the laboratory approach to mitochondrial diseases, reviewing new techniques that could be of great value in the research of mitochondrial function, such as the 2-keto[1-¹³C]isocaproic breath test.     

Classification tree methods provide a multifactorial approach to predicting insular body size evolution in rodents

Many hypotheses have been proposed to explain size changes in insular mammals, but no single variable suffices to explain the diversity of responses, particularly within Rodentia. Here in a data set on insular rodents, we observe strong consistency in the direction of size change within islands and within species but (outside of Heteromyidae) little consistency at broader taxonomic scales. Using traits of islands and of species in a classification tree analysis, we find the most important factor predicting direction of change to be mainland body mass (large rodents decrease, small ones increase); other variables (island climate, number of rodent species, and area) were significant, although their roles as revealed by the classification tree were context dependent. Ecological interactions appear relatively uninformative, and on any given island, the largest and smallest rodent species converged or diverged in size with equal frequency. Our approach provides a promising framework for continuing examination of insular body size evolution.     

Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases

Abstract

The text describes a preventive clinical trial with drug treatment in a very rare neurodegenerative disease (Fatal familial Insomnia, FFI) designed with the help of individuals at genetic risk of developing the disease, asymptomatic carriers, who have agreed to be exposed over a 10-year period to doxycycline, an antibiotic with anti-prion activity. At least 10 carriers of the FFI mutation over 42 y old will be treated with doxycycline (100 mg/die) and the incidence of the disease will be compared to that of an historical dataset. For ethical reasons a randomized, double-blind, placebo-controlled trial was not feasible, however the study design and the statistical analysis ensure the scientific value of the results. This approach might represent an important breakthrough in terms of potential therapy and knowledge of rare diseases that could give some hopes to these neglected patients.     

Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases

The text describes a preventive clinical trial with drug treatment in a very rare neurodegenerative disease (Fatal familial Insomnia, FFI) designed with the help of individuals at genetic risk of developing the disease, asymptomatic carriers, who have agreed to be exposed over a 10-year period to doxycycline, an antibiotic with anti-prion activity. At least 10 carriers of the FFI mutation over 42 y old will be treated with doxycycline (100 mg/die) and the incidence of the disease will be compared to that of an historical dataset. For ethical reasons a randomized, double-blind, placebo-controlled trial was not feasible, however the study design and the statistical analysis ensure the scientific value of the results. This approach might represent an important breakthrough in terms of potential therapy and knowledge of rare diseases that could give some hopes to these neglected patients.     

Atherosclerosis risk factors in children of high risk families

The Objective of this study was to determine the frequency of care reactive atherosclerosis risk factors in children of parents with premature coronary heart disease observed before their 45 years of age for the promotion of the effectivity of the preventive work started in childhood and adolescent ages. METHODS: Height and weight was measured. Body mass index (BMI) was calculated. Fat analysis was performed in children with overweight. Blood pressure was measured and both 24 hour monitoring and fundoscopy were performed in cases with a blood pressure higher than 90 centile values. Fasting blood sugar (BS) level was measured. Oral glucose tolerance test was made in cases with a fasting BS level higher than 5 mmol/l. Serum total cholesterol (TC), HDL-cholesterol (HDLC) and total triglyceride (TT) levels were measured and LDL-cholesterol (LDLC) level was calculated. The plasma thiobarbituric acid reactive system (TBARS) was investigated. Statistical analyses were performed by chi2 and Student t-probes. Data of 1140 offsprings and 457 referents without any high atherosclerotic risk family history were analyzed. RESULTS: BMI of 87 offsprings was higher than the 90 centile value. The fat percent of the body of these children was higher than 40. The blood pressure of 311 children and adolescents was higher than the 90 centile value. Fasting BS level was higher than 5 mmol/l in 47 cases 17 of them showed a pathologic oral glucose tolerance test. High serum TC level was observed in 67 cases, high serum TT level was found in 8 cases. 245 offsprings had a low serum HDLC level. The plasma TBARS level was high in 241 cases. Data of referents differed significantly from those of offsprings. Their serum TC, LDLC levels and plasma TBARS level were lower, serum HDLC level was higher than that of children and adolescents with high risk atherosclerotic family history. CONCLUSION: Risk factors of atherosclerosis are detectable in children and adolescents of high risk families. The measurement of these factors may help the efficacy of the preventive work.     

Multivariate approach to the analysis of the growth processes in the peripuberty period of human ontogeny

Factor analysis by principal components with the Warimax rotation has been conducted on 26 anthropometric traits of 2200 children aged 6.75 to 17.25. Mean values of traits have been calculated at half-year intervals within each sex. Two orthogonal components accounting 96.5% of the total variation have been chosen. Individual factor values have been analysed to determine their relationship with age. The classification of objects is constructed by the cluster analysis in the space of factors. Four different morphological types within each sex have been found. The age limits between the revealed clusters differ for both sexes.     

A standardised approach to calculating floodplain tree condition to support environmental watering decisions

Ground-based visual assessment of crown condition is a cornerstone of tree condition assessment globally, and numerous condition assessment approaches have evolved to address the needs and perspectives of different users. In Australia’s iconic Murray–Darling Basin (MDB), stands of floodplain eucalypts are increasingly vulnerable to a range of interacting stressors related to climate change and over-extraction of water for consumptive and agricultural use. A standardised approach developed in 2008 for assessing floodplain trees within the MDB provides extensive guidance to ensure field data is collected consistently. However, there is minimal instruction on how to interpret data, and consequently a range of evaluation approaches have evolved. The lack of a standardised reporting framework generated by these different approaches makes it difficult for floodplain managers and environmental water holders to make repeatable, robust decisions for prioritising water allocations across competing locations. To provide improved lines of evidence to support decision making, this paper describes a ‘best-practise’ approach to calculating a tree condition score from field data. Within, we document existing approaches in the southern Murray–Darling Basin, and recommend a method that meets the needs of floodplain managers as a pragmatic reporting, communication and decision support tool that does not require statistical analysis. Case studies and a revised conceptual model of tree decline and recovery are provided to demonstrate the validity of the recommended approach.