Painful decisions: How classifying sensations can change the experience of pain.

BACKGROUND: Categorizing perceptual stimuli is a mechanism for facilitating the processing of sensory input from our environment. This facilitation of perception is achieved through generalization (assimilation) of stimulus characteristics within categories and accentuation between categories. These categorization processes have been demonstrated in visual, auditory, tactile and social perception, but never in pain perception. METHOD: We presented participants with six thermal noxious stimuli, increasing in steps of 0.5 °C. In an experimental group, stimuli were assigned to two categories labelled A and B containing the three lower (A1, A2, A3) and three higher (B1, B2, B3) stimuli. A control group did not receive such category information (stimuli were labelled S1-S6). In a first part of the experiment, participants simply rated pain intensity and unpleasantness for all stimuli. In a second part, we presented stimuli without labels and participants had to identify the label of each stimulus. RESULTS: We found evidence for categorization effects in both pain ratings and stimulus identification data. In particular, unpleasantness ratings within categories were more similar to each other, and ratings between categories less similar, in the experimental compared to control group. Participants in the experimental group also confused stimuli more often within than between categories, and were more confident about category membership of stimuli at the category border, compared to participants in the control group. CONCLUSIONS: Mere category information, using abstract category labels, significantly changes pain perception. Implications for our understanding of cognitive pain modulation mechanisms, as well as clinical implications of categorization effects are discussed. SIGNIFICANCE: Categorization effects in pain perception are demonstrated. Classifying and labelling painful events can modulate early perceptual processes, lead to under- or overestimation of pain symptoms and affect decision-making behaviour related to pain.

A BRCA1 founder mutation, identified with haplotype analysis, allowing genotype/phenotype determination and predictive testing.

We searched for a founder mutation in a population from one geographic region of Norway with prevalent breast/ovarian cancer families. We sampled 33 breast/ovarian cancer families and determined haplotypes of four markers linked to the BRCA1 region. Of the affected 33 index women, 13 (39.4%) shared one haplotype. In five (15% of total), an identical mutation was indicated by an abnormal truncated protein test (PTT) of exon 11 and shown to represent a 1675delA mutation. In the other index women, PTT of exon 11 showed no abnormality. No other BRCA1 founder mutation of this prevalence is likely because no other haplotype was more frequent in affecteds than in controls. All families with the 1675delA mutation in this geographic region may be considered as part of one large kindred. This allows a genotype-phenotype correlation to be precisely determined and used in genetic counselling for predictive testing within this kindred. Identification of identical haplotypes between unrelated affected individuals may be used to estimate the extent of founder effects for any mapped disease, without knowledge of the specific founder mutation.

Haplotype sharing analysis in affected individuals from nuclear families with at least one affected offspring.

In diseases with a complex mode of inheritance, families with multiple affected individuals are difficult to ascertain. The haplotype sharing statistic (HSS) uses (hidden) co-ancestry between affected individuals from a founder population. These affected individuals will likely not only share the same mutation(s), but also the surrounding haplotype. We show that this method gives a low false positive rate, but does not detect genes in the nuclear families of Problem 2A of the GAW data. We also give evidence based on simulations and empirical studies in real population based data that the HSS method has statistical power.

Genomic sharing surrounding alleles identical by descent: effects of genetic drift and population growth.

The number of identical deleterious mutations present in a population may become very large, depending on the combined effect of genetic drift, population growth and limited negative selection. The distribution of the length of the shared area between two random chromosomes carrying the mutations has been investigated for a number of generations varying from 20-100 since introduction. The consequences for investigations using association and haplotype sharing methods are discussed.

Recurrence risk for germinal mosaics revisited.

A formula to calculate recurrence risk for germline mosaicism published by Hartl in 1971 has been updated to include marker information. For practical genetic counselling new, more elaborate tables are given.

Perspectives of identity by descent (IBD) mapping in founder populations.

In a founder population patients with a genetic disease are likely to share predisposing genes from a common ancestor. We show that, depending on the distance of the relationship, patients are expected to share extended segments of DNA around the disease gene. Because of the size of the shared segment, a genomic search with DNA markers for such shared segments, identity by descent (IBD) mapping, can efficiently find the map position of genes, particularly due to genetic drift leading to reduction of heterogeneity and the large number of meioses that is implicitly observed. The statistical power of this method and the approximate cost are given as a function of the density of the map of tested markers and the number of generations since a common ancestor. Initial marker spacings between 5 and 15 centiMorgans are shown to be optimal. IBD mapping is applicable to many genetic diseases, because it does not presuppose a specific genetic model.

Linkage analysis by two-dimensional DNA typing.

In two-dimensional (2-D) DNA typing, genomic DNA fragments are separated, first according to size by electrophoresis in a neutral polyacrylamide gel and second according to sequence by denaturing gradient gel electrophoresis, followed by hybridization analysis using micro- and minisatellite core probes. The 2-D DNA typing method generates a large amount of information on polymorphic loci per gel. Here we demonstrate the potential usefulness of 2-D DNA typing in an empirical linkage study on the red factor in cattle, and we show an example of the 2-D DNA typing analysis of a human pedigree. The power efficiency of 2-D DNA typing in general is compared with that of single-locus typing by simulation. The results indicate that, although 2-D DNA typing is very efficient in generating data on polymorphic loci, its power to detect linkage is lower than single-locus typing, because it is not obvious whether a spot represents the presence of one or two alleles. It is possible to compensate for this lower informativeness by increasing the sample size. Genome scanning by 2-D DNA typing has the potential to be more efficient than current genotyping methods in scoring polymorphic loci. Hence, it could become a method of choice in mapping genetic traits in humans and animals.

Refinement by linkage analysis in two large families of the candidate region of the third locus (SCA3) for autosomal dominant cerebellar ataxia type I.

The autosomal dominant cerebellar ataxias (ADCA) are clinically and genetically heterogeneous. To date, several loci (SCAI-V) have been identified for ADCA type I. We have studied two large families from the northern part of The Netherlands with ADCA type I with a broad intra-familial variation of symptoms. In both families significant linkage is shown of the disease to the markers of the SCA3 locus on chromosome 14. Through recombinations, the candidate region for SCA3 could be refined to a 13-cM range between D14S256 and D14S81. No recombinations were detected with the markers D14S291 and D14S280, which suggests that the SCA3 gene lies close to these loci. This finding will benefit the individuals at risk in these two families who are seeking predictive testing or prenatal diagnosis.

Haplotype identity between individuals who share a CFTR mutation allele "identical by descent": demonstration of the usefulness of the haplotype-sharing concept for gene mapping in real populations.

Cystic fibrosis (CF) patients with the A455E mutation, in both the French Canadian and the Dutch population, share a common haplotype over distances of up to 25 cM. French Canadian patients with the 621+1G-->T mutation share a common haplotype of more than 14 cM. In contrast, haplotypes containing the delta F508 mutation show haplotype identity over a much shorter genomic distance within and between populations, probably because of the multiple introduction of this most common mutation. Haplotype analysis for specific mutations in CF or in other recessive diseases can be used as a model for studying the occurrence of genetic drift conditional on gene frequencies. Moreover, from our results, it can be inferred that analysis of shared haplotypes is a suitable method for genetic mapping in general.