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Predictive testing for Huntington's disease with linked DNA markers.

Availability of new DNA markers, more tightly linked to the Huntington's disease (HD) locus than the original G8 (D4S10) probes, has improved predictive accuracy for both presymptomatic and prenatal exclusion testing. 50 predictive tests were carried out on high-risk individuals. 6 of these were on first-trimester chorionic villus biopsy specimens; in 2 cases the HD gene was not transmitted to the fetus while in 4 cases no exclusion could be made. The remaining 44 tests were on adults with either 25 or 50% risk of manifesting the disease; 19 had a greatly increased risk and 25 a substantially decreased risk of HD. Family structures in Scotland are suitable for testing about 75% of potentially affected individuals, and the new generation of DNA markers makes virtually all families fully informative.

Adult↗

Ethics of predictive testing for Huntington's chorea: the need for more information.

The finding of a genetically linked polymorphic DNA marker has made possible a predictive test for Huntington's chorea. This DNA probe has so far been used only for research and has technical limitations, but some workers now wish to apply it to clinical predictions. Those identified by the probe as being probable carriers of the Huntington's chorea gene would be exposed to uncertain psychological risks and social pressures. Ethical guidelines should be established, but these require greater knowledge of the potential benefits and hazards of this powerful new procedure. Controlled clinical trials are urgently needed.

Ethics, Medical↗

[A method for modeling skin explants--an in vitro predictive test for graft vs host disease in allogenic hematopoietic cell transplantation].

BACKGROUND: Acute graft versus host disease (GvHD) remains a severe complication of allogeneic haematopoietic stem cell transplantation (HSCT). Our study summaries results of skin explant assay (SEA) as a pretransplant GvHD predictive test in a cohort of paediatric (n = 33) and adult (a = 8) patients receiving grafts from their HLA identical siblings (n = 28), haploidentical relatives (n = 3) and unrelated donors (n = 10). Results GvHD prediction are correlated with the occurrence and severity of acute GvHD posttransplant and effect of GvHD prophylaxis on GvHD clinical outcome is evaluated. METHODS AND RESULTS: SEA utilises responding lymphocytes of the donor, which are sensitized firstly in vitro by mononuclears cells of patient in allogeneic mixed lymphocyte culture (MLC) and subsequently co-cultured with recipient's skin. Histopathological changes found in patients' skin explants are evaluated according to standard Lerner classification for acute GvHD. In general, GvHD predictive results in SEA correlated with GvHd clinical outcome in 28 out of 41 tested patients (68%, p = 0.015). In a cohort of HLA identical sibling transplants GvHD predictive results correlated with clinical manifestation of acute GvHD only in 15 out of 28 patients on individual GvHD prophylaxis. GvHD prophylaxis in the form of cyclosporine A (CsA) combined with short-term methotrexate (MTX) reduced the risk of acute GvHD in 10 out of 14 transplanted patients (71%) meanwhile CsA alone prophylaxis only in 1 out of 5 patients (20%). In a cohort of unrelated pairs on CsA/MTX prophylaxis combined with horse anti-lymphocyte globuline (ALG) correlated the GvHD prediction with GvHD clinical outcome (100%, p = 0.003). In all patients transplanted with the grafts from their haploidentical relatives the occurrence of severe GvHD was predicted. CONCLUSION: Skin explant assay helps identify pretransplant patients at higher risk of severe acute GvHD. GvHD predictive results enable the transplantation team to individualise GvHD prophylaxis and to optimise selection of the donor.

Acute Disease↗

[Predictive tests of radiocurability: towards a custom-made radiotherapy?].

Up to now, radiation oncologists had at their disposal only a number of well-known histological and clinical factors in order to define the optimal dose which should be delivered to a given tumor. Recently, radibiological studies have suggested additional parameters which may play a major role in tumor radiocurability. These parameters are: the number of clonogenic cells, intrinsic radiosensitivity, hypoxia and proliferation kinetics. "Predictive" tests are being developed and evaluated for each of these parameters. The more advanced studies deal with intrinsic radiosensitivity; preliminary data show impressive variations in radiosensitivity within groups of clinically "homogeneous" tumors. Should these tests prove to be reliably predictive of radiocurability, it will be possible, in the near future, to propose to any given patient a "custom-made radiotherapy" adapted to the precise features of his or her tumor.

Animals↗

Assessing renal graft function in clinical trials: can tests predicting glomerular filtration rate substitute for a reference method?

BACKGROUND: In clinical trials, comparison of renal graft function needs a rigorous determination of glomerular filtration rate (GFR). Since reference methods to measure GFR cannot be easily implemented, a number of tests predicting GFR are usually used. However, little is known about their validity in renal transplant patients. We aimed to compare the performances of six GFR tests with inulin clearance in this population. METHODS: Five hundred consecutive inulin clearances performed in 294 renal transplant recipients with stable renal function were retrospectively selected. For each of them, we computed six estimates: the 24-hour creatinine clearance, the Cockcroft-Gault, Walser, Jelliffe, Nankivell, and Levey formulas. Their respective performance was assessed by correlation (simple linear regression), accuracy (dispersion of true error), and agreement (Bland and Altman method). RESULTS: Each GFR test closely correlated with inulin clearance (P < 0.0001). Comparisons between pairs of GFR tests did not show any significant difference in accuracy between the Levey, Jelliffe, and Walser formulas. Conversely, each of these formulas demonstrated a significant lower dispersion (P < 0.005) than the others. Nevertheless, all GFR tests displayed considerable lack of agreement with limits of agreement over 40 mL/min/1.73 m2 apart. The proportion of predicted GFR differing from inulin clearance by +/- 10 mL/min/1.73 m2, ranged from 34% for the Jelliffe formula to 53% for the Nankivell's one. CONCLUSION: None of these formulas seems to be able to safely substitute for inulin clearance. In clinical trials, renal graft function should be preferably assessed using a reference method of GFR measurement.

Adult↗

Attitudes towards predictive testing in Huntington's disease--a deep interview study in Sweden.

Ten persons with a 50% risk of inheriting Huntington's disease were interviewed in depth about experiences of the disease with special regard to their attitude to a predictive test. The persons showed great interest, concern and worry about a test: six were generally positive while four were negative or uncertain. Every interview had a very personal character and early life experiences seemed to have a determinative influence on the attitude to the test. Persons who were without symptoms of the disease and had passed the mean age of onset within the family (usually older individuals) were largely enthusiastic about a test, as were those with slight and undetermined symptoms. Younger persons, especially those with a qualitatively good contact with the affected parent, seemed to be less interested. Contradictions during the interview were more common among those positive to testing and an ambivalence among many was reflected in a tendency towards changing opinions over time.

Adult↗

Reluctance to undergo predictive testing: the case of Huntington disease.

The development of a presymptomatic test for Huntington Disease (HD) has enabled some persons at risk to determine whether or not they are gene carriers. The purpose of this study was to explore the reasons why those at risk choose not to be tested in a situation where testing is available and most of the test-associated costs are covered by state funding. Subjects were also asked their levels of knowledge about testing, attitudes towards aspects of the testing protocols, and intentions towards testing once the gene for HD is found. Sixty-six individuals at risk for HD who had chosen not to be tested completed a mailed questionnaire. The most important reasons for not being tested were increased risk to children if one was found to be a gene carrier, absence of an effective cure, potential loss of health insurance, financial costs of testing, and the inability to "undo" the knowledge. Individuals comprising this sample were quite knowledgeable about predictive testing. Most supported the availability of testing despite the lack of a cure, the need for special counseling prior to testing, and the idea that testing should be a voluntary decision. Most said they would take the test if a treatment was available, if the mechanics of the test were simplified, or if the test was 100% accurate. The risk to relatives, lack of treatment or cure, fear of losing one's health insurance, and the accuracy of the information to be gained from testing are important factors in the decision not to be tested.

Adult↗

Comparison of in vitro predictive tests for irritation induced by anionic surfactants.

Skin compatibility of anionic surfactants may often but not always be predicted by in vitro tests. For instance, the correlation between in vivo and in vitro data is classically hampered in the presence of magnesium. This ion is known to interfere with in vitro skin irritation predictive tests based on protein denaturation. This study was conducted to compare a recently introduced assay, corneosurfametry, with other in vitro tests including the pH-rise of bovine serum albumin, collagen swelling, and zein solubilization tests. Corneosurfametry entails collection of cyanoacrylate skin surface strippings and short contact time with surfactants, followed by staining samples with toluidine blue and basic fuchsin dyes. Measurements are made by reflectance colorimetry. Data show that irritation potentials predicted by corneosurfametry agree with those obtained by established in vivo and in vitro irritation tests. Moreover, corneosurfametry data are not artificially lowered by addition of magnesium in surfactant solutions. In conclusion, corneosurfametry should be viewed as one of the realistic predictive tests for surfactant irritancy.

Collagen↗

The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients.

UNLABELLED: Fibromyalgia (FM) is a challenging pain syndrome for which no reliable pharmacologic treatment exists. Recent clinical studies suggest that N-methyl-D-aspartate receptors might play a role in the pathogenesis of this disorder. To determine whether an intravenous (IV) ketamine test predicts the response to a therapeutic trial with an oral N-methyl-D-aspartate receptor antagonist, we performed a low-dose (0.1 mg/kg) IV ketamine infusion on 34 consecutive patients with FM, which was subsequently followed by an oral dextromethorphan (DX) treatment regimen. As per previous guidelines, the cutoff value for a positive response to the IV ketamine test was designated to be 67% pain relief, and a positive response to DX treatment was 50% pain reduction at 4- to 6-week follow-up visits. The degree of correlation between pain relief with ketamine and DX was highly significant (Pearson correlation coefficient, 0.66; P < .001). Ten patients responded positively to both ketamine and DX, 19 responded to neither drug, 3 had a positive response to ketamine but not DX, and 2 obtained good pain relief with DX but not ketamine. The sensitivity of the IV ketamine test was 83%, the specificity was 86%, the positive predictive value was 77%, and the negative predictive value was 91%. An association was also found between the development of side effects to the two treatments. PERSPECTIVE: The response to an IV ketamine infusion was found to predict the subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients, with an observed agreement of 83%. Considering the refractory nature of fibromyalgia to conventional pain treatments, the IV ketamine test might enhance patient care by saving time and reducing unnecessary treatment trials.

Administration, Oral↗

Mutations of the BRCA1 and BRCA2 genes and the possibilities for predictive testing.

Two cancer susceptibility genes, BRCA1 on chromosome 17q12-21 and BRCA2 on chromosome 13q12-13, are thought to be responsible for approximately 80% of families containing multiple cases of early-onset female breast cancer. Germline mutations of BRCA1 are also associated with ovarian cancer and mutations of BRCA2 are associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. The recent isolation of both genes should make possible the identification of the genetic defect that predisposes affected individuals to breast and ovarian cancer and might lead to the use of genetic information for predictive testing.

BRCA2 Protein↗

Pitfalls in experiments testing predictions from sperm competition theory.

As females of many species mate with more than one male, ejaculates often face competition from the sperm of other males. In recent years, numerous papers have been published on theoretical predictions of evolutionary, behavioural and physiological responses to variation in the strength of sperm competition (SC). These theoretical predictions have also been extensively tested. However, although predictions from SC theory are relatively straightforward, extra caution has to be paid in the design of experiments testing them. One difficulty is for example to disentangle immediate and mean SC risk and intensity. Without carefully designed experiments, it is also very easy to simultaneously increase SC risk and the probability of intense SC--a situation for which we currently have no clear predictions, as the theoretical models to date only assume variation in either SC risk or intensity. In this paper, we discuss these and some other pitfalls related to manipulations of SC risk and intensity and suggest how to avoid them.

Adaptation, Physiological↗

Psychomotor testing predicts rate of skill acquisition for proficiency-based laparoscopic skills training.

BACKGROUND: Laparoscopic simulator training translates into improved operative performance. Proficiency-based curricula maximize efficiency by tailoring training to meet the needs of each individual; however, because rates of skill acquisition vary widely, such curricula may be difficult to implement. We hypothesized that psychomotor testing would predict baseline performance and training duration in a proficiency-based laparoscopic simulator curriculum. METHODS: Residents (R1, n = 20) were enrolled in an IRB-approved prospective study at the beginning of the academic year. All completed the following: a background information survey, a battery of 12 innate ability measures (5 motor, and 7 visual-spatial), and baseline testing on 3 validated simulators (5 videotrainer [VT] tasks, 12 virtual reality [minimally invasive surgical trainer-virtual reality, MIST-VR] tasks, and 2 laparoscopic camera navigation [LCN] tasks). Participants trained to proficiency, and training duration and number of repetitions were recorded. Baseline test scores were correlated to skill acquisition rate. Cutoff scores for each predictive test were calculated based on a receiver operator curve, and their sensitivity and specificity were determined in identifying slow learners. RESULTS: Only the Cards Rotation test correlated with baseline simulator ability on VT and LCN. Curriculum implementation required 347 man-hours (6-person team) and 795,000 dollars of capital equipment. With an attendance rate of 75%, 19 of 20 residents (95%) completed the curriculum by the end of the academic year. To complete training, a median of 12 hours (range, 5.5-21), and 325 repetitions (range, 171-782) were required. Simulator score improvement was 50%. Training duration and repetitions correlated with prior video game and billiard exposure, grooved pegboard, finger tap, map planning, Rey Figure Immediate Recall score, and baseline performance on VT and LCN. The map planning cutoff score proved most specific in identifying slow learners. CONCLUSIONS: Proficiency-based laparoscopic simulator training provides improvement in performance and can be effectively implemented as a routine part of resident education, but may require significant resources. Although psychomotor testing may be of limited value in the prediction of baseline laparoscopic performance, its importance may lie in the prediction of the rapidity of skill acquisition. These tests may be useful in optimizing curricular design by allowing the tailoring of training to individual needs.

Adult↗

Hereditary breast and ovarian cancer: epidemiology, genetics, screening and predictive testing.

Inherited predisposition to cancer has become an increasingly important part of the practice of clinical genetics. Hereditary breast and ovarian cancer form a significant part of this new field. There are approximately 13,000 new cases of breast cancer diagnosed every year in Canada, and 5% of these can be expected to have a hereditary basis. Large studies implicated a dominant gene with a population frequency of 0.33% and high penetrance. Linkage analysis localised one such gene to chromosome 17q21 in 1990, and 1994 BRCA1 was cloned. The BRCA1 gene is large, and mutations are spread over the entire gene. There is evidence of common origins for some of the mutations. Early detection of hereditary breast and ovarian cancer is problematic. There is no evidence that early diagnosis by population-based mammography improves survival in sporadic premenopausal breast cancer. Multimodal screening for ovarian cancer has not been adequately assessed. Moreover, there is little evidence that such procedures are more likely to be effective in high-risk groups. Women who may gain initial benefit from the cloning of BRCA1 are from BRCA1-linked families who have living affected relatives. Over the next few years, it is likely that predictive testing for hereditary breast and ovarian cancer will become a routine clinical service in large centres.

Breast Neoplasms↗

The motivation of at-risk individuals and their partners in deciding for or against predictive testing for Huntington's disease.

Sixty-six percent of the at-risk persons and 74% of the partners in a large survey in Belgium have the intention of making use of predictive testing for Huntington's disease. One third of them, however, have expressed the intention of postponing the final decision for various reasons. The intention to be tested is not at all related to sociodemographic characteristics. A thorough exploration of the reasons for being in favour of or against taking the test reveals that the motivation inspiring this very personal decision is very complex. In the group of at-risk persons, less than half of the variation in the intention to be tested is explained by the role of a series of specific reasons as predictor variables in a regression analysis. The proportion of explained variation is slightly higher in the group of partners. 'To have certainty about my own future' and 'to make arrangements for the future' play a major part in the decision of the total group. 'Making decisions concerning children' and to a larger extent 'informing children about their risk status' are important factors in deciding in favour of the test.

Adult↗

Attitudes towards predictive testing in Huntington's disease: a recent survey in Belgium.

After the publication of evidence of the existence of a DNA polymorphism closely linked to the gene for Huntington's disease, attitudes towards predictive testing for Huntington's disease were evaluated in Belgium in a group of persons who are at risk for the disease and in a smaller group of their partners. The percentage of persons at risk who planned to take the test was smaller than in many previously published studies. Our results revealed a lack of association between the intention to take the test and social or demographic variables. Specific attention was paid to the difference in intention between a person at risk and his or her partner and to the opinions about the way the decision to take the test should be made.

Attitude↗

Older and younger adults' strategy choices in multiplication: testing predictions of ASCM using the choice/no-choice method.

The choice/no-choice method provides a means of obtaining unbiased estimates of the performance characteristics of strategies. The three experiments in the study illustrate the method's usefulness for testing predictions of alternative models of strategy choice. The experiments focused on 20- and 70-year-olds' choices among mental calculation, use of a calculator, and use of pencil and paper as strategies for solving multidigit multiplication problems. As predicted by the Adaptive Strategy Choice Model (ASCM), (a) differences in the speed and accuracy yielded by the strategies were the strongest predictors of the frequency with which each strategy was chosen on a given problem; (b) features of problems exerted an additional independent influence; and (c) having a choice resulted in better performance than not having one. These results held true for both older and younger adults. Potential extensions of the choice/no-choice method and of ASCM are discussed.

Adolescent↗