SNP selection for association studies: maximizing power across SNP choice and study size.

Selection of single nucleotide polymorphisms (SNPs) is a problem of primary importance in association studies and several approaches have been proposed. However, none provides a satisfying answer to the problem of how many SNPs should be selected, and how this should depend on the pattern of linkage disequilibrium (LD) in the region under consideration. Moreover, SNP selection is usually considered as independent from deciding the sample size of the study. However, when resources are limited there is a tradeoff between the study size and the number of SNPs to genotype. We show that tuning the SNP density to the LD pattern can be achieved by looking for the best solution to this tradeoff. Our approach consists of formulating SNP selection as an optimization problem: the objective is to maximize the power of the final association study, whilst keeping the total costs below a given budget. We also propose two alternative algorithms for the solution of this optimization problem: a genetic algorithm and a hill climbing search. These standard techniques efficiently find good solutions, even when the number of possible SNPs to choose from is large. We compare the performance of these two algorithms on different chromosomal regions and show that, as expected, the selected SNPs reflect the LD pattern: the optimal SNP density varies dramatically between chromosomal regions.

Specific bronchial reactivity to toluene diisocyanate: dose-response relationship.

20 patients with toluene diisocyanate (TDI)-induced asthma were examined in order to assess their threshold of response to TDI during specific bronchial provocative tests (BPT). Specific bronchial hyperresponsiveness was evaluated by performing, on different days, specific BPT with increasing concentrations of TDI until a positive response was obtained; the threshold of response to TDI (low: 0.02-0.05 ppm; moderate: 0.1 ppm; high: 0.2-0.25 ppm) and the pattern of positive response were evaluated in comparison with some clinical features of the disease. The threshold of airway response to TDI was low in 9, moderate in 7 and high in 4 patients. No evident relationship was observed between the threshold of response to TDI and the pattern of positive response to the lower TDI concentration (immediate in 5, late in 8 and dual in 7 subjects) or other clinical features (duration of asthmatic symptoms, smoking habits, cessation of work, nonspecific bronchial hyperresponsiveness to methacholine); however, 6 out of 9 patients with low threshold had nonspecific bronchial hyperreactivity in comparison with 6 out of 11 patients with moderate or high threshold. In 10 out of 13 patients who performed two positive BPT with different TDI concentrations, the pattern of response was the same either at lower and at higher TDI concentrations; 3 subjects who had a late reaction at the lower concentration showed a dual reaction to the higher TDI concentration. A relationship between the degree of the specific bronchial reaction (% fall in FEV1 from baseline value) and TDI concentration during BPT was observed for the immediate reaction but not for the late reaction.

TDI-induced oculorhinitis and bronchial asthma.

A case of allergic oculorhinitis induced by toluene diisocyanate (TDI) exposure in a subject who two years later developed bronchial asthma due to TDI is described. A 55-year-old nonatopic spray painter developed symptoms of oculorhinitis two or three hours after direct occupational exposure to polyurethane varnish; at the first examination neither specific nor nonspecific bronchial hyperresponsiveness was present. Two years later the patient, who had remained in his job, developed episodic dyspnea, wheezing, and cough immediately after TDI exposure, with persistence of oculorhinitis; at this time a slight immediate-type response to a specific bronchial provocative test with polyurethane varnish and TDI was observed. Nonspecific bronchial hyperresponsiveness was mild. Specific IgE to TDI-HSA conjugate was present at both the first and second examinations. We conclude that, in some cases, TDI may cause "allergic" oculorhinitis and bronchial asthma, probably with an immunological IgE-mediated mechanism.

Follow-up study of patients with respiratory disease due to toluene diisocyanate (TDI).

The outcome of the respiratory symptoms, pulmonary function tests and bronchial hyperresponsiveness was studied in forty-seven workers with respiratory disease due to toluene diisocyanate (TDI) (twenty-seven asthmatic and twenty non-asthmatic subjects) after about 2 years from the first examination. Eight of twelve asthmatic subjects who left the industry after the first examination complained at the follow-up of dyspnoea and wheezing, but pulmonary function tests were unchanged; bronchial hyperresponsiveness decreased in three, but most were still positive to challenge test with bethanechol at the follow-up. Fifteen subjects who continued their exposure to TDI showed at the follow-up a significant decrease of the spirometric parameters and an increase of the bronchial hyperresponsiveness, and symptoms of chronic bronchitis were more frequent at the second examination. Non-asthmatic subjects, both exposed and non-exposed to TDI at the second examination, showed a significant decrease of the pulmonary function tests but no relevant changes in bronchial hyperresponsiveness. Our data suggest that stopping occupational exposure to TDI frequently did not produce an improvement of the TDI bronchial asthma, and persistence of the occupational exposure causes a more rapid decline in the respiratory function.

[Validity of a specific bronchial provocation test with proteolytic enzymes in occupational bronchial asthma caused by enzymatic detergents]. / Validità di un test di broncostimolazione specifica con enzimi proteolitici nell'asma bronchiale professionale da detergenti enzimatici.

Six asthmatic subjects exposed to enzymatic detergents derived from B. Licheniformis were examined by means of a specific Bronchial Provocative Test (sBPT) with solutions of the enzyme. All subjects, except for one, were positive to prick tests with solutions of the "crude" enzyme and with Alcalase, and showed high levels of specific IgE by RAST. The sBPT with solutions of the enzyme, administered by means of a Bird Mark 7 nebulyzer in IPPB with measurement of the delivered dose, showed a positive response in all 6 subjects. No positive result was obtained in 5 normal subjects and in 5 non exposed asthmatic patients, even at much higher doses of the delivered enzyme. The occupational-type sBPT showed only two positive results out of the 6 examined. A good relationship was observed between bronchial hyperresponsiveness and provocative dose of the enzyme. Therefore, the sBPT with solutions of the enzyme is proved to be highly sensitive and specific in confirming the diagnosis of occupational asthma due to proteolytic enzymes.