Comparison of Marker Intervals and Number of Sib Pairs Used for Linkage Analysis on Simulated Nuclear Family Data

Using a two‐stage global scan design, we analyzed general population replicates 1 and 42 of the Genetic Analysis Workshop (GAW) 12 simulated data set using three methods: revisited Haseman‐Elston (HER), maximum likelihood variance estimation (ML), and variance components (VC). Three marker densities, 5‐, 10‐, and 15‐cM intervals, were examined in the first‐stage scan. We found that the 10‐cM interval appears to be the most cost‐effective approach in genotyping without sacrificing power when using a first stage significance level of 0.01. Subsequently, we performed the second‐stage scan at 1‐cM intervals for those putative positive regions identified in the first‐stage scan at a significance level of 0.01. We also compared the power to detect linkage using different numbers of sib pairs for a genome‐wide scan at a 10‐cM interval and found that power decreases nonlinearly as the number of sib pairs decreases. © 2001 Wiley‐Liss, Inc.     

Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma

BACKGROUND: Regular use of inhaled corticosteroids (ICSs) can improve asthma symptoms and prevent exacerbations. However, overall adherence is poor among patients with asthma. Objective To estimate the proportion of poor asthma-related outcomes attributable to ICS nonadherence. METHODS: We retrospectively identified 405 adults age 18 to 50 years who had asthma and were members of a large health maintenance organization in southeast Michigan between January 1, 1999, and December 31, 2001. Adherence indices were calculated by using medical records and pharmacy claims. The main outcomes were the number of asthma-related outpatient visits, emergency department visits, and hospitalizations, as well as the frequency of oral steroid use. RESULTS: Overall adherence to ICS was approximately 50%. Adherence to ICS was significantly and negatively correlated with the number of emergency department visits (correlation coefficient [ R ] = -0.159), the number of fills of an oral steroid ( R = -0.179), and the total days' supply of oral steroid ( R = -0.154). After adjusting for potential confounders, including the prescribed amount of ICS, each 25% increase in the proportion of time without ICS medication resulted in a doubling of the rate of asthma-related hospitalization (relative rate, 2.01; 95% CI, 1.06-3.79). During the study period, there were 80 asthma-related hospitalizations; an estimated 32 hospitalizations would have occurred were there no gaps in medication use (60% reduction). CONCLUSIONS: Adherence to ICS is poor among adult patients with asthma and is correlated with several poor asthma-related outcomes. Less than perfect adherence to ICS appears to account for the majority of asthma-related hospitalizations.     

Linkage relationships between a major gene for catechol-o-methyltransferase activity and 25 polymorphic marker systems

Segregation analysis has provided evidence suggesting the existence of a major gene for catechol-o-methyltransferase (COMT) activity in man. Five large families (4 Caucasian, 1 black), with a total of 1,189 individuals, were ascertained as part of a genetic study of blood pressure. Erythrocyte COMT activity and status at 25 polymorphic genetic marker loci were determined on more than 518 individuals in these pedigrees. Genetic linkage analysis of COMT with each of the 25 marker loci was performed in two ways: (1) using parameter estimates from segregation analysis of untransformed COMT activity, and (2) using parameter estimates from segregation analysis of the power transformation of the COMT activity that maximized the likelihood of the genetic hypothesis in each family. Tight and close linkage were excluded at 21 and 15 loci, respectively. A lod score of 1.27 at θ = 0.1 was found between the loci for COMT activity and phosphogluconate dehydrogenase (PGD). Transformation of the data had little effect on the outcome of the linkage analysis.     

Consensus guidelines on analgesia and sedation in dying intensive care unit patients

Background

Intensivists must provide enough analgesia and sedation to ensure dying patients receive good palliative care. However, if it is perceived that too much is given, they risk prosecution for committing euthanasia. The goal of this study is to develop consensus guidelines on analgesia and sedation in dying intensive care unit patients that help distinguish palliative care from euthanasia.

Methods

Using the Delphi technique, panelists rated levels of agreement with statements describing how analgesics and sedatives should be given to dying ICU patients and how palliative care should be distinguished from euthanasia. Participants were drawn from 3 panels: 1) Canadian Academic Adult Intensive Care Fellowship program directors and Intensive Care division chiefs (N = 9); 2) Deputy chief provincial coroners (N = 5); 3) Validation panel of Intensivists attending the Canadian Critical Care Trials Group meeting (N = 12).

Results

After three Delphi rounds, consensus was achieved on 16 statements encompassing the role of palliative care in the intensive care unit, the management of pain and suffering, current areas of controversy, and ways of improving palliative care in the ICU.

Conclusion

Consensus guidelines were developed to guide the administration of analgesics and sedatives to dying ICU patients and to help distinguish palliative care from euthanasia.     

Preliminary report of an ultrasonography and colour Doppler uterine score to predict uterine receptivity in an in-vitro fertilization programme

A total of 96 women undergoing in-vitro fertilization (IVF) treatment were examined by transvaginal ultrasonography with colour and pulsed Doppler ultrasound on the 22nd day of the menstrual cycle preceding IVF. We assessed endometrial thickness, endometrial morphology, myometrial echogenicity, subendometrial vascularization, the uterine artery pulsatility index, protodiastolic notch and end diastolic blood flow in order to define a uterine score which could be correlated with the pregnancy rate. The overall pregnancy rate was 30.2%, and there was no difference between the pregnant and non-pregnant groups with regard to any of the ultrasonographic and Doppler parameters when examined separately. However, the uterine score was significantly higher in the pregnant group (15.9 +/- 2.81 versus 12.7 +/- 5.3, P = 0.002; t-test). No pregnancy occurred if the score was between 0 and 10. With a score of 11-15 there was a 34.7% chance of pregnancy, and scores >16 had a 42% chance of pregnancy. In conclusion, individual ultrasonographic and Doppler parameters are not of sufficient accuracy to predict uterine receptivity. The uterine score calculated prior to IVF cycles appears to be a useful predictor of implantation.      

Fine Mapping Functional Sites or Regions from Case-Control Data Using Haplotypes of Multiple Linked SNPs

Previously, we reported an algorithm for scanning a large number of tightly linked single nucleotide polymorphisms (SNPs) for LD mapping of functional sites or regions from a family‐based association design. In the present study, we extend our method to a case‐control design. We first use the expectation maximization (EM) algorithm to estimate haplotype frequencies of multiple linked SNPs, and follow this by constructing a contingency table statistic S for LD analysis, based on the estimated haplotype frequencies. An empirical p‐value is obtained based on the null distribution of the maximum of S (S *) from a large number (e.g., 1,000 or more) of randomized permutations. The proposed algorithm has been implemented in a computer program in which window searching for functional SNP sites can cover any number of loci without limitation, except that of computer storage. Unlike other programs for a case‐control design that always conduct tests at a fix window width, in our program after setting a maximum size of haplotype window width, for a given maximum window width all possible widths of haplotypes are utilized to find the maximum statistic S * for each locus under investigation. The sensitivity of the proposed algorithm has been examined with simulated and real genotyping datasets. Association analyses indicate that our program is powerful enough to detect most, if not all, functional SNPs simulated in the original model or identified in the original report. Moreover, the program is very flexible and can be used in either regional or genome‐wide scanning for association analysis with SNP markers.