Bayesian Latent Variable Collapsing Model for Detecting Rare Variant Interaction Effect in Twin Study

By analyzing more next‐generation sequencing data, researchers have affirmed that rare genetic variants are widespread among populations and likely play an important role in complex phenotypes. Recently, a handful of statistical models have been developed to analyze rare variant (RV) association in different study designs. However, due to the scarce occurrence of minor alleles in data, appropriate statistical methods for detecting RV interaction effects are still difficult to develop. We propose a hierarchical Bayesian latent variable collapsing method (BLVCM), which circumvents the obstacles by parameterizing the signals of RVs with latent variables in a Bayesian framework and is parameterized for twin data. The BLVCM can tackle nonassociated variants, allow both protective and deleterious effects, capture SNP‐SNP synergistic effect, provide estimates for the gene level and individual SNP contributions, and can be applied to both independent and various twin designs. We assessed the statistical properties of the BLVCM using simulated data, and found that it achieved better performance in terms of power for interaction effect detection compared to the Granvil and the SKAT. As proof of practical application, the BLVCM was then applied to a twin study analysis of more than 20,000 gene regions to identify significant RVs associated with low‐density lipoprotein cholesterol level. The results show that some of the findings are consistent with previous studies, and we identified some novel gene regions with significant SNP–SNP synergistic effects.     

The myocardial function during and after whole-body therapeutic hypothermia for hypoxic–ischemic encephalopathy,a cohort study

Background

Therapeutic hypothermia has become standard treatment for moderate and severe neonatal hypoxic–ischemic encephalopathy (HIE) to reduce cerebral morbidity and mortality. The effect on the heart is incompletely explored.

Aim

To assess the myocardial function during and after whole-body therapeutic hypothermia for HIE.

Study design

Observational cohort study.

Subjects

Forty-four infants with HIE cooled for 72 hours were compared with 48 healthy term infants and 20 normothermic infants with HIE.

Outcome measures

Tissue Doppler deformation indices of myocardial function (peak systolic strain, peak systolic strain-rate, early diastole strain-rate and strain-rate in atrial systole) during (days 1 and 3) and after (day 4) therapeutic hypothermia.

Results

On days one and three all indices in both HIE groups were lower than the corresponding indices in the healthy infants. The two HIE groups had similar indices, except peak systolic strain-rate on days 1 and 3 and strain-rate in atrial systole on day 1. All strain-rate indices improved from day 3 to 4 (after rewarming) in the cooled group and achieved similar values to those in healthy infants on day 3. All indices were higher in the cooling-group after rewarming than in the normothermic infants with HIE on day 3, except early diastolic strain-rate.

Conclusions

Infants with HIE had similarly impaired myocardial function during days 1–3 whether normothermic or hypothermic. The myocardial function improved significantly at day 4 (after rewarming), approaching the day 3 levels in the healthy neonates.     

Evaluation of pure-tone audiometric protocols in vestibular schwannoma screening

The objective was to evaluate the pure-tone audiogram-based screening protocols in VS diagnostics. We retrospectively analyzed presenting symptoms, pure tone audiometry and MRI finding from 246 VS patients and 442 controls were collected to test screening protocols (AAO-HNS, AMCLASS-A/B, Charing Cross, Cueva, DOH, Nashville, Oxford, Rule3000, Schlauch, Seattle, Sunderland) for sensitivity and specificity. Results were pooled with data from five other studies, and analysis of sensitivity, specificity and positive likelihood ratio (LR+) for each protocol was performed. Our results show that protocols with significantly higher sensitivity (AMCLASS-A/B, Nashville) show also significantly lowest specificity, and tend to have low association (positive likelihood ratio, LR+) to the VS. The highest LR+ was found for protocols AAO-HNS, Rule3000 and Seattle. In conclusions, knowing their properties, screening protocols are simple decision-making tools in VS diagnostic. To use the advantage of the highest sensitivity, protocols AMCLASS-A + B or Nashville can be of choice. For more reasonable approach, applying the protocols with high LR+ (AAO-HNS, Rule3000, Seattle) may reduce the overall number of MRI scans at expense of only few primarily undiagnosed VS.     

Hemodynamic effects of pindolol and atenolol at rest and during isometric exercise: A noninvasive study with healthy volunteers

Summary Hemodynamic effects of intravenous and oral pindolol and atenolol were assessed in ten healthy volunteers by left ventricular echocardiography and systolic time intervals. Measurements were made at rest and during hand-grip-induced isometric exercise. Drug doses were pindolol 0.015 mg/kg intravenously and 10 mg/day orally, atenolol 0.1 mg/kg intravenously, and 50 mg/day orally.Heart rate at rest was reduced by both drugs. The reduction caused by atenolol during oral treatment was significantly greater (p<0.01). Intravenously only pindolol reduced mean arterial pressure. During oral treatment atenolol reduced the mean arterial pressure nonsignificantly. Both drugs lowered heart rate during isometric exercise, atenolol being significantly more effective. During oral treatment atenolol blunted the heart-rate reaction to exercise. Mean arterial pressure during isometric exercise rose slightly with both drugs after intravenous administration. During oral treatment only atenolol reduced the mean arterial pressure significantly. Intravenous atenolol reduced cardiac contractility at rest, indicated by significant decreases in fractional shortening, ejection fraction, and the mean velocity of circumferential fiber shortening. In contrast, intravenous pindolol and oral therapy with either drug did not change contractility. Intravenous atenolol raised total peripheral resistance. The preejection period/left ventricular ejection time ratio decreased with intravenous pindolol, while atenolol increased it.In conclusion, atenolol had more negative inotropic and chronotropic effects, especially after acute intravenous administration. Only atenolol reduced cardiac output and increased peripheral resistance. After repeated oral administration, these effects were less apparent.     

Exercise-induced proteinuria in children and adolescents with Type 1 (insulin dependent) diabetes

Summary The urinary excretion of albumin and -₂microglubulin was measured by radioimmunoassay in 64 children and adolescents with Type 1 (insulin dependent) diabetes and in 68 non-diabetic subjects aged from 9 to 19 years. At rest the albumin excretion of the diabetic subjects did not differ from that of the non-diabetic children and adolescents but during exercise the albumin excretion was significantly higher in children and adolescents with Type 1 diabetes (p<0.02). The excretion rate of ₂-microglobulin in diabetic subjects did not differ from that of the healthy subjects. Both at rest and during exercise the albumin excretion rate was highest in those diabetics with poorest metabolic control of their disease.     

Diet,cow's milk protein antibodies and the risk of IDDM in Finnish children

Summary Associations of infant feeding patterns and milk consumption with cow's milk protein antibody titres were studied in 697 newly-diagnosed diabetic children, 415 sibling-control children and 86 birth-date-and sex-matched population-based control children in the nationwide Childhood Diabetes in Finland study. IgA and IgG antibody titres to the proteins of cow's milk formula, BLG and BSA, and IgM antibody titres to cow's milk formula proteins were measured by ELISA. Several inverse correlations were observed between the duration of breast-feeding or age at introduction of dairy products and antibody titres, and positive correlations were observed between milk consumption and antibody titres in all three populations studied. Multivariate analyses which included the infant feeding variables, milk consumption and current age simultaneously showed that the earlier the introduction of dairy products and the greater the consumption of milk was, the higher several antibody titres were. High IgA antibody titres to cow's milk formula were associated with a greater risk of IDDM both among diabeticpopulation-control and diabetic-sibling-control pairs when adjusted for other cow's milk antibody titres, dietary variables and in diabetic-sibling-control pairs also for ICA. The results suggest that young age at introduction of dairy products and high milk consumption during childhood increase the levels of cow's milk antibodies and that high IgA antibodies to cow's milk formula are independently associated with increased risk of IDDM.Abbreviations IDDM Insulin-dependent diabetes mellitus - BLG betalactoglobulin - BSA bovine serum albumin - ICA islet cell antibodies - IAA insulin autoantibodies - OR odds ratio - CI confidence interval     

Sexual intercourse and current contraceptive use among university students in Finland

OBJECTIVE: To ascertain the current frequency of sexual intercourse, the current use of contraceptives, the ever use of emergency contraception, and the ever experience of condom failure among Finnish university students. STUDY DESIGN: The study population consisted of Finnish undergraduate university students (19-34 years of age) in 2004. The randomly selected sample comprised 5030 subjects. The data were collected by postal questionnaire, the response rate being 62.7%. Data were presented with frequency distributions and cross-tabulations. Chi-square test was used. Frequencies for women and men were presented and tested separately. RESULTS: A total of 80% of students were currently practicing sexual intercourse. Approximately half of the female students currently used hormonal contraception and one-third used a condom. Almost half of the men currently used a condom. The simultaneous use of condom and hormonal contraception was rare. Condom failure was common. The ever use of emergency contraception appeared to be associated with condom failure. CONCLUSION: Of Finnish university students 80% were sexually active and hormonal contraceptives were the most popular method of contraception among female students. The use of the condom should be practiced more often for prevention of sexually transmitted diseases.