Association of older paternal age with earlier onset among co-affected schizophrenia sib-pairs.

BACKGROUND: Advanced paternal age is associated with increased risk of schizophrenia. This study aimed to explore whether older paternal age is associated with earlier onset among co-affected schizophrenia sib-pairs with the same familial predisposition. METHOD: A total of 1297 patients with schizophrenia from 630 families, which were ascertained to have at least two siblings affected, throughout Taiwan were interviewed using the Diagnostic Interview for Genetic Studies. Both inter-family comparisons, a hierarchical regression model allowing for familial dependence and adjusting for confounders, and within-family comparisons, examining the consistency between onset order and birth order, were performed. RESULTS: An inverted U shape was observed between paternal age and onset of schizophrenia. Affected offspring with paternal age of 20-24 years had the oldest onset. As paternal age increased over 25 years, older paternal age exhibited a linear decrease in the onset of schizophrenia. On average, the onset was lowered by 1.5 years for paternal age of 25-29 years and by 5.5 years for paternal age ⩾50 years (p = 0.04; trend test). The proportion of younger siblings with earlier onset (58%) was larger than that of older siblings with earlier onset (42%) (p = 0.0002). CONCLUSIONS: These findings indicate that paternal age older than 25 years and younger than 20 years were both associated with earlier onset among familial schizophrenia cases. The associations of advanced paternal age with both increased susceptibility to schizophrenia and earlier onset of schizophrenia are consistent with the rate of increases in spontaneous mutations in sperm as men age.

Localization of a susceptibility locus for hepatocellular carcinoma to chromosome 4q in a hepatitis B hyperendemic area.

Chromosome 4q is one of the most common regions with a high frequency of allelic loss in hepatocellular carcinoma (HCC). To identify the HCC-susceptibility locus on chromosome 4q, we have performed linkage and family-based association analyses on Chinese families with HCC from Taiwan, where hepatitis B is hyperendemic. Using 77 microsatellite markers spanning chromosome 4q on 52 multiplex families, we found suggestive evidence of linkage to 4q22.3-28.1 with a maximum two-point heterogeneity LOD (HLOD) score of 2.55 at marker D4S3240 on chromosome 4q25. Multipoint analyses with microsatellite markers in the region 4q22.3-28.1 resulted in a maximum HLOD score of 3.12 and a maximum nonparametric linkage (NPL) Z score of 1.98 (pointwise P=0.0080; region-wide empirical P=0.021) for D4S3240. The evidence for linkage to D4S3240 was seen mostly in a subset of 28 families lacking affected parents, which showed multipoint HLOD and NPL scores of 3.25 and 2.79 (pointwise P=0.0028; region-wide empirical P=0.008), respectively. Family-based association analyses of the 77 microsatellite markers in 191 families (53 multiplex plus 138 singleton families) using the pedigree disequilibrium test provide further support for observed linkage. Additional genotyping in the 52 multiplex families informative for linkage analyses was performed for 29 single-nucleotide polymorphisms around D4S3240. A common haplotype (at markers rs7442180 and rs221330) positioned approximately 873 kb away from D4S3240 was associated with HCC, with P=0.0074.

Visual outcomes for high myopic patients with or without myopic maculopathy: a 10 year follow up study.

AIM: To evaluate the visual outcomes for high myopic patients aged 40 years and older with or without myopic maculopathy. METHODS: 552 high myopic (spherical equivalent < or =-6.0D or axial length > or =26.5 mm) patients were enrolled in the study, 230 cases with myopic maculopathy (at least lacquer cracks were identified) and 322 cases without maculopathy. The initial and final visual acuity (VA) (after 10 years) was compared between two groups. Additionally, the relation between sex, age, refraction, and axial length was analysed to find out the possible risk factors associated with visual outcome in myopic maculopathy. RESULTS: In 92% of patients aged 40-49, final VA was better than 20/40 after 10 years of follow up. However, it was less than 40% in those older than 60 years. For more than 50% of patients older than 40 years of age with maculopathy, their vision had decreased more than two lines in Snellen VA after 10 years of follow up, compared to only 4.3% of analogues without myopic maculopathy. Patchy atrophy and choroidal neovascularisation in myopic macular degeneration groups showed poorer visual outcome than lacquer cracks in the macular lesion group. Other prognostic factors of visual outcomes were myopic refraction, axial length, and ageing. CONCLUSIONS: Clearly, prognosis for patients with maculopathy is poorer than for those without maculopathy. Refractive status, axial length, and ageing are the main factors involved in determining the visual outcomes. The macular grading also affects the visual outcome for high myopic patients.

Performance of the Continuous Performance Test among community samples.

The Continuous Performance Test (CPT) has been modified to be used widely as a potential vulnerability marker of schizophrenia. In genetic analyses of schizophrenia, well-established norms for the CPT are essential in choosing a suitable threshold of CPT for classifying subjects as affected or unaffected. In this study, we investigated the performance of 115 adolescents and 345 adults, randomly sampled from a community, on two sessions of the CPT 1-9 (undegraded and 25% degraded). The results showed that an older age was associated with a decreasing hit rate and sensitivity (d'), while a higher level of education was associated with an increasing hit rate and d' for both sessions of the CPT. Men had higher hit rates and d' than women for the degraded CPT. A practice effect during the second session of the CPT was noted among 20 to 33 percent of the subjects. Poorer CPT performance was associated with schizotypy measured by the Perceptual Aberration Scale and the Schizotypal Personality Questionnaire. Thus, in assessing CPT performance among schizophrenia patients or high-risk populations, we must compare their results to age-, education-, and sex-corresponding norms. The data presented in this report will be valuable in this regard.

Schizotypy in community samples: the three-factor structure and correlation with sustained attention.

The authors examined cross-cultural applicability of the Schizotypal Personality Questionnaire (SPQ), the Perceptual Aberration Scale (PAS), and the Continuous Performance Test in community samples of Taiwanese adults and adolescents. The authors tested hypotheses that a 3-factor structure of the SPQ (Cognitive-Perceptual, Interpersonal, and Disorganization: A. Raine et al., 1994) exists for both samples and that the Interpersonal factor is associated with poorer attention. The authors replicated the 3-factor model for both samples, and they externally validated the model in adults: The Interpersonal factor and possibly the Disorganization factor were associated with poorer attention, whereas the Cognitive-Perceptual factor was not. The PAS differed from the Cognitive-Perceptual factor in its consistent association with poorer attention in both samples. These have important implications for the scales in the early detection of the schizotypy in various cultures.

Development of sustained attention assessed using the continuous performance test among children 6-15 years of age.

The Continuous Performance Test (CPT) is a widely used measure of sustained attention, which may rely on the efficiency of cognitive inhibition. We examined the relationships of age and sex with CPT performance among 341 randomly selected school children 6-15 years of age. Multiple regression analyses revealed that the hit rate, false alarm rate, and sensitivity of both the undegraded and the degraded CPT were associated with age by a quadratic relationship. The age-development curves for the hit rate and sensitivity were convex, whereas that for the false alarm rate was concave. Sex was associated with the hit rate and sensitivity on the degraded CPT only. Our findings are consistent with the hypothesis that sustained attention develops during the primary school ages. The data reported are essential for identifying children with conditions associated with sustained attention deficit, such as attention-deficit hyperactivity disorder, as well as those at an increased risk for developing schizophrenia.

Epidemiologic study of the prevalence and severity of myopia among schoolchildren in Taiwan in 2000.

BACKGROUND AND PURPOSE: A nationwide survey was performed in 2000 to determine the prevalence and severity of myopia among schoolchildren in Taiwan and to compare these findings with the results of the last survey performed in 1995. METHODS: We first divided the whole island into regions according to developmental grade scores and then sampled with the probability proportional to the size of the population within each stratum. A total of 10,889 students were enrolled, including 5,664 boys and 5,225 girls, with ages ranging from 7 to 18 years. The refractive status and corneal radius of each student were measured with an autorefractometer under cycloplegia and checked with retinoscopy. Axial length was measured using biometric ultrasound. RESULTS: The myopia rate increased from 20% at 7 years, to 61% at 12 years, and 81% at 15 years. A myopic rate of 84% was found for schoolchildren aged 16 years through 18 years. The mean refractive index reached myopic status at the age of 8, and increased to -4.12 D in girls and -3.15 D in boys at the age of 18 years. The prevalence of high myopia (> -6.0 D) at the age of 18 years was 24% in girls and 18% in boys. The increase in axial length corresponded with the progression of myopia. The anterior chamber depth was slightly deeper from 7 years to 13 years and then remained stable. The lens thickness decreased from 7 years to 11 years. After age 15, further thickening of the lens was correlated with both age and severity of myopia. However, the corneal curvature was not related to age or severity of myopia. Girls had a higher prevalence and more severe degree of myopia than boys. Children in urban areas had a higher prevalence and more severe degree of myopia than children in rural areas. CONCLUSION: The prevalence and severity of myopia in schoolchildren in Taiwan in 2000 increased compared to 1995, with the most severe increases occurring in younger age groups. Thus, preventing schoolchildren developing myopia at a young age may slow down the increase in severity of myopia in Taiwan.

Prevalence of myopia in Taiwanese schoolchildren: 1983 to 2000.

INTRODUCTION: To determine time trends in myopia over a 20-year period in Taiwan, we conducted 5 nationwide surveys pertaining to the ocular refraction of schoolchildren in 1983, 1986, 1990, 1995 and 2000. MATERIALS AND METHODS: The sampling technique used herein involved the assessment of stratified systematic clusters, with the unweighted myopic rate being represented using data derived from different sectors of the population, such as metropolitan, city, town, and aboriginal. The mean values for the spherical equivalent of the cycloplegic refractive status and the dimension of corneal radii as determined by the autorefractometer were used for the calculation. RESULTS: In our review of 5 nationwide myopia surveys, we found that the mean prevalence of myopia among 7 year olds increased from 5.8% in 1983 to 21% in 2000. At the age of 12, the prevalence of myopia was 36.7% in 1983 increasing to 61% in 2000, corresponding figures for 15-year-olds being 64.2% and 81%, respectively. The prevalence of myopia increased from 74% in 1983 to 84% in 2000 for children aged between 16 and 18 years, and, in addition, the prevalence of high myopia (over -6.0 D) increased from 10.9% in 1983 to 21% of 18-year-old students of Taiwan in 2000. The mean refractive status at the age of 12 deteriorated from -0.48 D in 1983 to -1.45 D in 2000, and from -1.49 D to -2.89 D for children aged 15, whilst for individuals aged 18, it deteriorated from -2.55 D in 1983 to -3.64 D in 2000. The mean ocular refraction began to progress to a myopic condition at the age of 11 in 1983, this becoming an age of 8 years in 2000. There appeared to be significant difference in both the prevalence and the degree of myopia between study participants residing in cities and villages. CONCLUSIONS: We conclude that the cause of the relative increasing severity of myopia among the schoolchildren was due to the onset of myopia at a very young, and progressively-decreasing, age over the study period. Thus, to reduce the prevalence and severity of myopia, we should pay more attention to the eye care of pre-schoolchildren.

Orthodontic correction of a mandibular first molar deeply impacted by an odontoma: a case report.

Orthodontic correction was used to a 12-year-old boy with a mandibular first molar deeply impacted by an odontoma. Following surgical removal of the odontoma, the molar was exposed and brought to a proper position by orthodontic traction. The treatment time was 29 months. After a 20-month follow-up, the molar was still in a satisfactory position.

Akt1 deficiency modulates reward learning and reward prediction error in mice.

In contemporary reinforcement learning models, reward prediction error (RPE), the difference between the expected and actual reward, is thought to guide action value learning through the firing activity of dopaminergic neurons. Given the importance of dopamine in reward learning and the involvement of Akt1 in dopamine-dependent behaviors, the aim of this study was to investigate whether Akt1 deficiency modulates reward learning and the magnitude of RPE using Akt1 mutant mice as a model. In comparison to wild-type littermate controls, the expression of Akt1 proteins in mouse brains occurred in a gene-dosage-dependent manner and Akt1 heterozygous (HET) mice exhibited impaired striatal Akt1 activity under methamphetamine challenge. No genotypic difference was found in the basal levels of dopamine and its metabolites. In a series of reward-related learning tasks, HET mice displayed a relatively efficient method of updating reward information from the environment during the acquisition phase of the two natural reward tasks and in the reverse section of the dynamic foraging T-maze but not in methamphetamine-induced or aversive-related reward learning. The implementation of a standard reinforcement learning model and the Bayesian hierarchical parameter estimation show that HET mice have higher RPE magnitudes and that their action values are updated more rapidly among all three test sections in T-maze. These results indicate that Akt1 deficiency modulates natural reward learning and RPE. This study showed a promising avenue for investigating RPE in mutant mice and provided evidence for the potential link from genetic deficiency, to neurobiological abnormalities, to impairment in higher-order cognitive functioning.

A Bayesian spatial multimarker genetic random-effect model for fine-scale mapping.

Multiple markers in linkage disequilibrium (LD) are usually used to localize the disease gene location. These markers may contribute to the disease etiology simultaneously. In contrast to the single-locus tests, we propose a genetic random effects model that accounts for the dependence between loci via their spatial structures. In this model, the locus-specific random effects measure not only the genetic disease risk, but also the correlations between markers. In other words, the model incorporates this relation in both mean and covariance structures, and the variance components play important roles. We consider two different settings for the spatial relations. The first is our proposal, relative distance function (RDF), which is intuitive in the sense that markers nearby are likely to correlate with each other. The second setting is a common exponential decay function (EDF). Under each setting, the inference of the genetic parameters is fully Bayesian with Markov chain Monte Carlo (MCMC) sampling. We demonstrate the validity and the utility of the proposed approach with two real datasets and simulation studies. The analyses show that the proposed model with either one of two spatial correlations performs better as compared with the single locus analysis. In addition, under the RDF model, a more precise estimate for the disease locus can be obtained even when the candidate markers are fairly dense. In all simulations, the inference under the true model provides unbiased estimates of the genetic parameters, and the model with the spatial correlation structure does lead to greater confidence interval coverage probabilities.

A grid-search algorithm for optimal allocation of sample size in two-stage association studies.

Multiple testing occurs commonly in genome-wide association studies with dense SNPs map. With numerous SNPs, not only the genotyping cost and time increase dramatically, many family wise error rate (FWER) controlling methods may fail for being too conservative and of less power when detecting SNPs associated with disease is of interest. Recently, several powerful two-stage strategies for multiple testing have received great attention. In this paper, we propose a grid-search algorithm for an optimal design of sample size allocation for these two-stage procedures. Two types of constraints are considered, one is the fixed overall cost and the other is the limited sample size. With the proposed optimal allocation of sample size, bearable false-positive results and larger power can be achieved to meet the limitations. The simulations indicate, as a general rule, allocating at least 80% of the total cost in stage one provides maximum power, as opposed to other methods. If per-genotyping cost in stage two differs from that in stage one, downward proportion of the total cost in earlier stage maintains good power. For limited total sample size, evaluating all the markers on 55% of the subjects in the first stage provides the maximum power while the cost reduction is approximately 43%.

Long-term visual prognosis of infantile-onset high myopia.

PURPOSE: To investigate the clinical course and changes of refractive status in infantile-onset myopic children who received fully corrected glasses and to determine their visual prognosis. METHODS: In all, 57 children with infantile-onset high myopia (spherical equivalent over -5.0 D prior to the age of 5 years) were included in this study. All children received initial full-correction glasses at the mean age of 3.52 years. The cycloplegic refraction, axial length, and the best-corrected visual acuity were collected every 6 months. The mean follow-up time was 9.36 years. RESULTS: We noted that the tendency toward progression or regression of myopia appeared to be related to the degree of refractive error. Lower grades of high myopia (-5.0 to -7.75 D) showed a greater tendency to progress than those of the highest initial myopic refraction level (< or = -11.0 D). While the latter group exhibited a more-substantial regression rate than those cases of the lower initial refraction level. About 80% of infantile-onset high myopes demonstrated a final best-corrected vision of greater than 20/40, with 37% of children revealing a best-corrected vision level even better than 20/25. CONCLUSION: Clinical course of infantile high myopia is different to school myopia. Usually, higher degree of high myopia showed a stable state of myopia, or even possible regression, whereas the lower grades of high myopia revealed a strong tendency to progress.

Alternative summary indices for the receiver operating characteristic curve.

The receiver operating characteristic curve (ROC) and its associated summary index, the area under the curve (AUC), have recently found an increasingly popular place in medical diagnosis and population screening surveys. Nevertheless, the index may erroneously rate a perfect or nearly perfect marker as having no diagnostic or screening value. In this paper, we propose two new summary indices, the projected length of the ROC curve (PLC) and the area swept out by the ROC curve (ASC), to summarize the ROC curve. Like the conventional AUC, these new indices both have clear probabilistic interpretations and are easily defined geometrically. In addition, they do not suffer from the shortcoming of the AUC. These properties render them good alternatives for evaluating the overall performance of a diagnostic or screening test.

Effects of implicit parameters in segregation analysis.

In human genetic analysis, data are collected through the so-called 'ascertainment procedure'. Statistically this sampling scheme can be thought of as a multistage sampling method. At the first stage, one or several probands are ascertained. At the subsequent stages, a sequential sampling scheme is applied. Sampling in such a way is virtually a nonrandom procedure, which, in most cases, causes biased estimation which may be intractable. This paper focuses on the underlying causes of the intractability problem of ascertained genetic data. Three types of parameters, i.e. target, design and nuisance parameters, are defined as the essences to formulate the true likelihood of a set of data. These parameters are also classified into explicit or implicit parameters depending on whether they can be expressed explicity in the likelihood function. For ascertained genetic data, a sequential scheme is regarded as an implicit design parameter, and a true pedigree structure as an implicit nuisance parameter. The intractability problem is attributed to loss of information of any implicit parameter in likelihood formulation. Several approaches to build a likelihood for estimation of the segregation ratio when only an observed pedigree structure is available are proposed.

Impaction of a mandibular permanent lateral incisor associated with fused primary teeth: a case report.

Although anesthetic and functional problems created by fused primary teeth are relatively transient, occlusal development should be monitored to prevent abnormal delays in the eruption of the permanent successors. This report describes an unusual case in which horizontal impaction of the permanent mandibular left lateral incisor was associated with fusion of the primary mandibular left lateral incisor and canine. After the fused primary tooth was extracted, the impacted lateral incisor was able to erupt without the aid of orthodontic forces. Early detection eliminated the need for surgical intervention at a later stage.

Comparing the performance of two indices for spatial model selection: application to two mortality data.

The statistical analysis of spatially correlated data has become an important scientific research topic lately. The analysis of the mortality or morbidity rates observed at different areas may help to decide if people living in certain locations are considered at higher risk than others. Once the statistical model for the data of interest has been chosen, further effort can be devoted to identifying the areas under higher risks. Many scientists, including statisticians, have tried the conditional autoregressive (CAR) model to describe the spatial autocorrelation among the observed data. This model has greater smoothing effect than the exchangeable models, such as the Poisson gamma model for spatial data. This paper focuses on comparing the two types of models using the index LG, the ratio of local to global variability. Two applications, Taiwan asthma mortality and Scotland lip cancer, are considered and the use of LG is illustrated. The estimated values for both data sets are small, implying a Poisson gamma model may be favoured over the CAR model. We discuss the implications for the two applications respectively. To evaluate the performance of the index LG, we also compute the Bayes factor, a Bayesian model selection criterion, to see which model is preferred for the two applications and simulation data. To derive the value of LG, we estimate its posterior mode based on samples derived from the BUGS program, while for Bayes factor we use the double Laplace-Metropolis method, Schwarz criterion, and a modified harmonic mean for approximations. The results of LG and Bayes factor are consistent. We conclude that LG is fairly accurate as an index for selection between Poisson gamma and CAR model. When easy and fast computation is of concern, we recommend using LG as the first and less costly index.

Performance on the Wisconsin Card Sorting Test among adolescents in Taiwan: norms, factorial structure, and relation to schizotypy.

The aims of this study were to assess developmental trends in performance on the Wisconsin Card Sorting Test (WCST) among 817 randomly selected adolescents aged 13-15 years, and to explore WCST performance factor structure and relationship to schizotypy. The results showed that of the nine WCST indexes, only the Categories Achieved and Failure to Maintain Set scores were associated with age, and only the Learning to Learn scores reached adult levels. Factor analysis of WCST performance scores yielded a three-factor structure. Psychometrically defined schizotypic subjects did not perform significantly worse than control subjects on any WCST indexes. These findings suggest that performance on various WCST indexes might indicate developmental changes at different ages, and deficits in WCST performance might not be sensitive indicators of vulnerability to schizophrenia in adolescence.

The impact of National Health Insurance on the volume and severity of emergency department use.

National Health Insurance (NHI) was introduced in Taiwan on March 1, 1995. To evaluate the Influence of NHI on the volume and severity of emergency department (ED) visits, a retrospective analysis was conducted. The results showed that NHI did not result in a substantial increase in ED volume (P > .05), but the severity as measured by triage nurses did increase (P < .01). There was no change in the number of admissions to the intensive care units of patients transferred from smaller hospitals, but its percentage significantly decreased (P < .05), which may be a result of the significant increase in the total number of interhospital transfers. It was hypothesized that the universal coverage and a copayment contributed to these changes.

An intervention trial on efficacy of atropine and multi-focal glasses in controlling myopic progression.

PURPOSE: This randomized clinical trial assessed the treatment effects of atropine and/or multi-focal lenses in decreasing the progression rate of myopia in children. METHODS: Two hundred and twenty-seven schoolchildren with myopia, aged from 6 to 13 years, who were stratified based on gender, age and the initial amount of myopia were randomly assigned to three treatment groups: 0.5% atropine with multi-focal glasses, multi-focal glasses, and single vision spectacles. Each subject was followed for at least eighteen months. These results report on the 188 patients available for the follow-up. RESULTS: The mean progression of myopia in atropine with multi-focal glasses group (0.41 D) was significantly less than the multi-focal (1.19 D) and single vision group (1.40 D) (p < 0.0001). But no significant difference was noted between the last two groups (p = 0.44). The progression of myopia was significantly correlated with the increases of axial length (r = 0.65, p = 0.0001), but not with the changes of corneal power (r=-0.09), anterior chamber depth (r = -0.023), lens thickness (r = -0.08), or intra-ocular pressure (r = -0.008). CONCLUSION: The 0.5% atropine with multi-focal lenses can slow down the progression rate of myopia. However, multi-focal lenses alone showed no difference in effect compared to control.