Streamlined analysis of pooled genotype data in SNP-based association studies

Several groups have developed methods for estimating allele frequencies in DNA pools as a fast and cheap way for detecting allelic association between genetic markers and disease. To obtain accurate estimates of allele frequencies, a correction factor k for the degree to which measurement of allele-specific products is biased is generally applied. Factor k is usually obtained as the ratio of the two allele-specific signals in samples from heterozygous individuals, a step that can significantly impair throughput and increase cost. We have systematically investigated the properties of k through the use of empirical and simulated data. We show that for the dye terminator primer extension genotyping method we have applied, the correction factor k is substantially influenced by the dye terminators incorporated, but also by the terminal 3' base of the extension primer. We also show that the variation in k is large enough to result in unacceptable error rates if association studies are conducted without regard to k. We show that the impact of ignoring k can be neutralized by applying a correction factor k(max) that can be easily derived, but this at the potential cost of an increase in type I error. Finally, based upon observed distributions for k we derive a method allowing the estimation of the probability pooled data reflects significant differences in the allele frequencies between the subjects comprising the pools. By controlling the error rates in the absence of knowledge of the appropriate SNP-specific correction factors, each approach enhances the performance of DNA pooling, while considerably streamlining the method by reducing time and cost.     

Analysis of case-control studies of genetic and environmental factors with missing genetic information and haplotype-phase ambiguity

Case-control studies of unrelated subjects are now widely used to study the role of genetic susceptibility and gene-environment interactions in the etiology of complex diseases. Exploiting an assumption of gene-environment independence, and treating the distribution of environmental exposures as completely nonparametric, Chatterjee and Carroll recently developed an efficient retrospective maximum-likelihood method for analysis of case-control studies. In this article, we develop an extension of the retrospective maximum-likelihood approach to studies where genetic information may be missing on some study subjects. In particular, special emphasis is given to haplotype-based studies where missing data arise due to linkage-phase ambiguity of genotype data. We use a profile likelihood technique and an appropriate expectation-maximization (EM) algorithm to derive a relatively simple procedure for parameter estimation, with or without a rare disease assumption, and possibly incorporating information on the marginal probability of the disease for the underlying population. We also describe two alternative robust approaches that are less sensitive to the underlying gene-environment independence and Hardy-Weinberg-equilibrium assumptions. The performance of the proposed methods is studied using simulation studies in the context of haplotype-based studies of gene-environment interactions. An application of the proposed method is illustrated using a case-control study of ovarian cancer designed to investigate the interaction between BRCA1/2 mutations and reproductive risk factors in the etiology of ovarian cancer.     

Sea change or quick fix? Policy on long‐term conditions in England

Long-term conditions is a policy area that has risen rapidly up the political agenda in England, culminating in the development of the National Health Service and Social Care Model in 2005, which is to be implemented over the following 2 years. The Model draws heavily upon US ideas of case management and proposes the creation of 3000 community matrons to undertake this role with the most vulnerable patients. Although welcomed in principle, the specific proposals in the Model have been subject to some criticism, and these issues are explored in the present paper. The problematic areas include patient identification, the transplanting of US models to England, the role of case management, workforce and funding issues, and the mix of medical and social models. The author concludes that there is a danger of long-term care policy developing an unduly health-focused approach at a time when the thrust of partnership working is towards an inclusive, whole-system model.     

职业病危害项目申报中存在的问题及对策

目的了解深圳市罗湖区职业病危害项目申报情况。方法结合经常性监测工作对285家用人单位的“职业病危害项目申报表”及其他申报资料进行分析。结果只有202家用人单位能够正确申报所有项目,28家用人单位拒绝申报。31家用人单位不如实申报,14家用人单位拒绝变更申报。结论应采取举办学习《中华人民共和国职业病防治法》等法律法规培训班、深入各大工业区现场宣传职业病危害项目申报工作等知识、加强经常性监测工作以及对拒绝申报、不如实申报的用人单位给予罚款处罚等对策。     

"Not that sort of practice": the views and behaviour of primary care practitioners in a study of advance provision of emergency contraception

BACKGROUND: Advance supplies of emergency contraception (EC) were made available to women aged 16-29 through general practice and family planning services in Lothian, Scotland. Although this intervention was not associated with an overall reduction in abortion rates in Lothian, it was hypothesized that some general practices may have been more successful than others in promoting and delivering the intervention. OBJECTIVE: To investigate, using comparative case studies, whether, and why, some general practices were more successful in promoting and delivering advance supplies of EC than others. METHODS: Eleven purposively sampled general practices from the 97 participating in the intervention were studied. The number of packs of advance supplies distributed was recorded and distribution rates per 100 eligible women per practice calculated. 44 semi-structured interviews with staff were used to describe the mechanisms through which advance supplies were distributed and health professionals' views of the intervention. RESULTS: Distribution rates varied from 0.9 to 32.0 per 100 eligible women. Respondents described three mechanisms through which advance supplies were distributed: passive, reactive and proactive. Views about EC, and the suitability of their patient population for advance supplies, varied and configured specific practice contexts that facilitated or hindered the delivery of advance supplies. Favourable views and pro-active mechanisms were associated with higher distribution rates, less favourable or ambivalent views and passive delivery mechanisms with lower distribution rates. CONCLUSION: If primary care professionals are to actively engage with a sexual health promotion agenda they need to develop appropriate interpersonal skills and address their values, attitudes and cultural competences.     

Cobalamin deficiency and subacute combined degeneration after nitrous oxide anesthesia: a case report

We report on a diabetic man in his early forties with a history of disabling left-hemisphere stroke and hyperhomocystinemia who developed new sensorimotor symptoms and urinary incontinence 4 weeks after prolonged exposure to nitrous oxide (N(2)O) related to arterial occlusive disease and amputation. Physical examination at rehabilitation hospital admission showed preexisting severe nonfluent multimodality language impairment, new ataxic quadriparesis superimposed on static spastic right hemiparesis, diffusely blunted muscle stretch reflexes, impaired cutaneous sensation and proprioception, diminished alternating motion rates, and impaired truncal balance. Laboratory tests revealed low serum cobalamin and hyperhomocystinemia. Magnetic resonance imaging of the spinal cord showed dorsal T2-signal hyperintensity. Treatment included vitamin replacement and comprehensive rehabilitation. His response to hospital-based and outpatient treatment led to successful prosthetic fitting. This case shows the importance of screening for and treating cobalamin deficiency before exposing patients with known risk to N(2)O and highlights the potential diagnostic and therapeutic challenges of subacute combined degeneration when it occurs with a setting of preexisting disabling neurologic impairment.     

One rare side effect of zolpidem--sleepwalking: a case report

Zolpidem is an imidazopyridine agent indicated for the short-term treatment of insomnia. Sleepwalking is a rare side effect of zolpidem. A review of the literature produced only 2 cases. We report a case of a male rehabilitation inpatient in his mid fifties with a history of alcoholism and traumatic brain injury who had undergone a right hip hemiarthroplasty. He had no history of somnambulism or insomnia but walked in his sleep on 2 nonconsecutive nights after taking zolpidem. He had exhibited no such behavior before taking zolpidem, on the intervening night that was he was not given medication, and after the medication was discontinued. We conclude that zolpidem can cause sleepwalking, and patients who have suffered a brain injury may be more susceptible to this side effect. Here we describe the clinical presentation and review the relevant literature on zolpidem and sleepwalking.     

Intracerebral hemorrhage secondary to autonomic dysreflexia in a young person with incomplete C8 tetraplegia: A case report

Intracerebral hemorrhage is an unusual complication of autonomic dysreflexia and can be fatal if massive bleeding occurs with brain herniation. We report the case of a man in his midthirties with incomplete tetraplegia who suffered right putaminal hemorrhage during an episode of autonomic dysreflexia. Prompt recognition and removal of the triggering factors of autonomic dysreflexia quickly brought his blood pressure under control and the patient had a favorable functional outcome after rehabilitation. A review of the literature suggests that the location of hemorrhage in autonomic dysreflexia-induced cases is similar to that in the general population. The most common triggering factors are bladder distension in men and labor induction in women. Hemorrhagic stroke can also occur in patients with incomplete spinal cord injury (SCI) who develop autonomic dysreflexia. The role of sympathetic skin response examination is also discussed. This life-threatening complication should be kept in mind in the case of people with SCI.     

Early case conferences shorten length of stay in children admitted to hospital with suspected child abuse

OBJECTIVE: To compare the outcomes of two models for the management of children admitted to hospital with suspected child abuse: routine early case conferencing versus standard evaluation. METHODS: Between March 2001 and February 2002 professionals from the Royal Children's Hospital, Melbourne, Victoria Police and Child Protection services collaborated on a randomized controlled study involving children admitted to hospital with suspected child abuse. The intervention group (n = 13) received a case conference within 24 h of the child's admission to hospital. The control group (n = 12) were managed according to standard procedures whereby each organization conducted their own evaluation (and a case conference might or might not have been held). Patients were followed for 3 months with data collected from all three professional groups. RESULTS: The process of evaluation, the eventual diagnosis of child abuse and the confidence with which professionals made this diagnosis was not significantly different between the groups. Case conferences were judged to be useful regardless of their timing. Mean length of stay in the intervention group was significantly less than in controls (42.4 h vs 99.7 h, P = 0.01). CONCLUSION: Early case conferences appear to shorten the period of time children spend in hospital when child abuse is suspected. This has significant implications for reducing costs for all organizations involved in the evaluation of suspected child abuse.     

Dumbbell trigeminal schwannoma in a child: complete removal by a one-stage pterional surgical approach

Objective The objective was to describe a rare case of a trigeminal schwannoma in a child and the surgical procedure performed for therapy.Patient and methods A 6-year-old girl presented with tiredness, dysarthric speech and cerebellar symptoms. Imaging studies revealed a unilateral dumbbell-shaped tumour, extending into both the middle and posterior fossa, centred over Meckels cave. One-stage surgery was performed by pterional craniotomy. The tumour was first debulked in the middle fossa, then peeled from the wall of the cavernous sinus, followed by extirpation of the tumour from the posterior fossa. The tumour extended to the caudal cranial nerves and was completely removed. Trigeminal fascicles were distributed throughout the tumour. Histopathological examination revealed a schwannoma.Conclusion Trigeminal schwannoma is a tumour that occurs rarely in childhood. Although several, often multistaged surgical strategies have been reported in the literature, this tumour was eradicated by a one-stage pterional approach.