Uniparental disomy: can SNP array data be used for diagnosis?

PurposeSingle-nucleotide polymorphism microarray analysis identifies copy-number variants and blocks of homozygosity, suggestive of consanguinity or uniparental disomy. The purpose of this study was to validate chromosomal microarray analysis for the identification of uniparental disomy in a clinical laboratory.MethodsIn phase I of this retrospective study, nine cases with uniparental disomy for chromosomes 7 (n = 1), 14 (n = 1), and 15 (n = 7), identified by conventional polymorphic microsatellite marker analysis were analyzed on the Affymetrix 6.0 single-nucleotide polymorphism array. In phase II, four cases of uniparental disomy 15 showing heterozygosity for all microsatellite markers were analyzed using the same array.ResultsChromosomal microarray analysis detected blocks of homozygosity in eight of the nine cases in phase I. Phase II analysis of molecularly defined heterodisomy failed to detect blocks of homozygosity in three of the four cases. The four cases in which microarray did not detect blocks of homozygosity all involved chromosome 15.ConclusionA failure to recombine may predispose to nondisjunction and, therefore, to uniparental disomy. Four cases of heterodisomy 15 were not detected by array, suggesting a lack of recombination. Therefore, a normal chromosomal microarray result for chromosome 15 does not exclude the possibility of uniparental disomy. This observation may apply to other chromosomes; however, further study is needed.Genet Med 2012:14(8):753–756     

How can machine-learning methods assist in virtual screening for hyperuricemia? A healthcare machine-learning approach

ObjectOur purpose was to develop a new machine-learning approach (a virtual health check-up) toward identification of those at high risk of hyperuricemia. Applying the system to general health check-ups is expected to reduce medical costs compared with administering an additional test.MethodsData were collected during annual health check-ups performed in Japan between 2011 and 2013 (inclusive). We prepared training and test datasets from the health check-up data to build prediction models; these were composed of 43,524 and 17,789 persons, respectively. Gradient-boosting decision tree (GBDT), random forest (RF), and logistic regression (LR) approaches were trained using the training dataset and were then used to predict hyperuricemia in the test dataset. Undersampling was applied to build the prediction models to deal with the imbalanced class dataset.ResultsThe results showed that the RF and GBDT approaches afforded the best performances in terms of sensitivity and specificity, respectively. The area under the curve (AUC) values of the models, which reflected the total discriminative ability of the classification, were 0.796 [95% confidence interval (CI): 0.766–0.825] for the GBDT, 0.784 [95% CI: 0.752–0.815] for the RF, and 0.785 [95% CI: 0.752–0.819] for the LR approaches. No significant differences were observed between pairs of each approach. Small changes occurred in the AUCs after applying undersampling to build the models.ConclusionsWe developed a virtual health check-up that predicted the development of hyperuricemia using machine-learning methods. The GBDT, RF, and LR methods had similar predictive capability. Undersampling did not remarkably improve predictive power.     

Should GLP-1 receptor agonists be used with caution in high risk population for colorectal cancer?

Glucagon-like peptide-1 (GLP-1) receptor agonists, with few reported side effects, are a kind of very promising anti-diabetes drugs. They are thus being paid high hopes on by both doctors and patients. GLP-1 receptor agonists, however, have not been used in clinic for a long time. Some unknown potential adverse effects may exist. Because GLP-1 receptor agonists enhance β cells proliferation in pancreas via influencing Wnt/β-catenin pathway, a pathway which is associated with tumorigenesis in colon, we then assume that GLP-1 receptor agonists may increase the risk for colorectal cancer.     

How can the postgraduate training program in pathology departments in India be improved?

There exists a wide variation in the competence of the postgraduate residents trained in pathology in different institutions across India. This results in strong disparities in the clinical diagnostic skills, teaching skills, research capabilities and the managerial skills of the graduates. The end users of this training, namely the community, clinicians and health care institutions would benefit from a more uniform and better trained pathologist. The article reviews the reasons for the variation in the quality of the training programs. The main deficiencies include, lack of well-defined criteria for recruitment of residents, training facilities, faculty resources, curriculum with well-defined learning objectives and competencies, hands-on experiences in diagnostic and research activities, diagnostic specimens and medical autopsies, exposure to molecular pathology, pathology informatics, electron microscopy, research experiences, communication skills, professional behavior and bioethics, business practices in pathology and quality assurance. There is also a lack of defined career tracks in various disciplines in laboratory medicine, standard protocols for evaluation and regional and national oversight of the programs. The steps for rectification should include defining the competencies and learning objectives, development of the curriculum including teaching methods, facilities and evaluation strategies, communication skills, professional behavior skills, teaching skills, legal aspects of practicing pathology and the various career pathways to subspecialties in pathology. The training should include defined exposure to molecular pathology, electron microscopy, quality control and assurance, laboratory accreditation, business aspects of pathology practice, review of literature, evidence-based medicine, medical autopsy and medical informatics. Efforts should be made to share human and laboratory resources between regional cooperation. The oversight and accreditation policies should be evolved and well-documented. Web-based platforms need to be developed for easy interaction among residents, faculty and administrators on a national level.     

Should androgen supplementation be used for poor ovarian response in IVF?

Poor ovarian response is reported in 9-24% of IVF cycles. Several interventions have been proposed to improve the outcome, although evidence to support these has been scant. There has been interest in the use of adjuvant androgens in this context and a recent worldwide survey showed that nearly a quarter of IVF clinicians used dehydroepiandrosterone (DHEA) in poor responders. We examine the rationale for the use of adjuvant androgens and suggest that the current clinical uncertainty should be addressed by a randomized controlled trial of DHEA in poor responders.     

Should placebo be used routinely for chronic pain in older people?

As research expands our understanding of underlying placebo mechanisms, interest turns to the clinical application of placebos. Whether placebos are appropriate and effective in the management of chronic pain in older people deserves considerable attention. The evidence suggests that adults of any age are responsive to placebos, and that placebo treatments can be effective for many conditions prevalent in older people. Though placebos in general already seem to be used with some regularity in medical practice, the use of placebos alone for chronic pain is probably unjustified unless other treatments are inadvisable or have been exhausted. However maximising the mechanisms that underpin placebo analgesia such as expectancy or the psychosocial context should be encouraged and would be considered a feature of good clinical practice. It would also be anticipated that older people may see an additional benefit with placebo treatments when such treatments reduce existing or planned medication regimes, as older people typically experience more comorbidities, increased susceptibility to adverse drug reactions, and altered pharmacological responses to drugs. Further research is still needed in placebo-related treatment paradigms for the management of chronic pain in older people.     

Is there a common genetic basis for autoimmune diseases?

Autoimmune diseases (ADs) represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. The commonality between them however, is the damage to tissues and organs that arises from the response to self-antigens. The presence of shared pathophysiological mechanisms within ADs has stimulated searches for common genetic roots to these diseases. Two approaches have been undertaken to sustain the "common genetic origin" theory of ADs. Firstly, a clinical genetic analysis showed that autoimmunity aggregates within families of probands diagnosed with primary Sj?gren's (pSS) syndrome or type 1 diabetes mellitus (T1D). A literature review supported the establishment of a familiar cluster of ADs depending upon the proband's disease phenotype. Secondly, in a same and well-defined population, a large genetic association study indicated that a number of polymorphic genes (i.e. HLA-DRB1, TNF and PTPN22) influence the susceptibility for acquiring different ADs. Likewise, association and linkage studies in different populations have revealed that several susceptibility loci overlap in ADs, and clinical studies have shown that frequent clustering of several ADs occurs. Thus, the genetic factors for ADs consist of two types: those which are common to many ADs (acting in epistatic pleitropy) and those that are specific to a given disorder. Their identification and functional characterization will allow us to predict their effect as well as to indicate potential new therapeutic interventions. Both autoimmunity family history and the co-occurrence of ADs in affected probands should be considered when performing genetic association and linkage studies.     

How effective are screening tests for microalbuminuria in random urine specimens?

The effectiveness of four urine screening tests-microalbumin (MAlb), total protein (TProt), total protein/creatinine ratio (TProt/Cr R), and dipstick (DPalb) test for albumin-were evaluated for the detection of MAlb in random urine specimens. The following criteria were used to assess the effectiveness of each urine screening test: 100% specificity (no false positive results); cost effectiveness; rapidity and ease of performing the screening test; and increased laboratory efficiency. A "gold standard" for presence of MAlb in random urine samples was defined as a microalbumin/creatinine ratio (MAlb/Cr R) of > or = 30 mg/g. The least costly urine screening test was the DPalb, which, if assigned a value of 1.0, allowed a cost ranking order for the screening tests-DPalb (1.0) < urine TProt (1.03) < urine TProt/Cr R (2.1) < urine MAlb (7.0). Two hundred urine samples from diabetic inpatients and outpatients were tested. Only two screening tests--MAlb and DPalb--achieved 100% specificity without increasing laboratory costs (small net savings), whereas the other two screening tests--TProt and TProt/Cr R-only achieved 100% specificity with increased laboratory costs. Theoretical prevalence rate analysis showed that urine MAlb screening would be effective at all prevalence rates for overt nephropathy. TProt and DPalb urine screening testing would be most effective in populations with prevalence rates of > or = 15% for overt nephropathy. The TProt/Cr R ratio would only be effective in populations with prevalence rates of > or = 30%. Of the four urine screening tests, only DPalb would significantly streamline the process of measuring urine MAlb. The dipstick test is inexpensive, easy and rapid to perform, does not delay measuring the ratio, since there is no wait for the screening test result, and can be used by referring laboratories to screen urine specimens before they are submitted to a central laboratory, thereby reducing laboratory workload.     

Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases?

The mood stabilizing drug lithium has emerged as a robust neuroprotective agent in preventing apoptosis of neurons. Long-term treatment with lithium effectively protects primary cultures of rat brain neurons from glutamate-induced, NMDA receptor-mediated excitotoxicity. This neuroprotection is accompanied by an inhibition of NMDA-receptor-mediated calcium influx, upregulation of anti-apoptotic Bcl-2, downregulation of pro-apoptotic p53 and Bax, and activation of cell survival factors. Lithium treatment antagonizes glutamate-induced activation of c-Jun-N-terminal kinase (JNK), p38 kinase, and AP-1 binding, which has a major role in cytotoxicity, and suppresses glutamate-induced loss of phosphorylated cAMP responsive element binding protein (CREB). Lithium also induces the expression of brain-derived neurotrophic factor (BDNF) and subsequent activation TrkB, the receptor for BDNF, in cortical neurons. The activation of BDNF/TrkB signaling is essential for the neuroprotective effects of this drug. In addition, lithium stimulates the proliferation of neuroblasts in primary cultures of CNS neurons. Lithium also shows neuroprotective effects in rodent models of diseases. In a rat model of stroke, post-insult treatment with lithium or valproate, another mood stabilizer, at therapeutic doses markedly reduces brain infarction and neurological deficits. This neuroprotection is associated with suppression of caspase-3 activation and induction of chaperone proteins such as heat shock protein 70. In a rat model of Huntington's disease (HD) in which an excitotoxin is unilaterally infused into the striatum, both long- and short-term pretreatment with lithium reduces DNA damage, caspase-3 activation, and loss of striatal neurons. This neuroprotection is associated with upregulation of Bcl-2. Lithium also induces cell proliferation near the injury site with a concomitant loss of proliferating cells in the subventricular zone. Some of these proliferating cells display neuronal or astroglial phenotypes. These results corroborate our findings obtained in primary neuronal cultures. The neuroprotective and neurotrophic actions of lithium have profound clinical implications. In addition to its present use in bipolar patients, lithium could be used to treat acute brain injuries such as stroke and chronic progressive neurodegenerative diseases.     

Should hepatitis B vaccine be used for infants?

Chronic hepatitis B virus infection causes nearly all the deaths from this virus. As the initial infection occurs without symptoms and decades prior to the onset of cirrhosis and liver cancer, these consequences are rarely recognized as being caused by the virus. Consequently, its public health importance is under-recognized. Safe and effective vaccines have now been available for over 20 years. Concerns have been raised regarding the mercury preservative in vaccines leading to potential toxicity. But the evidence to date does not support any association of hepatitis B vaccine with serious adverse consequences. Protecting infants through immunization is the most effective control strategy. By 2005, over 80% of countries had implemented routine infant immunization. In countries with relatively low rates of hepatitis B virus infection, some have argued to defer immunization until later life. However, these arguments focus on the more visible acute infection. The possible future cost from a single infant infection argues for universal infant hepatitis B immunization--given the very high costs of treating its consequences (e.g., liver transplant) and the very low price of the vaccine.     

Can topical duloxetine be used for neuropathic pain?

Duloxetine is a serotonin and norepinephrine re-uptake inhibitor with both anti-depressant and pain-relieving properties. Its pain-relieving properties are due to its action on the descending inhibitory pain pathways. However, the fast onset of analgesia may be mediated by mechanisms other than the descending inhibitory pain pathways. This study posits the hypothesis that duloxetine may have pain-relieving property by peripheral analgesic effects. Ways of testing this hypothesis and its potential topical use are discussed.     

How can self-efficacy be increased? Meta-analysis of dietary interventions

Targeting individuals' beliefs that they are able to eat healthily can improve dietary-related behaviours. However, the most effective behaviour change techniques (BCTs) to promote dietary self-efficacy have not been systematically reviewed. This research addressed this gap. Studies testing the effect of interventions on healthy eating and underlying dietary-related self-efficacy, within randomised controlled trials, were systematically reviewed in MEDLINE, EMBASE and PSYCINFO. Two reviewers independently coded intervention content in both intervention and comparison groups. Data pertaining to study quality were also extracted. Random effects meta-analysis was used to calculate an overall effect size on dietary self-efficacy for each study. The associations between 26 BCTs and self-efficacy effects were calculated using meta-regression. In some of the analyses, interventions that incorporated self-monitoring (tracking one's own food-related behaviour), provided feedback on performance, prompted review of behavioural goals, provided contingent rewards (rewarding diet success), or planned for social support/social change increased dietary self-efficacy significantly more than interventions that did not. Stress management was consistently associated with self-efficacy effects across all analyses. There was strong evidence for stress management and weaker evidence for a number of other BCTs. The findings can be used to develop more effective, theory- and evidence-based behavioural interventions.     

Newborn screening for neurodevelopmental diseases: Are we there yet?

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.