Genetic testing for respiratory disease: Are we there yet?

The human genome project promised a revolution in health care – the development of ‘personalized medicine’, where knowledge of an individual’s genetic code enables the prediction of risk for specific diseases and the potential to alter that risk based on preventive measures and lifestyle modification. The present brief review provides a report card on the progress toward that goal with respect to respiratory disease. Should generalized population screening for genetic risk factors for respiratory disease be instituted? Or not?     

Genetic testing for atherosclerosis risk: Inevitability or pipe dream?

Family history is a risk factor for coronary artery disease (CAD). However, defining this risk at the DNA level has been elusive. In 2007, four genome-wide association studies reported a strong association between CAD and a region on chromosome 9p21. The high-risk genotype was identified in up to 30% of individuals, creating the potential for a clinical genetic test to assist in the calculation of a patient's CAD risk. However, the reported effect size of the association is modest (OR of approximately 1.3). The present paper examines the feasibility of including DNA tests in CAD risk prediction algorithms. The greatest contribution from the 9p21 association is likely yet to come, as further studies identify the mechanistic basis for the association, possibly leading to additional insights into the progression, prevention and treatment of CAD.     

Genetic testing for risk stratification in hypertrophic cardiomyopathy and long QT syndrome: fact or fiction?

PURPOSE OF REVIEW: Hypertrophic cardiomyopathy, affecting 1 in 500 persons, is the most common identifiable cause of sudden cardiac death in the young, whereas congenital long QT syndrome, affecting 1 in 5000 persons, is perhaps one of the most common causes of autopsy negative sudden unexplained death. Since May 2004, genetic testing has been available as a clinical diagnostic test for both hypertrophic cardiomyopathy and long QT syndrome. It is now critical to carefully scrutinize the relationships between genotype and phenotype as they pertain to clinical practice. RECENT FINDINGS: In 1990, the molecular underpinnings of hypertrophic cardiomyopathy were exposed with the identification of a mutation in the MYH7-encoded beta myosin heavy chain. Since then, hundreds of mutations scattered among at least 14 genes confer the pathogenetic substrate for this 'disease of the sarcomere'. In 1995, the discipline of cardiac channelopathies was born with the revelation that mutations in critical cardiac channel genes cause long QT syndrome. Today, hundreds of mutations involving several cardiac channel genes account for approximately 75% of long QT syndrome. Over the past decade, scores of genotype-phenotype correlation studies in both hypertrophic cardiomyopathy and long QT syndrome have been conducted. SUMMARY: Genomic medicine has now entered the clinical practice as it pertains to the evaluation and management of both hypertrophic cardiomyopathy and long QT syndrome. The diagnostic utility of genetic testing for both diseases is clearly evident, as well as current limitations. While treatment decisions are certainly influenced by knowing the underlying genotype in long QT syndrome, there seems to be negligible prognostic value associated with particular hypertrophic cardiomyopathy-causing mutations at this time.     

Colonoscopy,pain and fears: Is it an indissoluble trinomial?

Colonoscopy is the reference method in the secondary prevention,diagnosis and,in some cases,treatment of colorectal cancer.It can often cause pain associated with embarrassment,anxiety,and physical and emotional discomfort.Pain intensity is influenced by a lot of factors,and there is a strict relationship among pain,pain perception,and mind.Several methods can be used to break the trinomial colonoscopy,pain and fear.Sedoanalgesia is recommended by several guidelines.If no sedation is offered,the patient must accept a higher chance of unacceptable discomfort and the endoscopist a lower chance of completing the procedure because of patient discomfort.Other non-pharmacologic methods such as acupuncture,music,and hydrocolonoscopy can be used as alternatives to pharmacologic sedoanalgesia.Furthermore,new endoscopic technologies such as variable-stiffness colonoscopes and ultrathin colonoscopes,or the use of carbon dioxide instead of air for colon insufflation,can reduce the pain caused by colonoscopy.In the future,technical improvements such as wireless capsules or robotic probes,will probably enable to overcome the present concept of colonoscopy,avoiding the use of traditional endoscopes.However,at present the poor attention paid by endoscopists to the pain and discomfort caused by colonoscopy can not be justified.There are several methods to reduce pain and anxiety and to break the trinomial colonoscopy,pain and fear.We must use them.     

Opt-out HIV testing in prison: informed and voluntary?

HIV testing in prison settings has been identified as an important mechanism to detect cases among high-risk, underserved populations. Several public health organizations recommend that testing across health-care settings, including prisons, be delivered in an opt-out manner. However, implementation of opt-out testing within prisons may pose challenges in delivering testing that is informed and understood to be voluntary. In a large state prison system with a policy of voluntary opt-out HIV testing, we randomly sampled adult prisoners in each of seven intake prisons within two weeks after their opportunity to be HIV tested. We surveyed prisoners' perception of HIV testing as voluntary or mandatory and used multivariable statistical models to identify factors associated with their perception. We also linked survey responses to lab records to determine if prisoners' test status (tested or not) matched their desired and perceived test status. Thirty-eight percent (359/936) perceived testing as voluntary. The perception that testing was mandatory was positively associated with age less than 25 years (adjusted relative risk [aRR]: 1.45, 95% confidence interval [CI]: 1.24, 1.71) and preference that testing be mandatory (aRR: 1.81, 95% CI: 1.41, 2.31) but negatively associated with entry into one of the intake prisons (aRR: 0.41 95% CI: 0.27, 0.63). Eighty-nine percent of prisoners wanted to be tested, 85% were tested according to their wishes, and 82% correctly understood whether or not they were tested. Most prisoners wanted to be HIV tested and were aware that they had been tested, but less than 40% understood testing to be voluntary. Prisoners' understanding of the voluntary nature of testing varied by intake prison and by a few individual-level factors. Testing procedures should ensure that opt-out testing is informed and understood to be voluntary by prisoners and other vulnerable populations.     

Genetic testing for lung cancer risk: if physicians can do it,should they?

Advances in genetics have increased our ability to assess an individual's genetic risk for disease. There is a hypothesis that genetic test results will motivate high-risk individuals to reduce harmful exposures, to increase their surveillance for disease, or to seek preventive treatments. However, genetic testing for genes associated with an increased risk of lung cancer would not change physicians' recommendations regarding smoking cessation. Limited studies suggest that test results that demonstrate an increased risk of lung cancer do not improve smoking cessation success. These test results may even distort an individual's risk perceptions. Before recommending genetic testing to assess risk for disease, physicians need to consider whether knowledge about genetic susceptibility will alter patient management.     

Genetic testing for cardiovascular disease susceptibility: a useful clinical management tool or possible misinformation?

Genetic susceptibility tests are already advertised on the Internet to identify individuals at above average risk for cardiovascular disease (CVD), such as deep vein thrombosis, hyperlipidemia, or atherosclerosis, whereas other tests claim to predict response to a particular drug treatment. Some kits are available to the public directly, bypassing a doctor. Their value, however, must be considered carefully, because although a genotype may be strongly and consistently associated with an intermediate trait, and because the intermediate trait is a strong predictor of CVD risk, there may be little or no association of genotype with risk over and above that of the measured trait. This is because multigenic effects and environmental modification (context dependency) of genotype effects determine CVD risk. An individual's personal characteristics and plasma risk-trait levels (which reflect both genotype and exposure) at present are the best predictors of clinical outcome. Only when genetic tests surpass this, possibly by the inclusion of many functional common variants, in conjunction with their context-dependent effects on risk, might their usefulness in clinical management be realized. Here we review some of the particular issues and concerns raised by CVD-risk genetic testing, and suggest areas of further research to address these issues.     

Clopidogrel and genetic testing: is it necessary for everyone?

Clopidogrel is a widely used antiplatelet agent to treat and prevent a variety of atherothrombotic diseases. More than a decade after its initial Food and Drug Administration approval, studies have emerged raising concerns regarding its possible reduced efficacy in patients who have impaired conversion of clopidogrel to its active metabolite (ie, poor metabolizers). Research has implicated genetic variations in the CYP2C19 isozyme as at least partly responsible for the variable antiplatelet response seen with clopidogrel. Studies have shown that patients possessing genetic variants of the CYP2C19 isozyme may be at increased risk of adverse cardiovascular events due to impaired clopidogrel efficacy, although this has not been definitively demonstrated. The Food and Drug Administration has issued a boxed warning regarding this concern. However, specific recommendations on genetic testing and alternative therapeutic strategies are not currently available. Genetic testing is commercially available to test patients for variability in the CYP2C19 isozyme, but altering antiplatelet therapy based on the results of this testing has not been adequately studied, and it is therefore not clear how to adjust therapy based on the results of this genetic testing. In addition, there are many other factors that may contribute to the variability in antiplatelet effect seen with clopidogrel besides CYP2C19 genetic polymorphisms. Ongoing trials dealing with adjusting antiplatelet therapy based on genetic testing will hopefully provide more useful information on how to appropriately integrate pharmacogenomics with the care of patients with atherothrombotic disease.     

Audit of HIV testing: who, why and when?

The risk factors, referral pattern and presence/absence of genital tract symptoms and/or sexually transmitted infections (STIs) in 189 patients having HIV counselling and/or testing at genitourinary medicine (GUM) clinics are reviewed. Eighty per cent were concerned about heterosexual transmission, 9.5% men who have sex with men (MSM) and 4.8% intravenous drug users (IDUs). Heterosexuals and first-time GUM attenders were more likely to have sought prior advice from their general practitioner (GP). The majority were asymptomatic for genital tract infections, but 83% accepted an STI screen, with 44 STIs being diagnosed. Only one individual who had attended primarily for HIV screening was found to have an STI. About half of individuals presented within the window period, and of those stating that they wished to proceed with deferred testing, half subsequently failed to return, resulting in wasted health adviser appointments.     

Patient safety and quality in laboratory and hemostasis testing: a renewed loop?

More than three decades ago, George Lundberg first introduced the concept of the brain-to-brain loop for laboratory diagnostics. According to this pioneering model, the first step in the loop involves the selection of laboratory tests in the brain of the physician caring for the patient, and the final step is the transmission of test results back to the ordering physician. There are several intermediary steps, some of which are preanalytical (e.g., identification of patient and blood samples, the process of blood collection, and specimen handling); some are analytical and relate to the actual performance of the test(s); whereas others are postanalytical and involve release of test results into the medical record and further steps such as the physician's reaction to laboratory information, their interpretation of these results, and subsequent appropriate clinical action. Hemostasis testing should also be viewed within such a paradigm, so that quality throughout the total testing process can be assured. For hemostasis testing, particular attention is required to ensure provision of appropriate test samples in the preanalytical phase. Nevertheless, the timeliness of testing and an appropriate interpretation of test results are also paramount. This article overviews the concept of quality testing within hemostasis as critical to ensuring patient safety and optimal clinical and therapeutic management.     

Reflux and sex: what drives testing, what drives treatment?

Gastroesophageal reflux (GER) affects ～10-20% of American adults. Although symptoms are equally common in men and women, we hypothesized that sex influences diagnostic and therapeutic approaches in patients with GER. PubMed database between 1997 and October 2011 was searched for English language studies describing symptoms, consultative visits, endoscopic findings, use and results of ambulatory pH study, and surgical therapy for GER. Using data from Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality, we determined the sex distribution for admissions and reflux surgery between 1997 and 2008. Studies on symptoms or consultative visits did not show sex-specific differences. Even though women are less likely to have esophagitis or Barrett's esophagus, endoscopic studies enrolled as many women as men, and women were more likely to undergo ambulatory pH studies with a female predominance in studies from the US. Surgical GER treatment is more commonly performed in men. However, studies from the US showed an equal sex distribution, with Nationwide Inpatient Sample data demonstrating an increase in women who accounted for 63% of the annual fundoplications in 2008. Despite less common or severe mucosal disease, women are more likely to undergo invasive diagnostic testing. In the US, women are also more likely to undergo antireflux surgery. These results suggest that healthcare-seeking behavior and socioeconomic factors rather than the biology of disease influence the clinical approaches to reflux disease.