在医疗保健领域开发和使用生物标记物的政策性问题

描述了发展中的生物标记物所处的科学、产业、监管和医疗保健管理系统背景,指出了可能阻碍生物标记物研究、发现、发展、商业化及最终临床应用的一些障碍,聚焦了医疗保健中基于生物标记物的诊断方法和医学检验的应用,探索了生物标记物在改良药物开发中的应用。     

Biomarkers in molecular epidemiology studies for health risk prediction

The field of molecular epidemiology is very promising, as sophisticated techniques are being developed to address etiology, genetic susceptibility and mechanisms for induction of disease. The use of biomarkers plays a key role in these investigations because the information can be used to predict the development of disease and to implement disease prevention programs. However, as emphasized by Frederica P. Perera, the field is strewn with studies either that failed to use validated biomarkers or whose designs did not adequately consider the biology of the endpoints, and the availability of validated biomarkers of health risk is still limited. In this review, we have briefly described the usefulness of certain biomarkers for the documentation of exposure and early biological effects, with special concern for the prediction of cancer. An emphasis is placed on understanding the biological and health significance of biomarkers. By building reliable biomarker databases, a promising future is the integration of information from the genome programs to expand the scientific frontiers on etiology, health risk prediction and prevention of environmental disease.     

Blood-Borne Biomarkers of Mortality Risk: Systematic Review of Cohort Studies

Background

Lifespan and the proportion of older people in the population are increasing, with far reaching consequences for the social, political and economic landscape. Unless accompanied by an increase in health span, increases in age-related diseases will increase the burden on health care resources. Intervention studies to enhance healthy ageing need appropriate outcome measures, such as blood-borne biomarkers, which are easily obtainable, cost-effective, and widely accepted. To date there have been no systematic reviews of blood-borne biomarkers of mortality.

Aim

To conduct a systematic review to identify available blood-borne biomarkers of mortality that can be used to predict healthy ageing post-retirement.

Methods

Four databases (Medline, Embase, Scopus, Web of Science) were searched. We included prospective cohort studies with a minimum of two years follow up and data available for participants with a mean age of 50 to 75 years at baseline.

Results

From a total of 11,555 studies identified in initial searches, 23 fulfilled the inclusion criteria. Fifty-one blood borne biomarkers potentially predictive of mortality risk were identified. In total, 20 biomarkers were associated with mortality risk. Meta-analyses of mortality risk showed significant associations with C-reactive protein (Hazard ratios for all-cause mortality 1.42, p<0.001; Cancer-mortality 1.62, p<0.009; CVD-mortality 1.31, p = 0.033), N Terminal-pro brain natriuretic peptide (Hazard ratios for all-cause mortality 1.43, p<0.001; CHD-mortality 1.58, p<0.001; CVD-mortality 1.67, p<0.001) and white blood cell count (Hazard ratios for all-cause mortality 1.36, p = 0.001). There was also evidence that brain natriuretic peptide, cholesterol fractions, erythrocyte sedimentation rate, fibrinogen, granulocytes, homocysteine, intercellular adhesion molecule-1, neutrophils, osteoprotegerin, procollagen type III aminoterminal peptide, serum uric acid, soluble urokinase plasminogen activator receptor, tissue inhibitor of metalloproteinases 1 and tumour necrosis factor receptor II may predict mortality risk. There was equivocal evidence for the utility of 14 biomarkers and no association with mortality risk for CD40 ligand, cortisol, dehydroepiandrosterone, ferritin, haemoglobin, interleukin-12, monocyte chemoattractant protein 1, matrix metalloproteinase 9, myelopereoxidase, P-selectin, receptor activator of nuclear factor KappaB ligand, sex hormone binding globulin, testosterone, transferrin, and thyroid stimulating hormone and thyroxine.

Conclusions

Twenty biomarkers should be prioritised as potential predictors of mortality in future studies. More studies using standardised protocols and reporting methods, and which focus on mortality rather than risk of disease or health status as an outcome, are needed.     

Biomarkers for cardiovascular disease: challenges and future directions

The accurate diagnosis and prevention of cardiovascular disease (CVD) is an important public health goal. Although clinical characteristics such as age and gender are well-established risk factors for CVD, such features are not sufficient to identify all patients at risk. Cardiovascular biomarkers have the potential to augment clinical risk stratification by aiding in screening, diagnosis and assessment of prognosis. However, most current biomarkers have only modest predictive value, and there is a need to identify additional biomarkers from new biological pathways. The availability of platforms for profiling DNA, RNA, proteins and metabolites in clinical specimens has facilitated the 'unbiased' search for new biomarkers, which can now be tested in a clinical setting. This review highlights recent developments in the field of cardiovascular biomarkers and describes the use of new technologies for the identification of biomarkers.     

The state of health of oncology nurses characterized by genetic and immunotoxicologic biomarkers

Statistical data indicate a chronic shortage of work-force due to overwork, ill health state and increased risk of chronic noninfectious diseases in Hungarian health care personnel, which needs investigations in order to decrease the risk. Nurses of oncology units, often exposed to carcinogens when preparing and handling cytostatic drugs, are especially at high risk. In the present publication we report a complex clinical, geno- and immunotoxicology risk assessment of altogether 500 nurses, performed during the last 10 years at various oncology units in Hungary. The obtained results indicate that the health status of nurses at oncology units is better than the Hungarian average, especially of hypertonia and type II diabetes. However, the prevalence of iron deficiency anemia and different thyroid gland diseases is significantly higher than those of the controls matched for sex and age. The results suggest that iron deficiency can potentiate the resistance to insulin, i.e. the persistence of iron deficiency may increase the serum glucose levels and thus the risk of diabetes. Among the studied geno- and immunotoxicology biomarkers, the frequency of chromosome aberrations, sister chromatid exchange and B lymphocytes was significantly increased compared to the matched controls. The obtained alterations demonstrate the occupational exposure of the nurses to cytostatic drugs, thus the introduction of more strict hygienic controls and compliance with the European Union chemical safety regulations is necessary.     

Continuous health monitoring: integrating biomarkers for the management of chronic diseases

With the recent progresses of the information and communication technologies, biosensors and nanotechnologies, the access to continuing health monitoring is becoming real. The development of efficient, accurate and interactive solutions integrating biomarkers for continuing health monitoring might contribute to an improved care of some chronic diseases like hypertension, diabetes or heart failure. Continuing health monitoring might also enhance the efficiency and safety of patient’s treatments.     

Prospects for incorporation of epigenetic biomarkers in human health and environmental risk assessment of chemicals

Epigenetic mechanisms have gained relevance in human health and environmental studies, due to their pivotal role in disease, gene × environment interactions and adaptation to environmental change and/or contamination. Epigenetic mechanisms are highly responsive to external stimuli and a wide range of chemicals has been shown to determine specific epigenetic patterns in several organisms. Furthermore, the mitotic/meiotic inheritance of such epigenetic marks as well as the resulting changes in gene expression and cell/organismal phenotypes has now been demonstrated. Therefore, epigenetic signatures are interesting candidates for linking environmental exposures to disease as well as informing on past exposures to stressors. Accordingly, epigenetic biomarkers could be useful tools in both prospective and retrospective risk assessment but epigenetic endpoints are currently not yet incorporated into risk assessments. Achieving a better understanding on this apparent impasse, as well as identifying routes to promote the application of epigenetic biomarkers within environmental risk assessment frameworks are the objectives of this review. We first compile evidence from human health studies supporting the use of epigenetic exposure‐associated changes as reliable biomarkers of exposure. Then, specifically focusing on environmental science, we examine the potential and challenges of developing epigenetic biomarkers for environmental fields, and discuss useful organisms and appropriate sequencing techniques to foster their development in this context. Finally, we discuss the practical incorporation of epigenetic biomarkers in the environmental risk assessment of chemicals, highlighting critical data gaps and making key recommendations for future research within a regulatory context.     

The use of biomarkers in surveillance, medical screening, and intervention

Building on mechanistic information, much of molecular epidemiologic research has focused on validating biomarkers, that is, assessing their ability to accurately indicate exposure, effect, disease, or susceptibility. To be of use in surveillance, medical screening, or interventions, biomarkers must already be validated so that they can be used as outcomes or indicators that can serve a particular function. In surveillance, biomarkers can be used as indicators of hazard, exposure, disease, and population risk. However, to obtain rates for these measures, the population at risk will need to be assessed. In medical screening, biomarkers can serve as early indicators of disease in asymptomatic people. This allows for the identification of those who should receive diagnostic confirmation and early treatment. In intervention (which includes risk assessment and communication, risk management, and various prevention efforts), biomarkers can be used to assess the effectiveness of a prevention or control strategy as well as help determine whether the appropriate individuals are assigned to the correct intervention category. Biomarkers can be used to provide group and individual risk assessments that can be the basis for marshalling resources. Critical for using biomarkers in surveillance, medical screening, and intervention is the justification that the biomarkers can provide information not otherwise accessible by a less expensive and easier-to-obtain source of information, such as medical records, surveys, or vital statistics. The ability to use validated biomarkers in surveillance, medical screening, and intervention will depend on the extent to which a strategy for evidence-based procedures for biomarker knowledge transfer can be developed and implemented. This will require the interaction of researchers and decision-makers to collaborate on public health and medical issues.     

Plasma extracellular vesicle protein content for diagnosis and prognosis of global cardiovascular disease

Cardiovascular disease is a major public health problem worldwide. Its growing burden is particularly ominous in Asia, due to increasing rates of major risk factors such as diabetes, obesity and smoking. There is an urgent need for early identification and treatment of individuals at risk of adverse cardiovascular events. Plasma extracellular vesicle proteins are novel biomarkers that have been shown to be useful in the diagnosis, risk stratification and prognostication of patients with cardiovascular disease. Ongoing parallel biobank initiatives in European (the Netherlands) and Asian (Singapore) populations offer a unique opportunity to validate these biomarkers in diverse ethnic groups.     

Gender-specific differences in biomarkers responses to acute coronary syndromes and revascularization procedures

A growing body of gender-related research in coronary artery disease is beginning to gradually elucidate differences between women and men. In patients presenting with acute coronary syndromes (ACS), these sex differences include varying risk factor profiles, accuracy of diagnostic testing, clinical presentations, treatment practices and outcomes. There is also a differential expression of cardiac biomarkers by sex, which remains unexplained. This paper reviews all the available information on the effect of gender on cardiac biomarkers by search of MEDLINE using the terms gender differences, biomarkers, ACS and revascularization procedures. A better understanding of the sex disparities in biomarkers along with all other clinical information is essential to optimal management and patient care in the future.     

军队医院医疗风险管理的措施及意义

随着我国法治社会的发展及医疗体制的改革,医疗风险成为军队医院管理面临的难题和挑战。目前,我国现有的医疗法规不够完善,医务人员与患者的医疗风险防范意识不足,社会舆论导向性偏移等问题制约着我国医疗系统的发展。作为医疗卫生系事业的重要力量,军队医院要加强医疗风险管理,制定风险评估方法,完善风险管理体系以及加强风险教育,进一步提高医疗服务质量,从而有利维护军队医院在群众心中的信誉和形象。     

Recent developments in diagnosis and risk stratification of non-ST-elevation acute coronary syndrome

In the past year, a number of important papers have been published on non-ST-elevation acute coronary syndrome, highlighting progress in clinical care. The current review focuses on early diagnosis and risk stratification using biomarkers and advances in intracoronary imaging.

     

Systematic Review of Screening and Surveillance Programs to Protect Workers from Nanomaterials

BackgroundScreening and surveillance approaches for workers exposed to nanomaterials could aid in early detection of health effects, provide data for epidemiological studies and inform action to decrease exposure. The aim of this review is to identify such screening and surveillance approaches, in order to extract available data regarding (i) the studies that have successfully been implemented in present day, (ii) identification of the most common and/or toxic nano-related health hazards for workers and (iii) possible exposure surveillance markers. This review contributes to the current understanding of the risk associated with nanomaterials by determining the knowledge gap and making recommendations based on current findings.MethodsA systematic review was conducted. PubMed and Embase were searched to identify articles reporting on any surveillance-related study that described both exposure to nanomaterials and the health indicators that were measured. Four reviewers worked in pairs to independently assess the eligibility of studies and risk of bias before extraction of data. Studies were categorised according to the type of study and the medical surveillance performed, which included the type of nanomaterial, any exposure details provided, as well as health indicators and biomarkers tested.ResultsInitially 92 studies were identified, from which 84 full texts were assessed for eligibility. Seven studies met all the inclusion criteria, i.e. those performed in Taiwan, Korea, Czech Republic and the US. Of these, six compared health indicators between exposed and unexposed workers and one study described a surveillance program. All studies were at a high risk of bias. Workers were exposed to a mix of nanomaterials in three studies, carbon-based nanomaterials in two studies, nano-silver in one study and nano-titanium oxide in the other study. Two studies did not find a difference in biomarkers between exposed and unexposed workers. In addition, differences in early effects on pulmonary function or neurobehavioral tests were not observed. One study found an increased prevalence of allergic dermatitis and “sneezing” in the exposed group.ConclusionsThis review of recently published data on surveillance studies proves that there is a gap in the current knowledge, where most of the surveillance-related studies reported do not follow a set format that provides the required information on ENM characterisation, the type of exposure and the measured indicators/biomarkers. Hence, there is very low quality evidence that screening and surveillance might detect adverse health effects associated with workplace exposure. This systematic review is relevant because it proves that, although surveillance programs have been initiated and preliminary results are being published, the current studies are actually not answering the important questions or solving the overall problem regarding what the potential health hazards are among workers either handling or potentially exposed to ENMs. The recommendations, thus proposed, are based on an obvious need for (i) exposure registries, where longitudinal follow-up studies should inform surveillance, (ii) known exposure measurements or summary indices for ENMs as a reference (iii) validation of candidate biomarkers and (iv) studies that compare the effects of these surveillance approaches to usual care, e.g. those commonly followed for bulk-size hazardous materials.     

Sequence Thyself: Personalized Medicine and Therapies for the Future: 2012 Yale Healthcare Conference

Now in its 8th year, the Yale Healthcare Conference has arguably come upon its most exciting and dramatic time within the U.S. health care system. Dynamic speakers from all over the country came together in April 2012 at Yale University to question, debate, creatively think, and examine challenges within health care organizations and institutions. One of the most prominent issues concerned the aftermath of sequencing the human genome and the explosion of information concerning gene polymorphisms and biomarkers in health and disease. Clinicians, scientists, and pharmaceuticals are looking to innovative individually tailored treatments for patients. During the conference breakout session, speakers Thomas Lynch, MD, director of the Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital, and Zen Chu, MBA, co-founder of Accelerated Medical Ventures and entrepreneur-in-residence at Massachusetts Institute of Technology, provided enriching discussion on the delivery of science and genetic care of the individual.     

Biomarkers of cellular senescence and risk of death in humans

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76–0.82) than the covariates alone (0.70, CI: 0.67–0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.     

Oral health care and aspiration pneumonia in frail older people: a systematic literature review

Objective: To systematically review the literature on oral health care interventions in frail older people and the effect on the incidence of aspiration pneumonia. Background: Oral health care seems to play an important role in the prevention of aspiration pneumonia in frail older people. Methods: Pubmed, Web of Science, Cochrane Library, EMBASE and CINAHL were searched for eligible intervention studies. Only publications with regard to hospitalized or institutionalized older people, who were not dependent on mechanical ventilation were eligible. Two authors independently assessed the publications for their methodological quality. Results: Five publications were included and reviewed. Two studies showed that improvement of oral health care diminished the risk of developing aspiration pneumonia and the risk of dying from aspiration pneumonia directly. The three studies remaining showed that adequate oral health care decreased the amount of potential respiratory pathogens and suggested a reduction in the risk of aspiration pneumonia by improving the swallowing reflex and cough reflex sensitivity. Conclusions: According to the results of the current systematic literature review oral health care, consisting of tooth brushing after each meal, cleaning dentures once a day, and professional oral health care once a week, seems the best intervention to reduce the incidence of aspiration pneumonia.     

Urinary biomarkers of physical activity: candidates and clinical utility

Chronic physical inactivity is a major risk factor for a number of important lifestyle diseases, while inappropriate exposure to high physical demands is a risk factor for musculoskeletal injury and fatigue. Proteomic and metabolomic investigations of the physical activity continuum – extreme sedentariness to extremes in physical performance – offer increasing insight into the biological impacts of physical activity. Moreover, biomarkers, revealed in such studies, may have utility in the monitoring of metabolic and musculoskeletal health or recovery following injury. As a diagnostic matrix, urine is non-invasive to collect and it contains many biomolecules, which reflect both positive and negative adaptations to physical activity exposure. This review examines the utility and landscape of biomarkers of physical activity with particular reference to those found in urine.     

What Can Be Done to Ensure the Usefulness of Epidemiologic Data for Risk Assessment Purposes?

Epidemiologic studies can play a central role in risk assessments. They are used in all risk assessment phases: hazard identification, dose-response, and exposure assessment. Epidemiologic studies have often been the first to show that a particular environmental exposure is a hazard to health. They have numerous advantages with respect to other sources of data which are used in risk assessments, the most important being that they do not require the assumption that they are generalizable to humans. For this reason, fewer and lower uncertainty factors may be appropriate in risk characterization based on epidemiologic studies. Unfortunately, epidemiologic studies have numerous problems, the most important being that the exposures are often not precisely measured. This article presents in detail the advantages of and problems with epidemiologic studies. It discusses two approaches to ensure their usefulness, biomarkers and an ordinance which requires baseline and subsequent surveillance of possible exposures and health effects from newly sited potentially polluting facilities. Biomarkers are biochemical measures of exposure, susceptibility factors, or preclinical pathological changes. Biomarkers are a way of dealing with the problems of poor measures, differential susceptibility and lack of early measures of disease occurrence that inherent in many environmental epidemiologic studies. The advantages of biomarkers is they can provide objective information on exposure days, months or even years later and evidence of pathology perhaps years earlier. The ordinance makes possible the use of a powerful epidemiologic study design, the prospective cohort study, where confounder(s) are best measured, and exposures, pathological changes, and health effects can be detected as soon as possible.     

Fair regression for health care spending

The distribution of health care payments to insurance plans has substantial consequences for social policy. Risk adjustment formulas predict spending in health insurance markets in order to provide fair benefits and health care coverage for all enrollees, regardless of their health status. Unfortunately, current risk adjustment formulas are known to underpredict spending for specific groups of enrollees leading to undercompensated payments to health insurers. This incentivizes insurers to design their plans such that individuals in undercompensated groups will be less likely to enroll, impacting access to health care for these groups. To improve risk adjustment formulas for undercompensated groups, we expand on concepts from the statistics, computer science, and health economics literature to develop new fair regression methods for continuous outcomes by building fairness considerations directly into the objective function. We additionally propose a novel measure of fairness while asserting that a suite of metrics is necessary in order to evaluate risk adjustment formulas more fully. Our data application using the IBM MarketScan Research Databases and simulation studies demonstrates that these new fair regression methods may lead to massive improvements in group fairness (eg, 98%) with only small reductions in overall fit (eg, 4%).     

Care Giver Perception of Children's Obesity‐Related Health Risk: A Study of African American Families

Objective: To examine care giver perception of children's weight‐related health risk in African American families. Research Methods and Procedures: One‐hundred and eleven families (representing 48 boys and 63 girls) screened for participation in a diabetes prevention study participated. Care givers completed a health awareness questionnaire that assessed their perception of the child's weight, eating habits, appearance, exercise habits, and health risk. The care givers also reported each subject's family history of obesity, diabetes, and other chronic diseases. After a physical examination, height and weight were used to compute an age‐ and sex‐adjusted body mass index for each child. Results: Despite the fact that a substantial number of children were obese (57%) and super‐obese (12%), only 44% of the care givers perceived the child's weight to be a potential health problem. Regression analysis showed that 21% of the variance in parental perception of obesity‐related health risk could be predicted by child age, body mass index, perception of frame size, and perception of exercise habits. Discussion: A number of reasons for the apparent minimization of child health risk are discussed, including cultural differences in the acceptance of a large body habitus, lack of knowledge about the connection between childhood obesity and future health risk, and an optimistic bias in the perception of personal health risk.