Assessment of Validation Studies from a Fractionator''s Point of View

NAT testing has become an integral part in the safety programs of both plasma fractionators and transfusion services. NAT testing for HCV RNA is now mandatory for plasma fractionators in Europe and for transfusion services in Germany and Austria. Before NAT testing of plasma could become mandatory, a defined environment had to be created to allow comparison of different NAT procedures. To create such an environment, international virus standards, as well as guidelines for validation, assessment of robustness, and quality assurance of NAT have been released. This paper is a critical review of currently available standards and national reference preparations, detection limits, and national regulations of NAT in view of the specific nature of NAT.     

Molecular genetic testing in the United States: comparison with international practice

OBJECTIVE: To compare data on the practices of molecular genetic testing (MGT) in laboratories in the United States with those in 18 other countries. METHODS: A Web-based survey of MGT laboratory directors (n = 827; response rate 63%) in 18 countries on three continents was carried out, and the response from U.S. laboratories compared to all others. Quality assurance and reporting indices were developed and calculated for each responding laboratory. RESULTS: A comparison of U.S. results with all other countries identified differences in laboratory setting, personnel qualifications, and the specific tests being offered, but similar rates of adherence to MGT quality standards and reporting practices were found. The survey also documented substantial transborder flow of specimens, most commonly due to the lack of availability of the test in the United States or because the test was available only through a research protocol, highlighting the need for common reporting and practice guidelines for the international MGT community. CONCLUSION: The findings presented here provide further support for the need to consider the application of the Organisation for Economic Cooperation and Development (OECD) Guidelines and the establishment of compatible accreditation programs or equivalent mechanisms across national borders to ensure the quality of laboratory services and the clinical usefulness of molecular genetic test reports for referred specimens.     

Improving Biological Dyes and Stains: Quality Testing Versus Standardization

This paper discusses the impact of both standardization and quality testing of dyes and stains in biology and medicine. After a brief review of why standardized dyes and stains are not presently available commercially, two types of testing and ways of improving dye quality are described. National or international organizations could be established to define standardization of dyes and stains. Standardization would be specifically defined as a list of physico-chemical parameters such as elaborated in this paper. Commercial batches of comparable quality may be labeled by the supplier as “standard dye.” a procedure currently performed by the European Council for Clinical and Laboratory Standardization (ECCLS). Also recommended to improve dye quality is commercial dye testing by independent laboratories with subsequent certification for use. This sort of quality control is currently carried out in the United States by the Biological Stain Commission (BSC). The advantages and disadvantages of both techniques and the use of image analysis for the definition of standards are discussed. A combination of both the BSC testing protocols and the ECCLS standards should be established for extended quality control of biological dyes and stains.     

Monitoring standards for molecular genetic testing in the United Kingdom, the Netherlands, and Ireland

Molecular genetic techniques have entered many areas of clinical practice. Public expectations from this technology are understandably high. To maintain confidence in this technology, laboratories must implement the highest standards of quality assurance (QA). External quality assessment (EQA) is recognized as an essential component of QA. The United Kingdom National External Quality Assessment Service (UKNEQAS) for Molecular Genetics, first set up in 1991, is currently the longest provider of EQA to molecular genetic testing laboratories in the UK, The Netherlands, and Ireland. Errors in the scheme are sporadic events. However, evidence from this and other EQA schemes suggests that a residual error rate persists, which should be taken into account in clinical practice. This EQA scheme has evolved from the respective scientific bodies of the constituent countries and retains a strong emphasis on collective peer review. It is essential that the steps taken to ensure quality in this rapidly expanding field are clear and transparent to participants and public alike. We describe the procedures developed and the governance imposed to monitor and improve analytical and reporting standards in participant laboratories and we compare our experiences with those of equivalent EQA services in the United States.     

A densitometrical method for the study of pattern formation in a ciliateChilodonella

Summary An easy and sensitive method is reported here for testing the similarities of individual patterns by photographically transforming maps of these patterns to given, deductively chosen conventions involving constant distances between selected reference points. A cumulative map is produced by loading all landmarks from a set of individual maps on to one sheet of paper. The use of various a priori conventions results in variable cumulative maps, which are then optically transformed on an analog digital converter, with additional input for optical picture processing. The densitometrical maps thus obtained may be compared as to the cumulative degree of areas of maximal and minimal density of landmarks. The best conventions are those that yield the map with the most contrast.Maps of spatial patterns of the sites of contractile vacuole pore (CVP) primordia in an early stage of divisional morphogenesis of the ciliateChilodonella steini were compared after four different transformations and adjustments of the same set of individual maps. The best focusing of the sites of CVP differentiation was achieved by use of the postoral axis, defined by the center of the oral apparatus and the posterior end of the cell as the scaling parameter. The composite domain map obtained by optical transformation of this cumulative map could distinguish the specific CVP territories observed in earlier work (Kaczanowska 1981). These results confirm earlier findings that indicated the site of the oral apparatus is an important reference point in CVP primordia positioning. They also strongly suggest the existence of an overriding scaling factor governing the positioning of sites of differentiation in both dimensions of the developmental field. The method of superposition and scaling of pattern maps is generally applicable to situations in which pattern elements appear at discrete points on a flat surface.     

食用菌产业化生产的质量安全保障措施

总结多年食用菌生产实践经验,并在多项科研项目中运用和充实,制定了《安全食用菌产品生产技术要求(企业标准)》。在食用菌产业化示范中对安全食用菌生产场地环境、制种和菌种经营、栽培工艺、产品质量等提出了专业和具体的要求,为食用菌生产技术的升级换代和规范化提供技术参数和质量指标,为提高食用菌产品质量、保障消费者安全与健康提供依据。     

Review: domestic animal forensic genetics – biological evidence,genetic markers,analytical approaches and challenges

This review highlights the importance of domestic animal genetic evidence sources, genetic testing, markers and analytical approaches as well as the challenges this field is facing in view of the de facto ‘gold standard’ human DNA identification. Because of the genetic similarity between humans and domestic animals, genetic analysis of domestic animal hair, saliva, urine, blood and other biological material has generated vital investigative leads that have been admitted into a variety of court proceedings, including criminal and civil litigation. Information on validated short tandem repeat, single nucleotide polymorphism and mitochondrial DNA markers and public access to genetic databases for forensic DNA analysis is becoming readily available. Although the fundamental aspects of animal forensic genetic testing may be reliable and acceptable, animal forensic testing still lacks the standardized testing protocols that human genetic profiling requires, probably because of the absence of monetary support from government agencies and the difficulty in promoting cooperation among competing laboratories. Moreover, there is a lack in consensus about how to best present the results and expert opinion to comply with court standards and bear judicial scrutiny. This has been the single most persistent challenge ever since the earliest use of domestic animal forensic genetic testing in a criminal case in the mid‐1990s. Crime laboratory accreditation ensures that genetic test results have the courts’ confidence. Because accreditation requires significant commitments of effort, time and resources, the vast majority of animal forensic genetic laboratories are not accredited nor are their analysts certified forensic examiners. The relevance of domestic animal forensic genetics in the criminal justice system is undeniable. However, further improvements are needed in a wide range of supporting resources, including standardized quality assurance and control protocols for sample handling, evidence testing, statistical analysis and reporting that meet the rules of scientific acceptance, reliability and human forensic identification standards.     

The Future Emerges from the Past

The case of Jordan (Mason 2017) highlights the gamble of connecting with the past through genomic testing. Unfortunately for Jordan, his genomic testing identified two variant genes which account for up to 75 per cent of early-onset Alzheimer’s disease cases. Furthermore, his children were identified as having a 50 per cent risk of inheriting the gene which corresponds to the majority of early-onset Alzheimer’s disease cases. Now Jordan is not only burdened with the foreknowledge that he will most likely develop Alzheimer’s disease at a relatively young age but also burdened with the knowledge that his children may share his fate. Jordan was overwhelmed by his attempts to understand the genetic tests and experienced substantial distress. This response highlights the need for industry-wide regulations that adequately prepare individuals for the decision of whether to initiate genomic testing and require the results to be interpreted with genetic counsellors or other suitably skilled doctors. Furthermore, these industry-wide regulations need to be accountable to the same evidence-based standards that regulate the rest of the medical professions.     

The diffusion of new genetic tests for predicting disease.

This paper examines the pathways by which new genetic tests will become available to the public. In view of the scarcity of genetic specialists, the pathway is likely to involve primary care physicians. Other pathways entail state-mandated testing, community-based programs, or testing by laboratories without much involvement of primary care physicians. When testing does become available the "destination" will be either family-centered testing or population-oriented screening. The deterrent to screening will not be the inability to detect disease-causing mutations but the costs and attitudes of providers and the public. When tests are provided primarily to provide information about risks to future children, some people will oppose screening on religious or moral grounds. When there are no inexpensive treatments, some will fear that insurance companies and employers will use tests to deny them health care coverage. Some may not want to know their risks for disorders about which little can be done. For common, multifactorial disorders, genetic tests will have low predictive value. Because of these problems, the decision to be tested, regardless of the destination, requires that "testees" be fully informed and consent to testing. When acceptance rates are low, screening is less likely to be cost-effective; family-centered testing becomes the default destination.     

Government regulation of nonhuman primate facilities

Myriad international, federal, and state laws, regulations, rules, guidelines, and standards directly affect the activities of all nonhuman primate research facilities. Federal regulations alone encompass every aspect of facility operations. They govern the procurement, possession, handling, care, and utilization of nonhuman primates, the design, construction, maintenance, and operation of the facility, and the occupational and environmental protection afforded not only facility personnel, but also the general public. Proper management of a nonhuman primate facility depends on continual monitoring of constantly changing laws and regulations applicable to the type of facility operated and research conducted. An in-house compliance assurance program is necessary to assure conformance with pertinent regulations.     

Exotic biological control agents: A solution or contribution to arthropod invasions?

Biological control is a valuable and effective strategy for controlling arthropod pests and has been used extensively against invasive arthropods. As one approach for control of invasives, exotic natural enemies  from the native range of a pest are introduced to areas where control is needed. Classical biological control began to be used in the late 1800s and its use increased until, beginning in 1983, scientists began raising significant concerns and questions about nontarget and indirect effects that can be caused by these introductions. In recent years, similar issues have been raised about augmentative use of exotic natural enemies. Subsequently, international guidelines, national regulations and scientific methods being used for exotic natural enemies in biological control have changed to require appropriate specificity testing, risk assessment and regulatory oversight before exotic natural enemies can be released. National and international standards aimed at minimizing risk have increased awareness and promoted more careful consideration of the costs and benefits associated with biological control. The barriers to the implementation of classical and augmentative biological control with exotic natural enemies now are sometimes difficult and, as a consequence, the numbers of classical biological control programs and releases have decreased significantly. Based in part on this new, more careful approach, classical biological control programs more recently undertaken are increasingly aimed at controlling especially damaging invasive arthropod pests that otherwise cannot be controlled. We examine evidence for these revised procedures and regulations aimed at increasing success and minimizing risk. We also discuss limitations linked to the apparent paucity of post-introduction monitoring and inherent unpredictability of indirect effects.     

The role of pharmacogenetics in treating central nervous system disorders

Symptoms of central nervous system (CNS) disorders include abnormalities in both physical and psychological domains. Many drugs indicated for the treatment of CNS disorders are fraught with side effects and/or poor efficacy which impact patients' quality of life and drives non-compliance. Moreover, for many CNS drugs such as antidepressants and antipsychotics, it takes time to determine whether a particular drug is efficacious in an individual patient. To optimize drug treatment for each patient, prescribing physicians often need to raise or lower doses, switch drug classes, or prescribe additional drugs to mitigate side effects, often in a "trial and error" fashion. Pharmacogenetic (PGx) testing, particularly in the realm of CNS therapy, can reduce the unpredictability of this process. By determining a patient's genetic profile, individual therapy parameters may be predicted pre-treatment for drug efficacy, optimal drug dose, and the risk of adverse drug reactions (ADRs). The intent of this review is to highlight the power of PGx testing to predict the likelihood of ADRs and efficacy during the treatment of the following CNS disorders: epilepsy, bipolar disorder, schizophrenia and depression.     

Development of Veterinary Laboratory Networks for Avian Influenza and Other Emerging Infectious Disease Control: The Southeast Asian Experience

The outbreak of highly pathogenic H5N1 avian influenza, with its international spread, confirmed that emerging infectious disease control must be underpinned by effective laboratory services. Laboratory results are the essential data underpinning effective surveillance, case diagnosis, or monitoring of responses. Importantly, laboratories are best managed within national and international networks of technological support rather than in isolation. A well planned laboratory network can deliver both a geographical spread of testing capacity and also a cost effective hierarchy of capability. Hence in the international context regional networks can be particularly effective. Laboratories are an integral part of a country’s veterinary services and their role and function should be clearly defined in the national animal health strategy and supporting government policies. Not every laboratory should be expected to deliver every possible service, and integration into regional and broader international networks should be a part of the overall strategy. The outputs required of each laboratory should be defined and then ensured through accredited quality assurance. The political and scientific environment in which laboratories operate changes continuously, not only through evolving national and regional animal health priorities but also through new test technologies and enhancements to existing technologies. Active networks help individual laboratories to monitor, evaluate, and respond to such challenges and opportunities. The end result is enhanced emerging infectious disease preparedness across the region.     

Microarray data quality - review of current developments

DNA microarray technologies have evolved rapidly to become a key high-throughput technology for the simultaneous measurement of the relative expression levels of thousands of individual genes. However, despite the widespread adoption of DNA microarray technology, there remains considerable uncertainty and scepticism regarding data obtained using these technologies. Comparing results from seemingly identical experiments from different laboratories or even from different days can prove challenging; these challenges increase further when data from different array platforms need to be compared. To comply with emerging regulations, the quality of the data generated from array experiments needs to be clearly demonstrated. This review describes several initiatives that aim to improve confidence in data generated by array experiments, including initiatives to develop standards for data reporting and storage, external spike-in controls, quality control procedures, best practice guidelines, and quality metrics.     

International standards for monoclonal antibodies to support pre- and post-marketing product consistency: Evaluation of a candidate international standard for the bioactivities of rituximab

The intrinsic complexity and heterogeneity of therapeutic monoclonal antibodies is built into the biosimilarity paradigm where critical quality attributes are controlled in exhaustive comparability studies with the reference medicinal product. The long-term success of biosimilars will depend on reassuring healthcare professionals and patients of consistent product quality, safety and efficacy. With this aim, the World Health Organization has endorsed the need for public bioactivity standards for therapeutic monoclonal antibodies in support of current controls. We have developed a candidate international potency standard for rituximab that was evaluated in a multi-center collaborative study using participants' own qualified Fc-effector function and cell-based binding bioassays. Dose-response curve model parameters were shown to reflect similar behavior amongst rituximab preparations, albeit with some differences in potency. In the absence of a common reference standard, potency estimates were in poor agreement amongst laboratories, but the use of the candidate preparation significantly reduced this variability. Our results suggest that the candidate rituximab standard can support bioassay performance and improve data harmonization, which when implemented will promote consistency of rituximab products over their life-cycles. This data provides the first scientific evidence that a classical standardization exercise allowing traceability of bioassay data to an international standard is also applicable to rituximab. However, we submit that this new type of international standard needs to be used appropriately and its role not to be mistaken with that of the reference medicinal product.     

Genetic reference materials and their application to haematology

Genetic investigations are becoming increasingly useful and widespread in many areas of human health. However, there is a worldwide lack of certified reference materials for use in genetic testing, meaning that tests are being run without well validated controls and new assays are more difficult to develop and validate. We have responded to this challenge by starting a programme of developing genetic reference materials (GRMs) for international accreditation and worldwide distribution. Our approach has been to make materials for disorders where testing is commonplace and genotyping errors have been demonstrated. To ensure a continuing supply of DNA, cell lines are established from consenting, phenotypically well-characterised patients and are then grown up in bulk for genomic DNA extraction to yield up to 100 milligrams of DNA. In most cases the DNA is then formulated, freeze-dried and sealed in glass ampoules to ensure greater stability over time and obviate the need for chilled transportation. In this paper we explore the options and routes available to the production of DNA reference materials and describe the establishment of the first internationally recognised reference materials for human genomic DNA, with particular reference to some genetic tests carried out frequently within haematological and cardiovascular laboratories.     

Children and biobanks: a review of the ethical and legal discussion

The use of tissue samples from children is vital to genetic research. Collections of such tissue, in so-called biobanks, can take the form of large-scale prospective cohort studies or disease-specific studies using tissue of children with that specific disease. Collections of samples gathered in a diagnostics context, such as blood spot cards, can also be used for genetic research. Research on stored tissue samples from children poses ethical questions that are different from those posed by the use of samples from adults. Also, the ethical questions raised by the participation of children in biobanks are not analogous to those raised by the participation of children in clinical trials. In this review we first give an overview of the international ethical guidelines and legal regulations concerning biobanking and minors. Next, we review the different themes that occur in the ethical literature on this subject. Specifically we focus on questions of risk and benefit, consent and assent and the return of individual results. We also discuss the concept of solidarity, which is a relatively new concept in the context of children and biomedical research. To conclude, we discuss the gaps and questions raised by the review.     

Genetic tests obtainable through pharmacies: the good,the bad,and the ugly

Genomic medicine seeks to exploit an individual’s genomic information in the context of guiding the clinical decision-making process. In the post-genomic era, a range of novel molecular genetic testing methodologies have emerged, allowing the genetic testing industry to grow at a very rapid pace. As a consequence, a considerable number of different private diagnostic testing laboratories now provide a wide variety of genetic testing services, often employing a direct-to-consumer (DTC) business model to identify mutations underlying (or associated with) common Mendelian disorders, to individualize drug response, to attempt to determine an individual’s risk of a multitude of complex (multifactorial) diseases, or even to determine a person’s identity. Recently, we have noted a novel trend in the provision of private molecular genetic testing services, namely saliva and buccal swab collection kits (for deoxyribonucleic acid (DNA) isolation) being offered for sale over the counter by pharmacies. This situation is somewhat different from the standard DTC genetic testing model, since pharmacists are healthcare professionals who are supposedly qualified to give appropriate advice to their clients. There are, however, a number of issues to be addressed in relation to the marketing of DNA collection kits for genetic testing through pharmacies, namely a requirement for regulatory clearance, the comparative lack of appropriate genetics education of the healthcare professionals involved, and most importantly, the lack of awareness on the part of both the patients and the general public with respect to the potential benefits or otherwise of the various types of genetic test offered, which may result in confusion as to which test could be beneficial in their own particular case. We believe that some form of genetic counseling should ideally be integrated into, and made inseparable from, the genetic testing process, while pharmacists should be obliged to receive some basic training about the genetic tests that they offer for sale.     

Quality control in molecular genetic testing

DNA-based testing for genetic diseases has developed from nothing into a principal part of laboratory medicine over the past 15 years. In the rush to bring these powerful new technologies into medical use, issues of quality have not always been given sufficient attention. Efforts are now being made to assess the quality of the output of genetic testing laboratories, and the results show that there is room for improvement.