Human subject protections in genetic research

The Certificate of Confidentiality (COC) is a voluntary tool to protect researchers from being compelled to release identifying information about their subjects. Institutional review board (IRB) review and informed consent (IC) procedures are mandatory tools to protect human subjects. Although many studies reveal poor documentation of IRB and IC procurement, most published research undergoes IRB review and has appropriate IC procedures. There are no empirical data about the use of COCs. We examined the procurement and documentation of all these human subject protections in the genetics literature. A total of 112 (55%) articles documented IRB review, 108 (53%) document IC, and 82 (41%) documented both. None documented the procurement of a COC. Returned surveys provided additional information that confirmed that at least 74% (n = 150) of research had received appropriate IRB review, at least 71% (n = 143) had procured IC, and at least 10% (n = 21) had obtained a COC. An additional 22 respondents had procured COCs for other research, whereas 17 respondents were unaware of them and their purpose. In this era of public scrutiny of medical research, we recommend greater familiarity with and documentation of all human subject protections.     

Quality-by-Design: Are We There Yet?

In 2012, the Quality-by-Design and Product Performance Focus Group of AAPS conducted a survey to assess the state of adoption and perception of Quality-by-Design (QbD). Responses from 149 anonymous individuals from industry—including consultants—(88%), academia (7%), and regulatory body (4%), were collected. A majority of respondents (54% to 76%) reported high frequency of utilization of several tools and most QbD elements outlined by International Conference on Harmonization Q8, with design of experiments, risk assessment, and the quality target product profile ranked as the top three. Over two thirds of respondents agreed that the benefits of QbD included both the positive impact it can have on the patient (78%), as well as on internal processes such as knowledge management (85%), decision making (79%), and lean manufacture (71%). However, more than 50% from industry were neutral about or disagreed with QbD leading to a better return on investment. This suggests that, despite the recognized scientific, manufacture, and patient-related benefits, there is not yet a clearly articulated business case for QbD available. There was a difference of opinion between industry and regulatory agency respondents as to whether a QbD-based submission resulted in increased efficiency of review. These contrasting views reinforce the idea that QbD implementation can benefit from further dialog between industry and regulatory authorities. A majority of respondents from academia indicated that QbD has influenced their research. In total, the results indicate the broad adoption of QbD but also suggest we are yet in a journey and that the process of gathering all experience and metrics required for connecting and demonstrating QbD benefits to all stakeholders is still in progress.     

Challenges in constructing statistically based structure-activity relationship models for developmental toxicity

Regulatory agencies are increasingly called upon to review large numbers of environmental contaminants that have not been characterized for their potential to pose a health risk. Additionally, there is special interest in protecting potentially sensitive subpopulations and identifying developmental toxicants that may be present in the environment. Thus, there is an urgent need for efficient methods to screen large numbers of chemicals for their potential to pose a developmental hazard. One potential screening method involves the use of statistically based structure-activity relationship (SAR) tools to predict activity of untested chemicals. Such systems rely on statistical analyses to discern relationships between structure and activity for a training set of substances. Predictions can then be made for an untested substance as long as its structural features are encompassed by chemicals of the training set. In theory, such systems could assist regulatory agencies in their screening efforts; however, to date, there has been little independent evaluation of these tools for this use. To contribute to such an evaluation, the International Life Sciences Institute Risk Science Institute (ILSI RSI) convened a Working Group to examine methodology used to construct statistically based SAR systems for developmental toxicity. This document reports on the deliberations of the Working Group, which concluded that an improved process is needed for utilizing developmental toxicity data in the construction of statistically based SAR models. The process must be objective, reproducible, rational and transparent. Moreover, it must be informed by the expertise of developmental toxicologists and biologists and must be subject to peer review.     

Studying statistical properties of regulatory DNA sequences, and their use in predicting regulatory regions in the eukaryotic genomes

There are no well-known properties in regulatory DNA analogous to those in coding sequences; their spatial location is not regular, the consensus regulatory elements are often degenerate and there are no understandable rules governing their evolution. This makes it difficult to recognize regulatory regions within genome. We review developments in the statistical characterization of regulatory regions and methods of their recognition in eukaryotic genomes.     

Phenotyping of genetically engineered mice: humane, ethical, environmental, and husbandry issues

The growing use of genetically engineered (GE) mice in scientific research has raised many concerns about the animal welfare of such mice. The types of welfare concerns may differ within the three stages that comprise the establishment of GE animal models: development, production, and research use. The role and impact of the members of the research team on these concerns may also vary with each stage. To make both scientific and animal welfare decisions at each stage, it is necessary to have a thorough knowledge of the animal model-in this case, the phenotypic expression of the GE animal. Phenotype screening is the analysis of visible or measurable characteristics of an animal that result from the genotype and its interaction with the environment. Phenotypes expressed that are relevant to the research program are usually carefully investigated; however, those that may have an impact on the animal's welfare but have little or no impact on the disease process under study are often less carefully studied. Thorough analysis and documentation of the animal welfare aspects of phenotype provide the research team with the information they need to control the environment to minimize negative animal welfare effects. Such information is also essential to allow members of the institutional animal care and use committee to perform necessary cost:benefit ethical review of proposed GE animal studies. Investigators who submit information about models for publication should document all aspects of a phenotype, including the area of scientific interest as well as those areas that affect animal welfare, for clarity and for subsequent research with the respective models.     

Proposed Standards for Variable Harmonization Documentation and Referencing: A Case Study Using QuickCharmStats 1.1

Comparative statistical analyses often require data harmonization, yet the social sciences do not have clear operationalization frameworks that guide and homogenize variable coding decisions across disciplines. When faced with a need to harmonize variables researchers often look for guidance from various international studies that employ output harmonization, such as the Comparative Survey of Election Studies, which offer recoding structures for the same variable (e.g. marital status). More problematically there are no agreed documentation standards or journal requirements for reporting variable harmonization to facilitate a transparent replication process. We propose a conceptual and data-driven digital solution that creates harmonization documentation standards for publication and scholarly citation: QuickCharmStats 1.1. It is free and open-source software that allows for the organizing, documenting and publishing of data harmonization projects. QuickCharmStats starts at the conceptual level and its workflow ends with a variable recording syntax. It is therefore flexible enough to reflect a variety of theoretical justifications for variable harmonization. Using the socio-demographic variable ‘marital status’, we demonstrate how the CharmStats workflow collates metadata while being guided by the scientific standards of transparency and replication. It encourages researchers to publish their harmonization work by providing researchers who complete the peer review process a permanent identifier. Those who contribute original data harmonization work to their discipline can now be credited through citations. Finally, we propose peer-review standards for harmonization documentation, describe a route to online publishing, and provide a referencing format to cite harmonization projects. Although CharmStats products are designed for social scientists our adherence to the scientific method ensures our products can be used by researchers across the sciences.     

Inpatient to Outpatient Transfer of Diabetes Care: Planning for an Effective Hospital Discharge

ObjectiveTo review data on diabetes discharge planning, provide a definition of an effective diabetes discharge, and summarize one institution’s diabetes discharge planning processes in a teaching hospital.MethodsWe performed a MEDLINE search of the English-language literature published between January 1998 and December 2007 for articles related to the inpatient to outpatient transition of diabetes care. Regulatory guidelines about discharge planning were reviewed. We also analyzed our institution’s procedures regarding hospital discharge.ResultsWe define an effective diabetes discharge as one where the patient has received the necessary skills training and been provided with a clear and understandable postdischarge plan for diabetes care that has been clearly documented and is accessible by the patient’s outpatient health care team. Diabetes is one of the most common conditions managed in the hospital, yet how to transition a patient with diabetes to the outpatient setting is understudied, and the outcome of patients with diabetes after discharge is unknown. Strategies that can be used to ensure an effective diabetes discharge are early identification of patients in need of education, implementation of a clinical pathway, and clear instructions about medications and follow-up appointments at the time of discharge.ConclusionsEffective transfer of care from the inpatient to the outpatient setting remains a priority in the United States. Studies are needed to better define how best to ensure that patients with diabetes are successfully transitioned to ambulatory care. (Endocr Pract. 2009;15:263-269)     

Balancing animal research with animal well-being: establishment of goals and harmonization of approaches

A resource is provided for the creation of an institutional program that balances the scientific mission of an institution with the well-being of the animals used in support of the research. The concept of harmonizing scientific goals with animal well-being was first suggested in the early part of the twentieth century and later revitalized in the literature of the 1950s. Harmonization can best be achieved through the promotion of a team initiative. The team should include, at a minimum, the scientist, veterinarian, institutional animal care and use committee, and animal care staff. It is the responsibility of this animal research team to promote and balance the generation of scientifically valid data with animal well-being. The team must strive to minimize or eliminate non-protocol variables that could adversely affect the validity and repeatability of the experimental data. Good experimental design coupled with excellent communication between team members can often minimize or eliminate many variables and result in both better science and animal well-being. To ensure the scientific validity of experimental data, scientists must be aware of the complex nature of the environment in which their animals are maintained. To ensure repeatablity of an experiment, scientists must document and publish both the inanimate and social environments in which their animals are housed. Better documentation of environmental variables and their correlation with experimental results will promote critical knowledge about the relationships between an animal's environment, its well-being, and science.     

Researcher Perspectives on Publication and Peer Review of Data

Data “publication” seeks to appropriate the prestige of authorship in the peer-reviewed literature to reward researchers who create useful and well-documented datasets. The scholarly communication community has embraced data publication as an incentive to document and share data. But, numerous new and ongoing experiments in implementation have not yet resolved what a data publication should be, when data should be peer-reviewed, or how data peer review should work. While researchers have been surveyed extensively regarding data management and sharing, their perceptions and expectations of data publication are largely unknown. To bring this important yet neglected perspective into the conversation, we surveyed ∼ 250 researchers across the sciences and social sciences– asking what expectations“data publication” raises and what features would be useful to evaluate the trustworthiness, evaluate the impact, and enhance the prestige of a data publication. We found that researcher expectations of data publication center on availability, generally through an open database or repository. Few respondents expected published data to be peer-reviewed, but peer-reviewed data enjoyed much greater trust and prestige. The importance of adequate metadata was acknowledged, in that almost all respondents expected data peer review to include evaluation of the data’s documentation. Formal citation in the reference list was affirmed by most respondents as the proper way to credit dataset creators. Citation count was viewed as the most useful measure of impact, but download count was seen as nearly as valuable. These results offer practical guidance for data publishers seeking to meet researcher expectations and enhance the value of published data.     

Establishing a culture of care, conscience, and responsibility: addressing the improvement of scientific discovery and animal welfare through science-based performance standards

Science-based performance standards offer a viable means of reducing regulatory burden while ensuring that research animal welfare and high-quality research data are realized. Unlike rigid regulations, science-based performance standards evolve as new information becomes available, thereby allowing new discoveries to be implemented in a timely manner and in a way that more effectively benefits the animals and the science. The implementation of performance standards requires a well-coordinated institutional team composed of the administration, research staff, the institutional animal care and use committee, professional and technical animal care personnel, occupational health and safety staff, and physical plant staff. This animal program team is best supported in an institutional environment that reflects a culture of care, compliance, and responsibility. In such a culture, the professional judgment exercised by the team is well grounded in meeting the diverse needs of the program's customers, who include the animals, the researchers, and research stakeholders such as the public. The institutional culture of care, compliance, and responsibility fosters workplace integrity, an ethics-based decision-making paradigm, sound understanding of institutional expectations through good communication and clear lines of authority, the hiring and retention of trained and well-qualified individuals, and a system for continuous development and improvement of the program.     

"Non-trivial pursuit of physiology"

This article describes a novel way to conduct a review session that combines interactivity, team learning, and peer-to-peer instruction. It uses the format of the familiar game "Trivial Pursuit." To facilitate the game process and to encourage its use by others, we have developed custom software. It allows an instructor to run the game from the podium and to input questions/answers for a particular block or other area to be reviewed. In addition to the software itself, the online supplement (http://advan.physiology.org/cgi/content/full/00031.2004/DC1) contains 100 sample questions and answers written for the cardiovascular physiology review session. The developed game format and its software add to the arsenal of educational tools that can be used to enrich students' learning experiences.     

Analyzing and understanding the robustness of bioprocesses

The robustness of bioprocesses is becoming increasingly important. The main driving forces of this development are, in particular, increasing demands on product purities as well as economic aspects. In general, bioprocesses exhibit extremely high complexity and variability. Biological systems often have a much higher intrinsic variability compared with chemical processes, which makes the development and characterization of robust processes tedious task. To predict and control robustness, a clear understanding of interactions between input and output variables is necessary. Robust bioprocesses can be realized, for example, by using advanced control strategies for the different unit operations. In this review, we discuss the different biological, technical, and mathematical tools for the analysis and control of bioprocess robustness.     

环境因素诱导昆虫滞育发生的分子机制研究进展

滞育是生物体为了渡过恶劣环境而进行的一种停滞生长发育的生理状态,主要受遗传和环境因素的影响。研究发现光周期、温度、食物营养和体内激素水平等都能诱导昆虫滞育发生,然而滞育诱导是一个复杂的调控过程,对其分子机制的研究仍不清楚。本文对近年来在滞育诱导相关分子和分子信号通路方面取得的研究进展进行梳理,重点介绍了光周期和温度诱导昆虫滞育发生的分子级联系统,包括生物钟Per/Tim和Clk反馈回路、温度敏感型瞬时受体电位通道、γ-氨基丁酸GABA信号通路、珊瑚青素Corazonin信号通路和胰岛素信号途径等,该综述内容将为昆虫滞育研究提供帮助,同时为利用昆虫滞育进行农林害虫的防治及天敌保护提供理论参考。     

Forecasting species range dynamics with process‐explicit models: matching methods to applications

Knowing where species occur is fundamental to many ecological and environmental applications. Species distribution models (SDMs) are typically based on correlations between species occurrence data and environmental predictors, with ecological processes captured only implicitly. However, there is a growing interest in approaches that explicitly model processes such as physiology, dispersal, demography and biotic interactions. These models are believed to offer more robust predictions, particularly when extrapolating to novel conditions. Many process–explicit approaches are now available, but it is not clear how we can best draw on this expanded modelling toolbox to address ecological problems and inform management decisions. Here, we review a range of process–explicit models to determine their strengths and limitations, as well as their current use. Focusing on four common applications of SDMs – regulatory planning, extinction risk, climate refugia and invasive species – we then explore which models best meet management needs. We identify barriers to more widespread and effective use of process‐explicit models and outline how these might be overcome. As well as technical and data challenges, there is a pressing need for more thorough evaluation of model predictions to guide investment in method development and ensure the promise of these new approaches is fully realised.     

Secrets of caveolae- and lipid raft-mediated endocytosis revealed by mammalian viruses

In recent years, it has been unambiguously shown that caveolae and lipid rafts can internalize cargo upon stimulation by multivalent ligands, demonstrated by the infectious entry routes of certain non-enveloped viruses that bind integrins or glycosphingolipids. We currently understand little about the membrane trafficking principles of this endocytic route, but it is clear that we cannot use paradigms from classical membrane traffic. Recent evidence indicates that caveolae- and lipid raft-mediated endocytosis plays important roles in cell adhesion and anchorage-dependent cell growth, but the underlying mechanisms are not known. In this review, I will introduce new models based on current research that aims at identifying the core machinery, regulatory components and design principles of this endocytic route in order to understand its role in cellular physiology. Again, viruses are proving to be excellent tools to reach that goal.