科学研究的伦理道德第一讲
这个是我博士一年级的必修课程的笔记，课程内容信息量非常大，但是7成以上的同学都是没有学习，因为考核方式很诡异，纯粹的选择题，而且可以无限选择，不停地试错，和给出正确答案再重新选择，导致很多人取巧就随随便便过关了！
全文比较长，希望我的粉丝都尽量花时间读一下，里面也有很多科学故事，不失趣味性！
人类研究相关注意事项
1.名词解释
Institutional Review Board (IRB)
federal regulations
U.S. Public Health Service (PHS)
U.S. Food and Drug Administration (FDA)
Council for International Organizations of Medical Sciences (CIOMS)
Health and Human Services (HHS)
International Committee of Medical Journal Editors (ICMJE)
HSS把参与实验研究的受试者分成4种：
Subpart C: Protections for Children in Research
Subpart D: Additional Protections for Children Involved as Subjects in Research
Subpart B: Additional Protections for Children Involved as Subjects in Research
Subpart A: The Common Rule
Family Educational Rights and Privacy Act (FERPA)
Protection of Pupil Rights Amendment (PPRA)
massively multiplayer online role-playing games (MMORPGs)
Health Insurance Portability and Accountability Act (HIPAA)
Office for Human Research Protections (OHRP)
2.知情同意书informed consent
requirements
information/comprehension/voluntariness
general
research purpose/foreseeable risk or discomforts/benefits/courses of treatment / comensation / further explanation / voluntary
additional
Unforeseeable risks / stop at any time / costs / withdraw / continue participation / approxiamate number of subjects.
Language issues and cultural issues
The informed consent process involves three key features:
(1) disclosing to potential research subjects information needed to make an informed decision;
(2) facilitating the understanding of what has been disclosed
(3) promoting the voluntariness of the decision about whether or not to participate in the research.
中风的老人得了肺癌，他的妻子正好外出，虽然他愿意参加新药试验，这个时候研究者应该怎么做呢？
发邮件给他的妻子知情同意书，得到他妻子的同意才能参加。
一个46岁的男性患者正在参加一个新药的临床2期试验，但同时期有一个同功效或者更好的药物上市了，这时候研究者一个怎么做呢？
给他详细的描述新药的优缺点，允许受试者自己决定是否退出。
知情同意书的目的是？
为可能的参与者提供详尽的适当的信息，使之更好的做决定。
知情同意书里面不应该出现有争议的语言，Exculpatory language，比如？
患者自愿放弃参与研究过程中受伤的补偿。
如果某患者正面临生命危险却无法签署知情同意书，又不得不立马参与一个测试性的治疗，应该如何呢？
研究者和医师可以同意该患者参与试验性的治疗，这种情况下可以豁免知情同意书，但是随后要上报IRB。
3.道德伦理故事
起源于纳粹医生在二战期间做的毫无人性的实验
关于研究道德伦理的故事：
Landmark social sciences studies such as Milgram's Obedience to Authority study, Zimbardo's Stanford Prison Experiment, and Humphreys's Tearoom Trade study
The experiments conducted by Nazi doctors and scientists on concentration camp prisoners during World War II, and the U.S. Public Health Service (PHS) study titled "Tuskegee Study of Untreated Syphilis in the Negro Male" (Tuskegee Study). These abuses led to the creation of codes of research ethics in Europe and the U.S. In the wake of the Second World War, the subsequent Nuremberg Trials on war crimes produced the Nuremberg Code, which outlined ten points for conducting ethical research with human subjects.
"The Stanford Prison Experiment," Philip Zimbardo's 1971 landmark psychological study of the human response to captivity, specifically prison life. Zimbardo assigned roles to normal male student volunteers to create groups of "prisoners" and "guards." The simulation became so intense that physical and psychological abuse of "prisoners" by "guards" escalated and several of the subjects experienced distress less than 36 hours after the study began.
In Laud Humphreys's study, detailed in his book Tearoom Trade: Impersonal Sex in Public Places, the researcher observed men meeting other men for casual sexual encounters in public restrooms. Humphreys, then a sociology graduate student, gained the confidence of the men by pretending to be a participant and acting as a lookout. While Humphreys eventually revealed himself as a researcher to some of the men and was able to interview them openly, he withheld his identity from many others, recording the license plate numbers of a subset of 100 other tearoom regulars in order to contact them for interviews at a later date.
还有一个Harvard "Tastes, Ties, and Time (T3)" study (2006-2009)” study没有保护好受试者的隐私。
对应招募3原则，尊重个人，受益，公平！
The Belmont Report identified three basic principles relevant to the ethical conduct of research involving human subjects:
Respect for Persons(知情同意书+保护隐私)
Beneficence(risks and benefits)
Justice(志愿，随时退出，随机挑选受试者)
These three principles "provide an analytical framework that will guide the resolution of ethical problems arising from research involving human subjects" (The National Commission 1979).
4.什么是人类研究受试者
这个定义很严格：a systematic investigation including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge
because the intention of the study is to answer "about what" questions rather than "about whom" questions.
5.人类研究的伦理历史
一些被指责的历史事件：
Edward Jenner (1789), who tested smallpox vaccine,
Claude Bernard (1865), who developed ethical maxims regarding human research,
Louis Pasteur (1885), who tested the rabies vaccine
Walter Reed (1900), who studied yellow fever
Willowbrook studies (1956-1970), where children with intellectual disabilities were deliberately infected with the hepatitis virus
Jewish Chronic Disease Hospital study (1963), where live cancer cells were injected into 22 cognitively impaired patients.
Nuremberg Code: These rules include, among other ethical principles:
A requirement for voluntary consent
That the research have scientific merit
That the benefits of the research outweigh risks
That the subjects have the ability to terminate participation in the research at anytime
写的很好，可是没有被正式采纳实施过，上述4条被扩充解释为10条。但是促进了National Commission的成立，渐渐的形成了Belmont Report 招募3原则！
Beecher article让人们意识到并不是只有纳粹在做坏事
National Research Act of 1974
Death of Jesse Gelsinger
federal regulations
上个世纪70年代那些及其严重的医疗事故唤醒了人们对科学研究的伦理道德的关注。
Methods mentioned include surveys, interviews, focus groups, oral history, participant observation, observations of public behavior, and the analysis of existing data.
Topics include research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior.
IRB Review是可以加快或者豁免的
An IRB is a review committee established to ensure that the rights and welfare of human research subjects are protected.
IRB委员会至少要有5人，背景多元化，有项目知识，熟悉法规，他们的权利包括，同意
原则上尽可能的拒绝可能触发伦理道德的研究~
涉及囚犯的研究
以前认为囚犯已经被剥夺~~~，所以拿它们做药物测试，毒性测试很正常，可以不考虑它们的权益。比如Hornblum 1998测试化妆品毒性，还有 Atomic Energy Commission 对它们进行放射性照射。
搞清楚囚犯的定义以及可以对他们做哪些研究
涉及囚犯的实验仍然需要考虑 free choice, incentives,confidentiality,还列举了几个违法保密协议的例子
比如招募念童癖着，应该混合其它囚犯一起招募。还有研究HIV阳性患者囚犯的室友的生活质量。
同理IRB要求也有所不同，比如委员会至少得有一人是囚犯或者囚犯代表。
如果参与研究的受试者中途变成囚犯，呵呵
处于假释期的不算囚犯
涉及未成年的研究
The federal regulations do not require that child assent be documented.
涉及学生的研究
不允许 survey procedures, interview procedures, or participant observation 豁免
student's name, address, telephone number, date and place of birth, honors and awards, and dates of attendance.
教育部资助的研究都需要PPRA同意，PPRA管理学生调查表的问题，FERPA负责学生的成绩公布与否
基于网络的研究
U.S. researcher conducting a study in a non-U.S. setting
是否有海外机构参与研究：Will the researcher have collaborators at the research site abroad?
not consenting or performing any research procedures, or receiving or sharing any private, identifiable information.
Obtaining informed consent and conducting research interviews.
研究者只有亲自参与，与受试者网络接触了才算是利用互联网作为研究工具，比如在Facebook里面贴入了SurveyMonkey的调查链接，但是仅仅是注册一个账号，看资料是不能算的。
互联网上面没有绝对的安全，最理想的方式是对受试者解释好来龙去脉，包括数据的加密，IP的匿名等等。
防止泄密最好的方式是不要直接或者简介的标记受试者。
7.受试者的健康状态隐私
主要是HIPAA组织负责监督这个，当然联邦的其它组织也会检测这一块。
脱敏的健康隐私数据可以不经授权被研究者使用，在下面6种情况：
The research involves only minimal risk.
2.The research is used solely for activities preparatory to research.
3.Only deceased persons' information is used.
4.Only de-identified data is used.
5.Only a “limited data set” is used, under an approved “data use agreement.”
6.It is "grandfathered" research where all legal permissions were in place before HIPAA took effect.protected health information or simply “PHI”
哪怕是学生本身还是在受训阶段，也是需要跟研究人员一样遵守同等的保密规则，尽管学生是有导师的，但是也需要报告一切可疑情况，允许匿名打小报告。因为学生学习过程对受试者没有任何好处，只是对学生成长后的受试者有好处，所以对当下的受试者更应该高度负责。组织方需要确认哪些资料是可疑拿来给学生做培训的。受试者并不需要额外写同意书把他们的数据给学生练习。
8.IACUC动物保护
the "Institutional Animal Care and Use Committee" or IACUC.
做动物实验必须了解各单位的动保组织老大，还有兽医，动物房设施负责人。根据联邦法律，动保组织需要审核并且监督各种动物实验。
任何跟涉及到动物的科学实验开始前必须向IACUC汇报，申请获批。
联邦授权保护动物
United States Department of Agriculture (USDA) Animal Welfare Act 这个是最高法律。
动物的定义：不适用于Non-vertebrates, laboratory mice, and laboratory rats.
The Health Research Extension Act directed PHS to provide guidelines for animal research.
The Office of Laboratory Animal Welfare (OLAW) is responsible for monitoring institutional compliance with PHS policy and guidelines.
PHS agencies include the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration (FDA). 所有受PHS资助的单位都必须保护动物！
还有一个非盈利组织也在保护实验动物：The Association for Assessment and Accreditation of Laboratory Animal Care, International, or "AAALAC
The PHS Policy on Humane Care and Use of Laboratory Animals and the Guide for the Care and Use of Laboratory Animals.
兽医
要明白生物是有等级的，它们的排序如下：
Apes (orangutans, gorillas)
Monkeys (baboons, rhesus monkeys, marmosets, tamarins)
Larger animals commonly kept as pets such as dogs and cats
Larger animals such as pigs and goats commonly used as farm animals
Rabbits
Rodents (guinea pigs, hamsters, rats, mice)
Non-mammalian vertebrates (poultry, amphibians, reptiles, fish)
Invertebrates (crustaceans, slugs, insects, arachnids, worms, etc.)
Single cell organisms (yeast, bacteria)
three'R原则
replacement 能不用动物就不用用
reduction 能少用，就少用
refinement 不要虐待动物
仅此还不够，USDA Animal Welfare Act Regulations还要求IACUC保证两件事，需要PI确认考虑过替代方案，而且的确替代方案不适合。主要是记录好PI在哪些数据库搜索过自己的研究涉及的动物实验，防止不必要的浪费：
ALTBIB: Bibliography on Alternatives to Animal Testing.
University of California Center for Animal Alternatives.
Altweb. The Altweb website is run by the Johns Hopkins Center for Alternatives to Animal Testing (CAAT)
Medical Librarian.
AWIC, part of the USDA's National Agricultural Library, was established to to provide information for improved animal care and use in research, testing, teaching, and exhibition.
替代方案：
To search for procedures that may replace the use of animals, reduce the number of animals used, or refine the methodology to minimize animal pain or distress.
疼痛分级
USDA pain/distress categories in order from no pain/distress (B) to most pain/distress (E)：
Category B，繁育，被观察，挪窝
Category C，打针吃药
Category D，麻醉，镇静后的手术
Category E，不麻醉镇静就实验，包括IC50 （需要上报USDA）
实验动物有且只能有一个分类，必须是最疼的分类。
动物手术
采血
The rule is to collect no more than 1% of the body weight as blood.
Blood collections should be spaced far enough apart to prevent shock due to low blood volume and anemia.
安全意识
工作人员的职业风险：rabies immunizations, TB testing, and tetanus immunizations
BMBL划分了4级别的生物安全：Biosafety Level 1, Biosafety Level 2, Biosafety Level 3, and Biosafety Level 4，同理Risk Group也分成了4个等级，分别是
不影响健康
影响个人健康但是可以治疗
严重影响个人健康甚至可能致死但对社区危害不大
不仅仅影响个人健康对社会危害也大。
Standard Operating Procedures (SOPs) 很重要
需要多方人员共同保障安全：veterinarian, biosafety officer, biosafety committee, and animal facility manager
必须在Centers for Disease Control and Prevention (CDC) or USDA注册才能使用有毒的试剂和微生物。
重组DNA制品也需要十分注意，还专门有一个委员会负责，Recombinant DNA Advisory Committee
动物的社交
IACUC原则上不建议如实验动物太孤独，除非有行为特征，健康问题或者科研需要。比如这两种成年雄性小鼠C57BL/6 and BALB/c养在一起会打架，就不要混居。
锯齿动物喜欢solid bottom caging with soft bedding over wire mesh flooring
如果拿狗做实验动物千万要注意，狗是某些人类的朋友，需要跟兽医和IACUC密切讨论汇报情况，而且要经常遛狗，不能虐待他/她。而且IACUC还可以免除狗被做科研的命运。
灵长类动物更是如此，更需要注意，还得心理医生参与科研项目。
不要把人家动物持续实验12个小时，得经常休息，如无必要。
USDA AWA 定义了安乐死，需要受训后才能给实验动物实施安乐死
American Veterinary Medical Association (AVMA)规定了安乐死的细则，方法。分成了acceptable, acceptable with conditions, and adjunctive，Unacceptable 。方法有：
Inhaled Agents
Carbon Dioxide (CO2)
Noninhaled Agents
Cervical Dislocation，只能在small birds, poultry, mice, immature rats (< 200 g), and immature rabbits.
Decapitation
Exsanguination
Pithing，只是一个附加过程，保证待安乐死的对象已经失去了意识
这些方法的细节需要熟记
对初生动物，怀孕的，未出生的动物的安乐死要格外注意，比如新生动物能抵抗低氧，所以对二氧化碳致死的敏感度差一点，而且要遵守当地法律，还有就是安乐死的时候不要让其它动物看到，免得惊吓了它们，要确保死透了。
更改动物计划
首先任何更改都得必须得到IACUC的同意
IACUC给出两个方法：Full Committee review and Designated Member Review or "DMR."
USDA and OLAW给出一个方法：Veterinary Verification and Consultant or "VVC."
只要是PHS资金支持的课题，任何动物相关事宜都得汇报给USDA的动物福利保护组织，所有相关人员必须积极举报那些乱用，错用实验动物的行为。
我们的实验成功得益于动物的无私奉献，要感激爱护它们。
手术后动物的处理
各位PI要仔细思考如何让实验动物减轻痛苦
动物看护需要检查：Behavior /Appearance / Body functions 这3个方面。
锯齿动物的3个特性，决定了它比较难以被检查：
Small body size
Tendency to freeze when disturbed
Tendency to hide when disturbed
实验动物需要被详细观察
Activity Level
Attitude
Behavior, Spontaneous
Behavior, Provoked
Body Condition
Food and fluid intake, elimination of feces and urine.
Fur and skin
Eyes
Posture
Locomotion
Neurological
Vital Signs
Other clinical parameters that are relevant to your study
实验动物不善于表达其痛苦
As a 'prey species,' rodents are genetically programmed to mask signs of pain or distress. Post-operative analgesics should be used and daily post-procedural monitoring done by personnel familiar with rodent behavior. Spontaneous vocalization is rarely observed - hunched posture, inactivity, and decreased appetite all indicate distress in rats.
9.隐私
HIPAA (HHS 2013a) defines PHI as "any information" related to the "past, present or future physical or mental health condition" of a person.
总结
斑马鱼的研究
PHS funded research with zebrafish is regulated by PHS/OLAW and the Guide for the Care and Use of Laboratory Animals. As poikilotherms, zebrafish are not subject to regulations promulgated by the United States Department of Agriculture (USDA) under the Animal Welfare Act (AWA).
Successful breeding of zebrafish depends upon olfactory and visual clues and social interactions.
Zebrafish control buoyancy by regulating the volume of gas that enters the swim bladder.
Research has suggested that fish are capable of feeling both reflexive and cognitive pain.
"Postapproval Monitoring" (PAM) web-based course for IACUC members
PAM team members need practical knowledge, understanding and appreciation of the animal activities occurring at each site in order to recognize best practices and deviations from them. Members should also be knowledgeable of the animal care and use program, including protocols, grants, contacts and regulations, policies and procedures relevant to the program.
An effective PAM program relies upon cooperation and input from the IACUC, the veterinarian, animal care and technical staff, and the investigators
The three basic models for conducting PAM include PAM led by the Attending Veterinarian, PAM program led by the IACUC members or staff, and PAM program led by a compliance office. PAM is typically not led by the investigator.
Authors must make significant contributions to the research. In general, contributors who do not meet the criteria for authorship should, with their consent, be listed in the acknowledgments section.
the primary criterion for authorship is whether the person made a significant intellectual contribution to the work.
The organization that receives a federally-funded grant can typically claim ownership of the data from the project.
DLM refers to use of the range of technical tools and processes that protect data during a study’s lifecycle.
In general, data analytic methods should be specified before any data are collected to avoid the impression of picking a method to achieve a desired result. Acceptable data analysis methods often vary depending on the field and the research context.
The first two goals of information protection, confidentiality and availability, entail that data access should be limited to authorized users, while ensuring that data are available to those who should have access. Maintaining the trustworthiness, or integrity, of the data is the third goal of DLM.
HIPAA requires that organizations appoint a Privacy Officer to administer HIPAA rules.
One cannot control all disclosures of health information in one's record under HIPAA, only some of them.
The acknowledgment indicates only receipt of the notice, not understanding of it.
The privacy notice does not (and cannot) waive liability for privacy violations.
Information related to treatment, payment, and healthcare operations may generally be used or disclosed without any specific permission, at least under HIPAA. State law may set a higher standard.
学术不端
先 inquiry ，再 investigation
Responsible Conduct of Research (RCR)
挺复杂的，The list is heavily influenced by the U.S. Office of Research Integrity (ORI) and the NIH's RCR policy. 包括：
Animal Subjects Research
Authorship
Collaborative Research
Conflicts of Interest
Data Management
Humans Subjects Research
Mentoring
Peer Review
Research Misconduct
Safe Laboratory Practices
Social Responsibility
包含以下美德：
**Integrity **
**Honesty **
**Transparency **
Competence
Collegiality
Social Responsibility