Office For Human Research Protections Research Articles

Research Ethics Board of Health: a seven year review of the only ethics review board in Bhutan

Introduction: Research Ethics Board of Health (REBH), established in 2009, is the only ethics review board in Bhutan. The REBH was certified by the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), Forum for Ethical Review Committees in the Asian and Western Pacific Regions (FERCAP) in 2010 and recertified in 2013, and it received the Federal Wide Assurance (FWA) from the Office for Human Research Protections (OHRP), USA, in 2010 and in 2013. All researchers conducting health related research in Bhutan have to seek prior ethical clearance from REBH under the requirements of the National Health Policy 2011. Objective: The article aims to describe the performance of REBH, its standard and review procedure.
 Methods: A descriptive study of records and database of REBH from 2009 to 2015.
 Results: As of December 2015, the REBH has received 227 protocols with an average of 32 protocols per year. The median number of days for the initial review was 21 days (Min 0 days; Max 85 days). The median duration for approval of protocols from the date of receiving the application was 48 days. The average number of times the protocols were reviewed before issuing the approval letter was 2.
 Conclusions: There has been a progressive increase in the number of protocols submitted to REBH. This indicated an increasing research culture in Bhutan. It takes about one and half months to get an approval from REBH; therefore, researchers have to consider the time required for ethical clearance process while planning research projects.

IRB Protocol Starting Point for Those New to Geoscience Education Scholarship and Publication

Scholarly endeavors in geoscience education span a spectrum from the development and application of new geoscience teaching innovations and curricula to the development and testing of geoscience education research questions and hypotheses. These can be characterized as the scholarship of geoscience teaching and learning (geo-SoTL) and geoscience discipline-based educational research (geo-DBER). Both geo-SoTL and geo-DBER are important for improving the geoscience teaching practice. In terms of Journal of Geoscience Education (JGE) publication, geo-SoTL best aligns to the Curriculum & Instruction (CI these distinctions are largely in the purpose, study design, and methods. Data needed to determine if a teaching innovation is meeting its goal in a C&I study, or to test a particular research question or hypothesis in a Research study, often involve surveys or interviews of people. These could be, for example, students in a class, or participants in a workshop or field trip. While such human subject data is common to research in the social science disciplines, it is distinctly different from physical, chemical, or paleobiological data that geoscientists are trained in collecting and analyzing. For that reason, geoscientists who are interested in getting started in geo-SoTL or geoDBER need to become familiar with the rules that guide human subject research.The federal government, your institution (in most cases), and JGE each provide resources to help you understand what your responsibilities are when conducting research that involves human subjects. If you are new to geoscience education research and publication take the time to look at each of these resources as you plan your study:* Federal Government Resource: Recently the US Department of Health and Human Services Office for Human Research Protections (OHRP) published human subject regulation Decision Charts (http:// www.hhs.gov/ohrp/policy/checklists/decisioncharts. html) to assist investigators and institutions in determining whether an intended activity is human subject research, and if a study protocol may be eligible for exemption by a college or university's Institutional Review Board (IRB). These Decision Charts are in (mostly) plain language and ask a series of straight-forward yes/no questions. Working though the charts will not take long and can help investigators place their intended research in context of federal guidelines on human subject research.Based on the OHRP Decision Charts, most of the types of data collected, analyzed, and disseminated in geoscience education studies of adult populations are of minimal risk to study participants, and are therefore typically eligible for exemptions or expedited review by IRBs. For example, in most cases research that is conducted in classrooms or labs that focus on investigations of instructional strategies, curricula, and classroom management, and use educational tests, surveys, or interviews meet this criteria. In addition, studies that involve existing data (e.g., collected for the purpose of student assessment in a course) also meet this criteria. In all cases the privacy of the individuals will need to be assured so that study subjects cannot be identified or harmed by the reported results. …

Innovating consent for pediatric HCT patients

Informed consent is fundamental to ethical clinical practice and research. In the context of hematopoietic cell transplantation (HCT), informed consent struggles to meet its ideals of beneficence, justice, and respect for persons(1) given the severity of the disease and complexity of the treatment. As argued by D'Souza and colleagues in Bone Marrow Transplantation,(2) and as shown in other studies, including our own in the setting of pediatric HCT,(3) patient and caregiver expectations of consent are often left unmet in both adult and pediatric contexts. For example, participants enroll in studies with limited knowledge about what they are undertaking and find themselves involved in a rote, passive process that fails to inform and gets bogged down by legalistic language.(4) Consent is often requested under conditions characterized by duress. The medical urgency of HCT or associated treatments that are experimental often blurs the line between treatment and research, even from the clinicians’ perspective. Furthermore, miscommunication or misunderstanding is almost inevitable because the paper forms are overwhelmingly lengthy and complex.(5) Greater simplicity in terms of readability and length is a major goal of recent and forthcoming policy regarding informed consent. For example, the NCI’s Office of Human Research Protection and FDA developed a joint consensus in the “Development of Informed Consent Documents for Cancer Clinical Trials” for less complicated informed consent documents,(6) and the BMT CTN recently published new recommended guidelines for consent forms.(7) The Notice of Proposed Rule Making (NPRM) that would update the Common Rule calls for greater standardization, simplicity, and readability of forms.(8) However, improving patients’ comprehension of what they are consenting to will not be achieved without equal attention to the process of obtaining consent. Universal consent forms will always fall short of meeting the goals of being patient-centered, complete, and fulfilling institutional and regulatory requirements because of the diversity of individual patient needs.(9) Pediatric HCT provides an excellent case example of the need for a more personalized, two-way approach that promotes patient and caregiver activation and utilizes principles of shared decision-making.

Promoting Informed Decision Making for Comparative Effectiveness Randomized Trials.

The US Code of Federal Regulations governing human participants research requires that investigators disclose reasonably foreseeable risks of a research study to prospective participants during the informed consent process. Although this mandate appears straightforward, controversy surrounds how investigators should define and describe risks of comparative effectiveness randomized clinical trials (CE-RCTs) that compare treatments within accepted standards of care. The Office for Human Research Protections (OHRP) has published draft guidance prompted by the controversy of the Surfactant, Positive Pressure, and Pulse Oximetry (SUPPORT) trial of oxygenation targets in premature infants to address this question. The draft guidance concludes that “if a research study examining standards of care includes as a purpose evaluating identified risks associated with those standards of care, the identified risks associated with the standards of care being evaluated that are different from the risks of standards of care at least some of the subjects would be exposed to outside of the research study are generally considered…to be reasonably foreseeable risks of research.” 1 Given the often subtle ways in which participation in a CE-RCT alters risk compared with treatment outside the trial, accurately framing disclosures is challenging. Unfortunately, if implemented, the OHRP’s draft guidance will impede rather than promote informed decisions. Investigators and institutional review boards that follow the guidance are likely to formulate consent documents that mischaracterize the disadvantages of the study treatments compared with one another as foreseeable risks of participation, unnecessarily dissuading patients from enrolling. The OHRP should reconsider its guidance and instead support disclosures aimed at the following simple goal: to provide patients with information, including about risks, that they need to decide whether to join the trial, request one of the study treatments outside the trial, or select another available treatment. Organizing disclosure around 4 core questions can effectively accomplish this goal (Table).

Ethics in global health research: the need for balance.

Ethics in global health research: the need for balance.

Attitudes Toward Risk and Informed Consent for Research on Medical Practices: A Cross-sectional Survey.

The U.S. Office for Human Research Protections has proposed that end points of randomized trials comparing the effectiveness of standard medical practices are risks of research that would require disclosure and written informed consent, but data are lacking on the views of potential participants. To assess attitudes of U.S. adults about risks and preferences for notification and consent for research on medical practices. Cross-sectional survey conducted in August 2014. Web-based questionnaire. 1095 U.S. adults sampled from an online panel (n = 805) and an online convenience river sample (n = 290). Attitudes toward risk, informed consent, and willingness to participate in 3 research scenarios involving medical record review and randomization of usual medical practices. 97% of respondents agreed that health systems should evaluate standard treatments. Most wanted to be asked for permission to participate in each of 3 scenarios (range, 75.2% to 80.4%), even if it involved only medical record review, but most would accept nonwritten (oral) permission or general notification if obtaining written permission would make the research too difficult to conduct (range, 70.2% to 82.7%). Most perceived additional risk from each scenario (range, 64.0% to 81.6%). Use of hypothetical scenarios and a nonprobability sample that was not fully representative of the U.S. population. Most respondents preferred to be asked for permission to participate in observational and randomized research evaluating usual medical practices, but they are willing to accept less elaborate approaches than written consent if research would otherwise be impracticable. These attitudes are not aligned with proposed regulatory guidance. National Center for Advancing Translational Sciences at the National Institutes of Health.

Research on medical practices and the ethics of disclosure.

In March 2013, the Office of Human Research Protection (OHRP) issued a finding against the University of Alabama and other institutions for failing to meet regulatory informed consent requirements, in particular regarding reasonably foreseeable risks during the conduct of the Surfactant, Positive Pressure, and Oxygenation Randomized Trial.1 This study compared 2 different target oxygen saturation levels that were part of usual practice in extremely premature infants. As a result of public disagreement regarding whether the differences in outcomes should be considered a “research risk,” OHRP suspended the determination and held a public hearing in August 2013.2 On October 24, 2014, the OHRP released draft guidance, for public comment, on disclosing reasonably foreseeable risks in research evaluating “standards of care,” which on the surface, seems to be a reasonable approach.3 But a more careful analysis reveals a view that may hinder research without increasing protection of participants. The OHRP draft guidance mischaracterizes the purpose of research, which we agree should be disclosed to participants, as risks of research. The OHRP draft guidance misidentifies minimal-risk research as greater than minimal risk. This will result in requiring misleading information in the informed consent process by making research sound riskier than it really is. This will be particularly problematic for pediatric research, as parents and institutional review boards (IRBs) need sound advice to protect children from risky research and to encourage ethically acceptable research that is important to improve child health. We suggest a number of changes should be made before any guidance becomes finalized. First, OHRP should not use the terminology of “standard of care” research. “Standard of care” is a legal construct to define a floor of treatment below which claims of negligence are appropriate. To better capture the range of … Address correspondence to Benjamin S. Wilfond, MD, Treuman Katz Center for Pediatric Bioethics, Seattle Children’s Research Institute, 1900 9th Ave, Seattle, WA 98101. E-mail: benjamin.wilfond{at}seattlechildrens.org

Reading Level and Length of Written Research Consent Forms.

In 100 Institutional Review Board approved consent forms (CFs), we assessed pages, reading levels, and whether they included essential elements. CF page numbers ranged from 3 to 28 (mean, 10.3) and readability ranged from grades 5.6 to 28.9 (mean, 11.6). The CF mean score for including essential elements was 90.8% (range: 63.5-100%). There were no significant differences by specialty in number of pages (p = 0.053), but surgical specialties had the highest readability (mean, 13.1), and pediatrics the lowest (10.5), p = 0.008. While approved CFs generally included the Office for Human Research Protections recommended essential elements, they were very long, and even pediatric forms, which had the lowest reading levels, were written on average at a tenth grade level. Researchers need guidance to resolve pressure between regulatory mandates and guidelines and "keeping it simple and clear."

Knowledge of Federal Regulations for Mental Health Research Involving Prisoners

Background: Given their vulnerability to coercion and exploitation, prisoners who participate in research are protected by Office for Human Research Protections (OHRP) regulations designed to ensure their safety and wellbeing. Knowledge of these regulations is essential for researchers who conduct and institutional review boards (IRBs) that oversee mental health research in correctional settings. Methods: We explored depth of knowledge of OHRP regulations by surveying a nationwide sample of (1) mental health researchers who have conducted research in correctional settings, (2) mental health researchers who have conducted research in noncorrectional settings, (3) IRB members who have overseen mental health research in correctional settings, (4) IRB members who have overseen mental health research in in noncorrectional settings, and (5) IRB prisoner representatives. Participants responded to a 10-item knowledge questionnaire based on OHRP regulations. Results: There were 1,256 participants who provided usable data (44.9% response rate). Results revealed limited knowledge of OHRP regulations, with a mean across groups of 44.1% correct answers. IRB prisoner representatives, IRB members, and researchers with correctional experience demonstrated the highest levels of knowledge; however, even these participants were able to correctly answer only approximately 50% of the items. Conclusions: Although awareness that prisoners are a protected population and that different regulatory procedures apply to research with them is likely to be universal among researchers and IRB members, our findings reveal limited mastery of the specific OHRP regulations that are essential knowledge for researchers who conduct and IRB members who oversee mental health research in correctional settings. Given well-documented health and health care disparities, prisoners could potentially benefit greatly from mental health research; increasing knowledge of the OHRP regulations among researchers and IRB members is a crucial step toward meeting this important public health goal.

Creating an infrastructure for comparative effectiveness research in emergency medical services.

Emergency medical services (EMS) providers deliver the initial care for millions of people in the United States each year. The Institute of Medicine noted a deficit in research necessary to improve prehospital care, created by the existence of data silos, absence of long-term outcomes, and limited stakeholder engagement in research. This article describes a regional effort to create a high-performing infrastructure in southwestern Pennsylvania addressing these fundamental barriers. Regional EMS records from 33 agencies in January 2011 were linked to hospital-based electronic health records (EHRs) in a single nine-hospital system, with manual review of matches for accuracy. The use of community stakeholder engagement was included to guide scientific inquiry, as well as 2-year follow up for patient-centered outcomes. Local EMS medicine stakeholders emphasized the limits of single-agency EMS research and suggested that studies focus on improving cross-cutting, long-term outcomes. Guided by this input, more than 95% of EMS records (2,675 of 2,800) were linked to hospital-based EHRs. More than 80% of records were linked to 2-year mortality, with more deaths among EMS patients with prehospital hypotension (30.5%) or respiratory distress (19.5%) than chest pain (5.4%) or nonspecific complaints (9.4%). A prehospital comparative effectiveness research infrastructure composed of patient-level EMS data, EHRs at multiple hospitals, long-term outcomes, and community stakeholder perspectives is feasible and may be scalable to larger regions and networks. The lessons learned and barriers identified offer a roadmap to answering community and policy-relevant research questions in prehospital care.

US-funded measurements of cervical cancer death rates in India: scientific and ethical concerns.

Since 1998, randomised trials in India funded by the US National Cancer Institute (NCI) and the Bill and Melinda Gates Foundation have compared cervical cancer death rates among 224,929 women offered cervical screening to those among 138,624 women offered no screening whatsoever. To date, at least 254 women in unscreened control groups have died of cervical cancer. The United States Office for Human Research Protections (OHRP) determined that the subjects in the studies were not given adequate information for the purpose of providing informed consent. The determinations of the OHRP contradict assurances given by other American medical and bioethical leaders. CONCERNS: Defective scientific design required inadequate informed consent. US-funded measurements of death rates may have needlessly delayed development of indispensable, life-saving public health infrastructure. US-funded measurements of incidence and death rates proved to be scientifically irreproducible and unreliable. Predictably, nothing was learned from these measurements that was not already known. Statistical bias embedded in measurement of death rates yielded the absurd conclusion that Papanicolaou screening does not prevent cervical cancer, leading to a marketing campaign for a proprietary human papillomavirus (HPV) screening test unaffordable for the women among whom death rates had been measured. Inexplicably, measurements of death rates among unscreened women were continued even after the mortality benefit of screening had been confirmed. Quality management of NCI fundedvisual screening (VIA) in Mumbai failed catastrophically, with unsettling implications for VIA conducted by those with less expertise. High-quality screening must be provided to all surviving unscreened women without further delay. US-based global health organisations should institutionalise a commitment to “improving health outcomes as rapidly as possible among as many people as possible.” Those who suffered avoidable harm and death, as well as their families, should be promptly and fairly compensated. As another critic of these unfortunate studies concluded, “You can’t let people die to show something you already know.”

Informed Consent and Standard of Care: What Must Be Disclosed

The Office for Human Research Protections (OHRP) was correct in determining that the consent forms for the National Institutes of Health (NIH)-sponsored SUPPORT study were seriously flawed. Several articles defended the consent forms and criticized the OHRP's actions. Disagreement focuses on three central issues: (1) how risks and benefits should be described in informed consent documents; (2) the meaning and application of the concept of “standard of care” in the context of research; and (3) the proper role of OHRP. Examination of the consent forms reveals that they failed to disclose the reasonably foreseeable risks of the experimental interventions in the study, as well as the potential for differences in the degree of risk between these interventions. Although the concept of “standard of care” may be helpful in determining the ethical acceptability of other aspects of research, such as clinical equipoise, it is not helpful in discussing consent requirements.

SUPPORTing Premature Infants

* Abbreviations: OHRP — : Office for Human Research Protections SUPPORT — : Surfactant Positive Pressure, and Oxygenation Randomized Trial The Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) tried to determine the safest dose of oxygen for premature infants. The federal Office for Human Research Protections (OHRP) determined that the consent process for the study violated federal regulations by failing to inform parents of “reasonably foreseeable risks” of death or blindness.1 The New York Times agreed, calling these failures “startling and deplorable.2 The New England Journal disagreed. They found the consent forms adequate and the accused the OHRP of “casting a pall over the conduct of clinical research.”3 Leaders of the NIH agreed.4 The difference of opinion turns, in part, on the ways that we define the relative risks of research, on the one hand, and, on the other hand, the risks of widely used but inadequately studied conventional therapies. Ten years ago, Cole et al5 summarized the state of knowledge about oxygen therapy for premature infants: “We do not understand optimal oxygenation management in extremely low gestational age neonates (<28 weeks’ gestation). No randomized controlled trial has clarified the relation between retinopathy of prematurity and blood oxygen, transcutaneous oxygen, or oxygen saturation levels.” As a result, they noted, “neonatal care providers differ widely, with no consensus in their policies, practices, and strong beliefs regarding oxygen management in both the early and later neonatal courses of premature infants.” They called for prospective randomized trials to address this crucial gap in knowledge because “continued treatment of millions of premature infants in ignorance of what is safe and effective oxygenation is not an option.” Today, the situation is different because such studies were designed and conducted in the United States,6 Canada, Australia, New Zealand, and the United Kingdom.7 In the United States, SUPPORT was a National Institutes of Health–sponsored, multicenter, prospective randomized trial of … Address correspondence to John D. Lantos, MD, Children’s Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108. E-mail: jlantos{at}cmh.edu

Quality Improvement Ethics: Lessons From the SUPPORT Study

The Office of Human Research Protections was not justified in issuing findings against the SUPPORT Institutions. Our community can learn from the evolving healthcare transformation into learning health systems by thinking about the novel ethical issues about standard of care research raised by the SUPPORT with the same spirit of quality improvement. The current regulatory framework and the concept of foreseeable research risks is insufficient to advance the debate about the ethics of randomization of standard clinical interventions. This article uses the example of the Wisconsin cystic fibrosis randomized clinical trial for newborn screening trial to explore the distinctions between risks of research and clinical care and waivers of informed consent for randomization. Collaborative exploration of these complex policy issues is needed and further deliberation, community engagement, and social science research will be critical to advance novel approaches for informed consent.

Learning the right lessons from the SUPPORT study controversy

Ten years ago, there was well-known and widespread practice variation in the levels of oxygen that neonatologists provided to premature babies.1 Neonatal intensive care units (NICUs) targeted oxygen saturations ranging...

Around the World

In science news around the world, the Nobel Prize is to get a new home in Stockholm, the U.S. Office for Human Research Protections has shelved its decision to sanction the leaders of a controversial clinical trial on premature infants, China and the United States have agreed to cuts in atmospheric warming chemicals called hydrofluorocarbons, and Italian researchers gathered in a flash mob to protest misinformation about science.

Neonatal Trial Criticized for Inadequate Consent

The US Office for Human Research Protections (OHRP) has determined that a large multisite clinical trial comparing the effects of differing levels of oxygen supplementation for neonates failed to obtain proper consent from the parents of enrolled infants.

Use of central institutional review boards for multicenter clinical trials in the United States: A review of the literature

To improve the efficiency of conducting multicenter clinical trials, the Food and Drug Administration, the Office of Human Research Protections, and the Department of Health and Human Services have expressed support for using a centralized institutional review board (IRB) process. However, research institutions differ in their willingness to defer to central IRBs. We aimed to review and describe peer-reviewed journal articles on the use of central IRBs for multicenter clinical trials in the United States in an effort to inform the policy discussion about central IRBs. We used a PubMed search and consulted IRB experts and the bibliographies of other reviews to identify relevant commentaries and empirical studies. Our search identified 33 articles related to the use of central IRBs for multicenter trials in the United States. Of these, 22 were commentary pieces and 11 were empirical studies. Our review was restricted to journal articles about the use of central IRBs for multicenter clinical trials in the United States. There is limited empirical work on the use of central IRBs for multicenter trials in the United States. Most published studies focused on problems in efficiency associated with redundant local reviews of multicenter studies and the potential benefits of a centralized system. Because the absence of studies on the use of central IRBs may be due to their infrequent use, additional work is needed to generate data on the use of central IRBs and to elucidate and address the concerns that research institutions have about deferring ethical review to a central IRB.

Compassionate ethics for clinics

Biomedical ethicists and clinical practitioners both champion the good of the patient, but sometimes their approaches diverge. The harmony of the ideal and the real is our utmost goal, but we often confront situations where theory falls apart in practice. A neonatal study performed by several noted institutions that is being audited by the US Office for Human Research Protections (OHRP) is a case in point. Prematurely born infants have underdeveloped lungs that need an intentional oxygen supply. However, too much oxygen carries other risks. Thus, to determine the optimal oxygen level within the range of levels allowed in the current clinical guidelines, researchers at 23 well-known academic institutions carried out a US government-financed study, the Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT), from 2004 to 2009. According to their article in the New England Journal of Medicine (2010;362:1959-1969), infants receiving the lower oxygen concentration, which was 85 to 89 percent, showed a higher mortality rate than those in the higher oxygen concentration group, who received 91 to 95 percent. This result fundamentally changed the treatment guidelines for premature infants. The OHRP, however, has noted that the researchers did not properly notify the subjects that their babies could have faced differing risks of either death or developing serious ocular problems according to the treatment protocol randomly assigned to them. While the principle investigator of SUPPORT, Dr. Neil Finer at the University of California at San Diego, has argued that at the time of the study design, there was no basis in the literature for attributing a greater risk of death to the lower oxygen level, the OHRP has identified published research on the greater risk of blindness with the higher oxygen level. The OHRP acknowledges the value of the research objective of the SUPPORT group, but in a March 2013 letter, they suggested that the consent form for SUPPORT was not clearly written, such that the research institutions failed to warn the participants about these risks. Shades of the Tuskegee syphilis experiment in the 1930s come to mind, but the current case is not so cut and dried. Before drawing a hasty conclusion, the experience of Dr. Dan Brock, who is an ethics philosopher at Harvard Medical School, is worth considering. When he got cancer, he was forced to confront the interface between theory and practice. In Malignant: Medical Ethicists Confront Cancer, he described the mental anguish of trying to choose a treatment path alone when his physicians, following best practices, did not push him to pursue one treatment over another because definitive research evidence was lacking. When infants are treated, clinical practitioners usually make careful decisions based on the physical condition of the patients in consultation with their parents. This approach was taken in the SUPPORT study, given that the oxygen levels of all of the participants were within the standard range of the American Academy of Pediatrics' guideline. We await the outcome of the careful deliberations between the SUPPORT group and OHRP. Meanwhile, let our ethical standards be practical and compassionate and our clinical practice be theoretically sound. Both are equally vital in the treatment of our patients.

Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia

Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations.