Publications by authors named "G Bradley Schaefer"

473 Publications

Multimodal imaging of an RPGR carrier female.

Ophthalmic Genet 2021 Feb 23:1-5. Epub 2021 Feb 23.

Jones Eye Institute, Department of Ophthalmology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

: Retinitis pigmentosa GTPase regulator () gene mutations are a common cause of X-linked retinitis pigmentosa and X-linked cone-rod dystrophy. There have been no previous reports of association with crystalline retinopathy or pseudo-crystalline retinopathy.: We describe the history, clinical findings, retinal imaging, and electrodiagnostic studies of a patient with a tapetal-like reflex (TLR) and pseudo-crystalline retinopathy secondary to mutation.: Asymptomatic TLR secondary to mutation was diagnosed in a 14-year-old African American female with a family history of retinal dystrophy and no other past ophthalmic or medical history. Pseudo-crystalline retinopathy was observed on the Optos scanning laser ophthalmoscopy (SLO) imaging system but not on color fundus photography (CFP). Evidence of a TLR secondary to mutation was confirmed by CFP, autofluorescence, and genetic testing.: We present a case of pseudo-crystalline retinopathy seen on Optos imaging in a patient with a TLR secondary to mutation.
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http://dx.doi.org/10.1080/13816810.2021.1881981DOI Listing
February 2021

Will Protective Innovations Like the "Airway Box" Become Routine Practice After the Pandemic?: An Opinion Survey.

Cureus 2021 Feb 10;13(2):e13258. Epub 2021 Feb 10.

Anesthesiology, West Virginia University School of Medicine, Morgantown, USA.

Background Tracheal intubation carries an elevated risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to the generation of aerosols containing high concentrations of the virus. An airway box was designed to mitigate the exposure of healthcare professionals performing intubations. Aim We evaluated usability and sustainability in the routine practice of the "airway box" as a protective device during high-risk airway procedures.  Materials and methods After institutional review board approval, clinicians were educated on using the device through simulation, intranet learning modules, and emailed resources. The airway box was made available in the emergency department, critical care units, perioperative area, and operating rooms. QR codes affixed to the box, emailed, and displayed in common areas provided easy access to complete a REDcap survey (Vanderbilt University Nashville, USA) eliciting providers' experience. Data was collected and analyzed between April 1 and July 31, 2020, on REDcap, and the results were analyzed. Results 687 emergent intubations took place. 232 were performed by anesthesiologists, 315 by emergency department providers, and 140 by critical care specialists. 39 surveys were completed, 29 from intubations in the operating room, three from the critical care units, five from interventional radiology suites, and two perioperatively. Providers found the device to be readily available, with a score of 4.51/5, and the majority of providers, 60%, found the device easy to use, rating it either a 4 or 5 out of 5. Providers acquired a mean Mallampati score of 1.75 and 1.40 mean laryngoscopic grade view. Conclusion Intubation boxes may effectively mitigate high-risk viral exposure during airway procedures. Survey responses show that devices were easy to use and did not significantly affect visualization of the airway. Similar to mask use, enclosure devices in clinical practice could become a vital part of medical protective equipment even after the SARS-CoV-2 pandemic if they are effectively implemented.
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http://dx.doi.org/10.7759/cureus.13258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877255PMC
February 2021

Enhancing the WHO's Proposed Framework for Distributing COVID-19 Vaccines Among Countries.

Am J Public Health 2021 03;111(3):371-373

Ezekiel J. Emanuel is with the Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Florencia Luna is with the Program of Bioethics, FLACSO (Latin American University of Social Sciences) and CONICET (National Scientific and Technical Research Council), Buenos Aires, Argentina. G. Owen Schaefer is with the Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Kok-Chor Tan is with the Department of Philosophy, University of Pennsylvania, Philadelphia. Jonathan Wolff is with the Blavatnik School of Government, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.2105/AJPH.2020.306098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893355PMC
March 2021

End-to-end collaboration to transform biopharmaceutical development and manufacturing.

Biotechnol Bioeng 2021 Jan 22. Epub 2021 Jan 22.

National Institute for Innovation in Manufacturing Biopharmaceuticals, Newark, Delaware, USA.

An ambitious 10-year collaborative program is described to invent, design, demonstrate, and support commercialization of integrated biopharmaceutical manufacturing technology intended to transform the industry. Our goal is to enable improved control, robustness, and security of supply, dramatically reduced capital and operating cost, flexibility to supply an extremely diverse and changing portfolio of products in the face of uncertainty and changing demand, and faster product development and supply chain velocity, with sustainable raw materials, components, and energy use. The program is organized into workstreams focused on end-to-end control strategy, equipment flexibility, next generation technology, sustainability, and a physical test bed to evaluate and demonstrate the technologies that are developed. The elements of the program are synergistic. For example, process intensification results in cost reduction as well as increased sustainability. Improved robustness leads to less inventory, which improves costs and supply chain velocity. Flexibility allows more products to be consolidated into fewer factories, reduces the need for new facilities, simplifies the acquisition of additional capacity if needed, and reduces changeover time, which improves cost and velocity. The program incorporates both drug substance and drug product manufacturing, but this paper will focus on the drug substance elements of the program.
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http://dx.doi.org/10.1002/bit.27688DOI Listing
January 2021

Perspectives of Singaporean biomedical researchers and research support staff on actual and ideal IRB review functions and characteristics: A quantitative analysis.

PLoS One 2020 31;15(12):e0241783. Epub 2020 Dec 31.

Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Background: Biomedical research is overseen by numerous Institutional Review Boards (IRBs) in Singapore but there has been no research that examines how the research review process is perceived by the local research community nor is there any systematic data on perceptions regarding the review process or other research ethics processes and IRB characteristics. The aim of this study was to ascertain general views regarding the overall perceived value of ethics review processes; to measure perceptions about local IRB functions and characteristics; to identify IRB functions and characteristics viewed as important; and to compare these views with those of other international studies.

Methods: An online survey was used with the main component being the IRB-Researcher Assessment Tool (IRB-RAT), a validated tool, to evaluate perceptions of ideal and actual IRB functions and characteristics held by Singaporean researchers and research support staff. Data were analysed descriptively first, with mean and SD of each item of IRB-RAT questionnaire reported, excluding the respondents whose answers were unknown or not applicable. The Wilcoxon Sign Rank test was used to compare the ideal and actual ratings of each IRB-RAT item, while the Mann-Whitney U test was used to compare the ratings of each IRB-RAT item between respondents with different characteristics. The Z-test was used to compare the mean ratings of our cohort with the mean ratings reported in the literature. The correlation between our mean ideal scores and those of two international studies also employing the IRB-RAT was examined.

Results: Seventy-one respondents completed the survey. This cohort generally held positive views of the impact of the ethics review process on: the quality of research; establishing and maintaining public trust in research; the protection of research participants; and on the scientific validity of research. The most important ideal IRB characteristics were timeliness, upholding participants' rights while also facilitating research, working with investigators to find solutions when there are disagreements, and not allowing biases to affect reviews. For almost all 45 IRB-RAT statements, the rating of the importance of the characteristic was higher than the rating of how much that characteristic was descriptive of IRBs the respondents were familiar with. There was a significant strong correlation between our study's scores on the ideal IRB characteristics and those of the first and largest published study that employed the IRB-RAT, the US National Validation (USNV) sample in Keith-Spiegel et al. [19].

Conclusions: An understanding of the perceptions held by Singaporean researchers and research support staff on the value that the ethics review process adds, their perceptions of actual IRB functions and characteristics as well as what they view as central to high functioning IRBs is the first step to considering the aspects of the review process that might benefit from improvements. This study provides insight into how our cohort compares to others internationally and highlights strengths and areas for improvement of Singapore IRBs as perceived by a small sample of the local research community. Such insights provide a springboard for additional research and may assist in further enhancing good relations so that both are working towards the same end.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241783PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774925PMC
January 2021

In defence of a broad approach to public interest in health data research.

J Med Ethics 2020 Dec 10. Epub 2020 Dec 10.

Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

In their response to 'Public interest in health data research: laying out the conceptual groundwork', Grewal and Newson critique us for inattention to the law and putting forward an impracticably broad conceptual understanding of public interest. While we agree more work is needed to generate a workable framework for Institutional Review Boards/Research Ethics Committees (IRBs/RECs), we would contend that this should be grounded on a broad conception of public interest. This broadness facilitates regulatory agility, and is already reflected by some current frameworks such as that found in the guidelines approved under Australia's Privacy Act. It remains unclear which elements of our broad account Grewal and Newson would reject, or indeed where the substantive disagreement with our position lies.
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http://dx.doi.org/10.1136/medethics-2020-106880DOI Listing
December 2020

Embedding public health advocacy into the role of school-based nurses: addressing the health inequities confronted by vulnerable Australian children and adolescent populations.

Aust J Prim Health 2020 Dec 3. Epub 2020 Dec 3.

There has been a growth in Australian school-based nurses to address the inequities confronted by vulnerable students and school populations. Failure to address inequities can be evidenced in intergenerational poverty, poorer health and educational attainment and diminished life opportunities. School-based nurses are ideally located to advocate for public health policies and programs that address social determinants that detrimentally affect the health of school populations. However, school-based nurses can confront professional and speciality challenges in extending their efforts beyond individual student advocacy to effect change at the school population level. Guidance is required to redress this situation. This paper describes public health advocacy, the professional and speciality advocacy roles of school-based nurses and the barriers they confront in advocating for the health of school populations and strategies that can be used by key stakeholders to enhance school-based nursing public health advocacy efforts. School-based nurses who are competent, enabled and supported public health advocates are required if we are to achieve substantial and sustained health equity and social justice outcomes for vulnerable school populations.
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http://dx.doi.org/10.1071/PY20155DOI Listing
December 2020

Adjusted vs Total Body Weight-Based Dosing of Sedation and Analgesia Used in the Intensive Care Unit.

Hosp Pharm 2020 Dec 13;55(6):400-404. Epub 2019 Jun 13.

Ruby Memorial Hospital, Morgantown, WV, USA.

The purpose of this study was to evaluate if dosing fentanyl, dexmedetomidine, and propofol based on ideal or adjusted vs actual weight in patients would decrease overall opioid and sedative use. This was a retrospective chart review comparing adjusted vs actual weight-based dosing protocol of mechanically ventilated (MV) intensive care unit (ICU) adult patients who required fentanyl and either propofol or dexmedetomidine. A total of 261 patients were included in which 101 patients were in the actual weight group and 160 patients were in the adjusted weight group. Total doses per MV day of fentanyl was 1042 ± 1060 µg in the actual weight group vs 901 ± 1025 µg in the adjusted weight group ( = .13). Total doses per MV day of midazolam was 20 ± 19 mg in the actual group vs 15 ± 19 mg adjusted group ( = .02). Average MV days was 8.2 vs 7.1 days, ICU length of stay was 10.6 vs 9.4 days, and self-extubation rates were 17.8% vs 4.4% in the actual group and adjusted group, respectively. Total midazolam doses per MV day were lower in the adjusted group. No significant change was seen in MV days, ICU length of stay, or self-extubation rates.
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http://dx.doi.org/10.1177/0018578719851452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672665PMC
December 2020

"Who is watching the watchdog?": ethical perspectives of sharing health-related data for precision medicine in Singapore.

BMC Med Ethics 2020 11 19;21(1):118. Epub 2020 Nov 19.

Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.

Background: We aimed to examine the ethical concerns Singaporeans have about sharing health-data for precision medicine (PM) and identify suggestions for governance strategies. Just as Asian genomes are under-represented in PM, the views of Asian populations about the risks and benefits of data sharing are under-represented in prior attitudinal research.

Methods: We conducted seven focus groups with 62 participants in Singapore from May to July 2019. They were conducted in three languages (English, Mandarin and Malay) and analysed with qualitative content and thematic analysis.

Results: Four key themes emerged: nuanced understandings of data security and data sensitivity; trade-offs between data protection and research benefits; trust (and distrust) in the public and private sectors; and governance and control options. Participants were aware of the inherent risks associated with data sharing for research. Participants expressed conditional support for data sharing, including genomic sequence data and information contained within electronic medical records. This support included sharing data with researchers from universities and healthcare institutions, both in Singapore and overseas. Support was conditional on the perceived social value of the research and appropriate de-identification and data security processes. Participants suggested that a data sharing oversight body would help strengthen public trust and comfort in data research for PM in Singapore.

Conclusion: Maintenance of public trust in data security systems and governance regimes can enhance participation in PM and data sharing for research. Contrary to themes in much prior research, participants demonstrated a sophisticated understanding of the inherent risks of data sharing, analysed trade-offs between risks and potential benefits of PM, and often adopted an international perspective.
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http://dx.doi.org/10.1186/s12910-020-00561-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678103PMC
November 2020

International Reporting Mechanism for Unethical Germline Gene Editing Experiments Is Needed.

Trends Biotechnol 2020 Nov 4. Epub 2020 Nov 4.

Science, Health, and Policy-Relevant Ethics in Singapore (SHAPES), Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Recent reporting found that a number of scientists internationally knew about the experiment resulting in the birth of the first gene-edited babies well before the news broke. Because scientists have a responsibility to reveal such activities, an international governance mechanism for reporting unethical gene editing experiments should be established.
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http://dx.doi.org/10.1016/j.tibtech.2020.10.001DOI Listing
November 2020

A triple-star system with a misaligned and warped circumstellar disk shaped by disk tearing.

Science 2020 09;369(6508):1233-1238

Department of Physics and Astronomy, University of Nevada, Las Vegas, NV 89154, USA.

Young stars are surrounded by a circumstellar disk of gas and dust, within which planet formation can occur. Gravitational forces in multiple star systems can disrupt the disk. Theoretical models predict that if the disk is misaligned with the orbital plane of the stars, the disk should warp and break into precessing rings, a phenomenon known as disk tearing. We present observations of the triple-star system GW Orionis, finding evidence for disk tearing. Our images show an eccentric ring that is misaligned with the orbital planes and the outer disk. The ring casts shadows on a strongly warped intermediate region of the disk. If planets can form within the warped disk, disk tearing could provide a mechanism for forming wide-separation planets on oblique orbits.
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http://dx.doi.org/10.1126/science.aba4633DOI Listing
September 2020

Correction to: The Perfect Moral Storm: Diverse Ethical Considerations in the COVID-19 Pandemic.

Asian Bioeth Rev 2020 Jun 6. Epub 2020 Jun 6.

Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

[This corrects the article DOI: 10.1007/s41649-020-00125-3.].
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http://dx.doi.org/10.1007/s41649-020-00131-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275127PMC
June 2020

The Perfect Moral Storm: Diverse Ethical Considerations in the COVID-19 Pandemic.

Asian Bioeth Rev 2020 May 28:1-19. Epub 2020 May 28.

SHAPES Initiative, Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

The COVID-19 pandemic has both exposed and created deep rifts in society. It has thrust us into deep ethical thinking to help justify the difficult decisions many will be called upon to make and to protect from decisions that lack ethical underpinnings. This paper aims to highlight ethical issues in six different areas of life highlighting the enormity of the task we are faced with globally. In the context of COVID-19, we consider health inequity, dilemmas in triage and allocation of scarce resources, ethical issues associated with research, ethical considerations relating to tracing apps, and exit strategies such as immunity passports and COVID-19 vaccines. Finally, we consider environmental issues in light of COVID-19. The paper also offers some ethical reflection on these areas as many parts of the world contemplate the recovery phase.
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http://dx.doi.org/10.1007/s41649-020-00125-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255635PMC
May 2020

Guidance for Healthcare Providers Managing COVID-19 in Rural and Underserved Areas.

J Racial Ethn Health Disparities 2020 10 10;7(5):817-821. Epub 2020 Jul 10.

Department of Medicine, West Virginia University, PO Box 9156, Morgantown, WV, 26506, USA.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has ravaged many urban and high-density areas in the USA. However, rural areas (despite their low population density) may be especially vulnerable to poor outcomes from COVID-19, owing to limited healthcare infrastructure, long distances to advanced health care, and population characteristics (e.g., high tobacco use, hypertension, obesity, older age). A panel of experts who are actively engaged in treating and managing COVID-19 at a rural academic center was convened to address this topic. In this commentary, we provide readers with some specific issues faced by rural healthcare providers and offer guidance in overcoming these challenges. This guidance includes alternative ventilator strategies, personal protective equipment (PPE), and common therapeutic options.
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http://dx.doi.org/10.1007/s40615-020-00820-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351538PMC
October 2020

COVID-19 vaccine development: Time to consider SARS-CoV-2 challenge studies?

Vaccine 2020 07 4;38(33):5085-5088. Epub 2020 Jun 4.

Centre for Biomedical Ethics, National University of Singapore, Yong Loo Lin School of Medicine, Block MD11, Clinical Research Centre, #02-03, 10 Medical Drive, Singapore 117597, Singapore. Electronic address:

While a human challenge study holds the prospect of accelerating the development of a vaccine for the coronavirus SARS-CoV-2, it may be opposed due to risks of harm to participants and researchers. Given the increasing number of human deaths and severe disruption to lives worldwide, we argue that a SARS-CoV-2 challenge study is ethically justifiable as its social value substantially outweighs the risks. Such a study should therefore be seriously considered as part of the global research response towards the COVID-19 pandemic. In this paper, we contribute to the debate by addressing the misperception that a challenge study for the coronavirus would lower scientific and ethical standards for vaccine research and development, and examine how it could be ethically conducted. We also set out information that needs to be disclosed to prospective participants to obtain their consent.
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http://dx.doi.org/10.1016/j.vaccine.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269942PMC
July 2020

Navigating conflicts of justice in the use of race and ethnicity in precision medicine.

Bioethics 2020 10 19;34(8):849-856. Epub 2020 May 19.

Nanyang Technological University, School of Social Sciences, Lee Kong Chian School of Medicine and School of Biological Sciences, Singapore.

Given the sordid history of injustices linking genetics to race and ethnicity, considerations of justice are central to ensuring the responsible development of precision medicine programmes around the world. While considerations of justice may be in tension with other areas of concern, such as scientific value or privacy, there are also tensions between different aspects of justice. This paper focuses on three particular aspects of justice relevant to this precision medicine: social justice, distributive justice and human rights. We describe the implications of each for the use of race and ethnicity in precision medicine, and also how they intersect and potentially conflict with each another. By attending to these intersections, we aim to enrich and add nuance to debates over how best to proceed with precision medicine initiatives.
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http://dx.doi.org/10.1111/bioe.12757DOI Listing
October 2020

Public interest in health data research: laying out the conceptual groundwork.

J Med Ethics 2020 Sep 6;46(9):610-616. Epub 2020 May 6.

Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University Singapore, Singapore

The future of health research will be characterised by three continuing trends: rising demand for health data; increasing impracticability of obtaining specific consent for secondary research; and decreasing capacity to effectively anonymise data. In this context, governments, clinicians and the research community must demonstrate that they can be responsible stewards of health data. IRBs and RECs sit at heart of this process because in many jurisdictions they have the capacity to grant consent waivers when research is judged to be of particular value. However, several different terms are used to refer to this value (including public interest, public benefit, public good and social value), indicating a lack of conceptual clarity regarding the appropriate test for access to health data for research without consent. In this paper we do three things. First we describe the current confusion and instability in terminology relating to public interest in the context of consent waivers. Second we argue for harmonisation of terminology on the grounds of clarity, transparency and consistency. Third we argue that the term 'public interest' best reflects the normative work required to justify consent waivers because it is the broadest of the competing terms. 'Public interest' contains within its scope positive and negative implications of a study, as well as welfare, justice and rights considerations. In making this argument, we explain the normative basis for consent waivers, and provide a starting place for further discussion about the precise conditions in which a given study can be said to advance the public interest. Ipsos MORI study found that: … the public would be broadly happy with administrative data linking for research projects provided (1) Those projects have social value, broadly defined. (2) Data are de-identified. (3) Data are kept secure. (4) Businesses are not able to access the data for profit.
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http://dx.doi.org/10.1136/medethics-2020-106152DOI Listing
September 2020

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy.

Genet Med 2020 Aug 5;22(8):1413-1417. Epub 2020 May 5.

Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.

Purpose: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene.

Methods: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher.

Results: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay.

Conclusion: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.
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http://dx.doi.org/10.1038/s41436-020-0815-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394879PMC
August 2020

Rates of diagnostic genetic testing in a tertiary ocular genetics clinic.

Ophthalmic Genet 2020 06 27;41(3):271-274. Epub 2020 Apr 27.

Harvey and Bernice Jones Eye Institute, University of Arkansas for Medical Sciences College of Medicine , Little Rock, AR, USA.

Background: Clinical genetics has evolved significantly to become an efficient and effective means of diagnosing disease. Genetic treatments are now being developed which are showing promising results. However, ophthalmic patients are not utilizing genetic testing as part of their diagnostic workups. This paper explores the patient experience at the Ocular Genetics Clinic (OGC) at the University of Arkansas for Medical Sciences (UAMS) Jones Eye Institute and discusses reasons why patients continue to not pursue genetic testing.

Materials And Methods: We performed a retrospective chart review to understand the main reasons why patients were referred to the OGC between 2009 and 2018, with a detailed analysis of why patients did not pursue genetic testing.

Results: Patients mainly did not undergo testing due to the cost of testing. However, patient availability, patient interest, and diagnostic workup also drove a significant amount of this lack of testing.

Conclusions: Ocular genetic testing is becoming an increasingly beneficial tool for diagnosing ocular disease. However, to date, patients do not utilize this service fully. At the OGC, there are several main drivers for this lack of testing, namely finances, interest/availability, and diagnostic workup. As more ocular genetics clinics are established, it will be imperative to address reasons for forgoing genetic testing and to develop strategies to encourage patients to pursue this testing.
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http://dx.doi.org/10.1080/13816810.2020.1759107DOI Listing
June 2020

Transfer learning using a multi-scale and multi-network ensemble for skin lesion classification.

Comput Methods Programs Biomed 2020 Sep 21;193:105475. Epub 2020 Mar 21.

Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.

Background And Objective: Skin cancer is among the most common cancer types in the white population and consequently computer aided methods for skin lesion classification based on dermoscopic images are of great interest. A promising approach for this uses transfer learning to adapt pre-trained convolutional neural networks (CNNs) for skin lesion diagnosis. Since pre-training commonly occurs with natural images of a fixed image resolution and these training images are usually significantly smaller than dermoscopic images, downsampling or cropping of skin lesion images is required. This however may result in a loss of useful medical information, while the ideal resizing or cropping factor of dermoscopic images for the fine-tuning process remains unknown.

Methods: We investigate the effect of image size for skin lesion classification based on pre-trained CNNs and transfer learning. Dermoscopic images from the International Skin Imaging Collaboration (ISIC) skin lesion classification challenge datasets are either resized to or cropped at six different sizes ranging from 224 × 224 to 450 × 450. The resulting classification performance of three well established CNNs, namely EfficientNetB0, EfficientNetB1 and SeReNeXt-50 is explored. We also propose and evaluate a multi-scale multi-CNN (MSM-CNN) fusion approach based on a three-level ensemble strategy that utilises the three network architectures trained on cropped dermoscopic images of various scales.

Results: Our results show that image cropping is a better strategy compared to image resizing delivering superior classification performance at all explored image scales. Moreover, fusing the results of all three fine-tuned networks using cropped images at all six scales in the proposed MSM-CNN approach boosts the classification performance compared to a single network or a single image scale. On the ISIC 2018 skin lesion classification challenge test set, our MSM-CNN algorithm yields a balanced multi-class accuracy of 86.2% making it the currently second ranked algorithm on the live leaderboard.

Conclusions: We confirm that the image size has an effect on skin lesion classification performance when employing transfer learning of CNNs. We also show that image cropping results in better performance compared to image resizing. Finally, a straightforward ensembling approach that fuses the results from images cropped at six scales and three fine-tuned CNNs is shown to lead to the best classification performance.
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http://dx.doi.org/10.1016/j.cmpb.2020.105475DOI Listing
September 2020

Can reproductive genetic manipulation save lives?

Authors:
G Owen Schaefer

Med Health Care Philos 2020 Sep;23(3):381-386

Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Block MD11, Clinical Research Centre, #02-03, 10 Medical Drive, Singapore, 117597, Singapore.

It has recently been argued that reproductive genetic manipulation technologies like mitochondrial replacement and germline CRISPR modifications cannot be said to save anyone's life because, counterfactually, no one would suffer more or die sooner absent the intervention. The present article argues that, on the contrary, reproductive genetic manipulations may be life-saving (and, from this, have therapeutic value) under an appropriate population health perspective. As such, popular reports of reproductive genetic manipulations potentially saving lives or preventing disease are not necessarily mistaken, though such terminology still requires further empirical validation.
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http://dx.doi.org/10.1007/s11019-020-09947-2DOI Listing
September 2020

Clarifying how to deploy the public interest criterion in consent waivers for health data and tissue research.

BMC Med Ethics 2020 03 20;21(1):23. Epub 2020 Mar 20.

Centre for Biomedical Ethics, National University of Singapore, Yong Loo Lin School of Medicine, Block MD11, Clinical Research Centre, #02-03, 10 Medical Drive, Singapore, 117597, Singapore.

Background: Several jurisdictions, including Singapore, Australia, New Zealand and most recently Ireland, have a public interest or public good criterion for granting waivers of consent in biomedical research using secondary health data or tissue. However, the concept of the public interest is not well defined in this context, which creates difficulties for institutions, institutional review boards (IRBs) and regulators trying to implement the criterion.

Main Text: This paper clarifies how the public interest criterion can be defensibly deployed. We first explain the ethical basis for requiring waivers to only be granted to studies meeting the public interest criterion, then explore how further criteria may be set to determine the extent to which a given study can legitimately claim to be in the public interest. We propose an approach that does not attempt to measure magnitude of benefit directly, but rather takes into account metrics that are more straightforward to apply. To ensure consistent and justifiable interpretation, research institutions and IRBs should also incorporate procedural features such as transparency and public engagement in determining which studies satisfy the public interest requirement.

Conclusion: The requirement of public interest for consent waivers in secondary biomedical research should be guided by well-defined criteria for systematic evaluation. Such a criteria and its application need to be periodically subject to intra-committee and intra-institution review, reflection, deliberation and amendment.
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http://dx.doi.org/10.1186/s12910-020-00467-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083029PMC
March 2020

Context is Needed When Assessing Fair Subject Selection.

Authors:
G Owen Schaefer

Am J Bioeth 2020 02;20(2):20-22

National University of Singapore.

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http://dx.doi.org/10.1080/15265161.2019.1701742DOI Listing
February 2020

Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.

Am J Hum Genet 2020 02 9;106(2):234-245. Epub 2020 Jan 9.

Department of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address:

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010978PMC
February 2020

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability.

J Clin Invest 2020 03;130(3):1431-1445

Rosalind and Morris Goodman Cancer Research Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada.

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.
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http://dx.doi.org/10.1172/JCI131145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269600PMC
March 2020

A Multi-Organ Nucleus Segmentation Challenge.

IEEE Trans Med Imaging 2020 05 23;39(5):1380-1391. Epub 2019 Oct 23.

Generalized nucleus segmentation techniques can contribute greatly to reducing the time to develop and validate visual biomarkers for new digital pathology datasets. We summarize the results of MoNuSeg 2018 Challenge whose objective was to develop generalizable nuclei segmentation techniques in digital pathology. The challenge was an official satellite event of the MICCAI 2018 conference in which 32 teams with more than 80 participants from geographically diverse institutes participated. Contestants were given a training set with 30 images from seven organs with annotations of 21,623 individual nuclei. A test dataset with 14 images taken from seven organs, including two organs that did not appear in the training set was released without annotations. Entries were evaluated based on average aggregated Jaccard index (AJI) on the test set to prioritize accurate instance segmentation as opposed to mere semantic segmentation. More than half the teams that completed the challenge outperformed a previous baseline. Among the trends observed that contributed to increased accuracy were the use of color normalization as well as heavy data augmentation. Additionally, fully convolutional networks inspired by variants of U-Net, FCN, and Mask-RCNN were popularly used, typically based on ResNet or VGG base architectures. Watershed segmentation on predicted semantic segmentation maps was a popular post-processing strategy. Several of the top techniques compared favorably to an individual human annotator and can be used with confidence for nuclear morphometrics.
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http://dx.doi.org/10.1109/TMI.2019.2947628DOI Listing
May 2020

Toward Realism About Genetic Enhancement.

Authors:
G Owen Schaefer

Am J Bioeth 2019 07;19(7):28-30

National University of Singapore.

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http://dx.doi.org/10.1080/15265161.2019.1618964DOI Listing
July 2019

What is the sufficientarian precautionary principle?

Authors:
G Owen Schaefer

Bioethics 2019 11 11;33(9):1083-1084. Epub 2019 Sep 11.

National University of Singapore, Yong Loo Lin School of Medicine - Centre for Biomedical Ethics, Singapore.

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http://dx.doi.org/10.1111/bioe.12666DOI Listing
November 2019

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Authors:
Brett V Johnson Raman Kumar Sabrina Oishi Suzy Alexander Maria Kasherman Michelle Sanchez Vega Atma Ivancevic Alison Gardner Deepti Domingo Mark Corbett Euan Parnell Sehyoun Yoon Tracey Oh Matthew Lines Henrietta Lefroy Usha Kini Margot Van Allen Sabine Grønborg Sandra Mercier Sébastien Küry Stéphane Bézieau Laurent Pasquier Martine Raynaud Alexandra Afenjar Thierry Billette de Villemeur Boris Keren Julie Désir Lionel Van Maldergem Martina Marangoni Nicola Dikow David A Koolen Peter M VanHasselt Marjan Weiss Petra Zwijnenburg Joaquim Sa Claudia Falcao Reis Carlos López-Otín Olaya Santiago-Fernández Alberto Fernández-Jaén Anita Rauch Katharina Steindl Pascal Joset Amy Goldstein Suneeta Madan-Khetarpal Elena Infante Elaine Zackai Carey Mcdougall Vinodh Narayanan Keri Ramsey Saadet Mercimek-Andrews Loren Pena Vandana Shashi Kelly Schoch Jennifer A Sullivan Filippo Pinto E Vairo Pavel N Pichurin Sarah A Ewing Sarah S Barnett Eric W Klee M Scott Perry Mary Kay Koenig Catherine E Keegan Jane L Schuette Stephanie Asher Yezmin Perilla-Young Laurie D Smith Jill A Rosenfeld Elizabeth Bhoj Paige Kaplan Dong Li Renske Oegema Ellen van Binsbergen Bert van der Zwaag Marie Falkenberg Smeland Ioana Cutcutache Matthew Page Martin Armstrong Angela E Lin Marcie A Steeves Nicolette den Hollander Mariëtte J V Hoffer Margot R F Reijnders Serwet Demirdas Daniel C Koboldt Dennis Bartholomew Theresa Mihalic Mosher Scott E Hickey Christine Shieh Pedro A Sanchez-Lara John M Graham Kamer Tezcan G B Schaefer Noelle R Danylchuk Alexander Asamoah Kelly E Jackson Naomi Yachelevich Margaret Au Luis A Pérez-Jurado Tjitske Kleefstra Peter Penzes Stephen A Wood Thomas Burne Tyler Mark Pierson Michael Piper Jozef Gécz Lachlan A Jolly

Biol Psychiatry 2020 01 29;87(2):100-112. Epub 2019 Jun 29.

University of Adelaide and Robinson Research Institute, Adelaide, Australia. Electronic address:

Background: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.

Methods: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.

Results: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.

Conclusions: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.
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http://dx.doi.org/10.1016/j.biopsych.2019.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925349PMC
January 2020