Jalayne J. Arias

Confidentiality in preclinical Alzheimer disease studies When research and medical records meet

Clinical trials to advance the diagnosis and treatment of Alzheimer disease (AD) may expose research subjects to discrimination risks. An individual enrolled in a research study that uses positive test results from amyloid PET imaging or CSF measures of β-amyloid 42 as inclusion criteria has biomarkers indicative of AD pathology. If insurers and employers learn this information, it could expose subjects to discrimination. Unfortunately, current legal and regulatory mechanisms are not sufficient to protect against harms that have significant consequences for subjects. Existing law that prohibits employment and insurance discrimination based on genetic status does not apply to amyloid biomarkers or any other biomarkers for neurodegenerative diseases. Gaps in legal protections fail to protect research subjects from discrimination by long-term care and disability insurers. This risk is particularly concerning because individuals with AD dementia ultimately need long-term care services. To maximize subject protections and advance valuable research, policymakers, investigators, and research institutions must address shortcomings in the design of the electronic medical record, revise laws to limit discrimination, and develop practices that inform research participants of risks associated with loss of confidentiality.

The growth and gaps of genetic data sharing policies in the United States

The 1996 Bermuda Principles launched a new era in data sharing, reflecting a growing belief that the rapid public dissemination of research data was crucial to scientific progress in genetics. A historical review of data sharing policies in the field of genetics and genomics reflects changing scientific norms and evolving views of genomic data, particularly related to human subjects’ protections and privacy concerns. The 2013 NIH Draft Genomic Data Sharing (GDS) Policy incorporates the most significant protections and guidelines to date. The GDS Policy, however, will face difficult challenges ahead as geneticists seek to balance the very real concerns of research participants and the scientific norms that propel research forward. This article provides a novel evaluation of genetic and GDS policies’ treatment of human subjects’ protections. The article examines not only the policies, but also some of the most pertinent scientific, legal, and regulatory developments that occurred alongside data sharing policies. This historical perspective highlights the challenges that future data sharing policies, including the recently disseminated NIH GDS Draft Policy, will encounter.

A Time to Step In: Legal Mechanisms for Protecting Those with Declining Capacity

Current estimates approximate that the population over sixty-five years of age will increase from 40 million in 2010 to 72.1 million by 2030. As society ages, the number of elderly with cognitive deficits that impair decision-making abilities will also increase. This will place additional burdens on families and probate courts seeking to balance individual autonomy with necessary protections. A legal determination of incompetency is a prerequisite to a judicial order appointing a guardianship or other protective mechanism. The current legal-medical model for competency determinations fails to reflect the complexities of declining capacity in an aging population. A global structure for competency determinations leaves a critical gap between competent and incompetent. The gap between competence and incompetence not only raises concerns about how to classify those that fall between the two, but also highlights the lack of legal protections for those within the gap. A revised model is needed to provide protections to individuals who do not yet meet the threshold for incompetence but require additional protections for their personal or financial welfare. This Article provides an unprecedented examination of the legal model for determining competence through a comparison of the medical model for evaluating capacity. While a number of legal scholars have examined the appointment and oversight of guardians, fewer articles have critically examined the process by which individuals are declared incompetent. This Article presents a comprehensive overview of competency and clinical capacity determination procedures, legal mechanisms available to protect individuals with declining capacity, and policy recommendations for improving legal protections in light of inefficiencies related to legal competency determinations.

Trust, vulnerable populations, and genetic data sharing

Recent policies and proposed regulations, including the Notice of Proposed Rulemaking for the Common Rule and the 2014 NIH Genetic Data Sharing Policy, seek to improve research subject protections. Protections for subjects whose genetic data is shared are critical to reduce risks such as loss of confidentiality, stigma, and discrimination. In the article ‘It depends whose data are being shared: considerations for genomic data sharing policies’, Robinson et al. provide a response to our article, ‘The Growth and Gaps of Genetic Data Sharing Policies’. Robinson et al. highlight the importance of individual and group preferences. In this article, we extend the conversation on models for improving protections which will mitigate consequences for individuals and groups that are vulnerable to stigma and discrimination.

The Proactive Patient: Long-Term Care Insurance Discrimination Risks of Alzheimer's Disease Biomarkers

Previously diagnosed by symptoms alone, Alzheimers disease is now also defined by measures of amyloid and tau, referred to as “biomarkers.” Biomarkers are detectible up to twenty years before symptoms present and open the door to predicting the risk of Alzheimers disease. While these biomarkers provide information that can help individuals and families plan for long-term care services and supports, insurers could also use this information to discriminate against those who are more likely to need such services. In this article, we evaluate whether state laws prohibit long-term care insurers from making discriminatory or unfair underwriting and coverage decisions based Alzheimers disease biomarkers status. We report data demonstrating that current state laws do not provide meaningful protections from discrimination by long-term care insurers based on biomarker information.

PHYSICIAN-PERCEIVED RISKS AND BENEFITS OF AMYLOID IMAGING IN A PRECLINICAL POPULATION

cingulate to left supramarginal gyrus (r1⁄4 0.956, p< 2.0 x 10; Fig. 2). This relationship was not impacted by age or grey matter volume. No regions related to attention or executive function reached significance. Conclusions: Prior to dementia onset, we find that increased rs-fMRI strength within the DMN is positively related to memory scores. Compared to controls, previous work has found widespread increases in brain synchrony in those with DS (Anderson et al. 2013), and our own work has found both increased and decreased synchrony within the DMN (Koenig et al. 2015; 2017). Future work will include additional participants and will compare rs-fMRI to biological measures related to dementia. This work was supported by Alzheimer’s Association. The authors acknowledge technical support by Siemens Medical Solutions.

EMPLOYMENT DISCRIMINATION RISKS BASED ON PRECLINICAL ALZHEIMER’S DISEASE BIOMARKERS

Figure 2. Proportion of subjects in each category (normal vs abnormal) at each EBM stage. Proportion of negative scans in dark blue and positive scans in green. Each EBM stage on the x-axis corresponds to the occurrence of a new regional transition event. Stage 0 corresponds to no events having occurred and stage 20 is when all events have occurred. Events are ordered by the maximum likelihood event sequence for the whole population as shown in Figure 1.

UNCERTAINTIES AND ETHICAL CONSIDERATIONS FOR DECISION-MAKING REGARDING AMYLOID-RELATED IMAGING ABNORMALITIES IN CLINICAL TRIALS FOR ALZHEIMER’S DISEASE

Background: Amyloid-related imaging abnormalities (ARIA) are adverse drug events of anti-ß amyloid experimental therapies currently used in clinical trials for Alzheimer’s disease (AD). ARIA is associated with increased risk of severe neurologic complications; as such, its management requires investigators to exercise clinical judgment. Because the natural history of ARIA is incompletely understood, clinical decision-making cannot rely entirely on trial guidelines and a number of clinical and ethical dilemmas may arise. Methods: In this study, we use the case of a patient enrolled in an anti-ß amyloid trial to illustrate the difficulties interpreting incidental ARIA that impact medical management, trial completion and patient counseling. Results: An 87 year-old woman was enrolled in a phase 3 anti-ß amyloid program. Her screening brain MRI showed moderate atrophy and confluent white matter disease. During the course of the double-blind phase, she had persistent hypertension with fluctuating cognition. At the completion of the double-blind phase, she developed worsened dizziness and emergency neuroimaging revealed a new area of cortical superficial siderosis in the left middle frontal gyrus. After discussion of the uncertainties regarding the risks and benefits of the anti-ß amyloid therapy in the setting of hypertension and ARIA, a recommendation was made against enrollment in the open label phase of the trial. The patient opted to continue the trial, pending results of repeat neuroimaging. Conclusions: In the absence of comprehensive management guidelines and with the increased use of experimental anti-ß amyloid therapies, the ethical implications of interpreting incidental ARIA in AD trials are significant. Decision-making should emphasize acknowledgment and communication of the limitations of data availability. Informed consent processes that consider potential contingencies derived from data limitations and conservative management approaches are likely to improve on existing practices. There is a need for strategies to reduce risk in the setting of ARIA, and ultimately, a continuing debate regarding the balance of benefit and futility in AD trials.

Legal consequences and protections: Challenges for documenting preclinical biomarkers in patients' medical records

Background: Identification of lifestyle and dietary modifications which prevent or delay cognitive decline and Alzheimer’s disease (AD) would confer significant social and economic benefit. Yet, there is a relative lack of large-scale longitudinal investigations of lifestyle-related factors impacting cognitive decline and AD-related pathology. The Mediterranean diet (MeDi), has been widely recognised as a healthy eating model due to its correlation with low morbidity and mortality for many chronic diseases. In the context of AD, accumulating research including our own has linked MeDi adherence with slower cognitive decline and reduced risk of AD. However, only one study to date has examined the relationship between MeDi adherence and cerebral amyloid load, with the authors reporting reduced cerebral amyloid load cross-sectionally among individuals with high MeDi adherence. There is a critical need to further explore the relationship between MeDi and brain amyloid levels using longitudinal data collected from a well-characterised ageing cohort. Methods:We report on data collected over 36months from cognitively healthy control participants (n1⁄4119) of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. The Cancer Council of Victoria Food Frequency Questionnaire was used to generate a MeDi score for each participant at baseline. Cerebral amyloid load was quantified byPittsburghCompoundBpositron emission tomography at baseline, 18 and 36 months. The relationship betweenMeDi adherence and cerebral amyloid load was evaluated longitudinally using Analysis of Variance, correlations and Generalised Linear Models (age, gender, education and Apolipoprotein E ε4 carriage were included in the models). Results: Individuals with high MeDi adherence demonstrated less cerebral amyloid accumulation over 36 months compared to those with low adherence (0.04 vs. 0.08 mean change cerebral amyloid load respectively; p1⁄40.008). Conclusions: To our knowledge, this is the first study to assess the relationship between MeDi adherence and cerebral amyloid burden longitudinally. Our results suggest that MeDi adherence is associated with reduced cerebral AD pathology. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it appears that MeDi adherence warrants further investigation in the quest to delay AD onset.

Becoming the standard: how innovative procedures benefitting public health are incorporated into the standard of care.

journal of law, medicine & ethics Physicians’ resistance to implementing innovative medical procedures due to a perceived risk of liability can adversely affect the public’s health. This resistance prevents public access to procedures that could better treat communicable or chronic diseases. Innovative procedures, for the purpose of this article, are medical practices that require physicians to modify current clinical approaches to treating or diagnosing a patient’s condition and incorporate: (1) newly developed tests, treatments, drugs or devices (e.g., genetic screening to identify drug sensitivities to reduce adverse drug reactions1); or (2) novel methods not commonly used by a majority of physicians (e.g., partner delivered therapy to treat an intimate partner for a communicable disease2 or advanced prescription of naloxone to patients prone to an opioid overdose3). Innovative procedures do not include treatments provided during clinical research or those beyond a physician’s scope of practice. A physician’s choice to use any medical procedure is informed, in part, by a perceived risk of liability. Liability risks increase where a procedure is not currently within the standard of care, including most innovative procedures. However, a physician may mitigate liability risks by demonstrating that the procedure benefits the patient, without an increased risk of harm, as compared to the current standard clinical practice. It is less clear whether a physician can similarly mitigate liability risks by demonstrating that the procedure benefits public health, where the patient is neither at a greater risk of harm nor likely to experience significant benefits. Despite the impact of perceived liability, public health is not currently a factor in determining the standard of care underlying physician liability. Therefore, innovative procedures benefiting the public’s health may be underused in clinical practices. This article addresses the legal standard of care underlying medical malpractice liability and its connection to the adoption of innovative procedures to improve public health. First, the article demonstrates that physicians’ liability concerns can impede adoption of innovative procedures into practice, adversely affecting public health. Next, the article reviews the process of determining physician liability through the standard of care and how innovative procedures are incorporated into the standard. The final section addresses public health benefits as a method of mitigating heightened liability risks associated with innovative procedures.