A guide to writing systematic reviews of rare disease treatments to generate FAIR-compliant datasets: Building a Treatabolome

Background: Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families. Aims: This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare diseases' treatments in a manner that allows the capture of the results in a computer-accessible form. The published results need to comply with the FAIR guiding principles for scientific data management and stewardship to facilitate the extraction of datasets that are easily transposable into machine-actionable information. The ultimate purpose is the creation of a database of rare disease treatments ("Treatabolome") at gene and variant levels as part of the H2020 research project Solve-RD. Results: Each systematic review follows a written protocol to address one or more rare diseases in which the authors are experts. The bibliographic search strategy requires detailed documentation to allow its replication. Data capture forms should be built to facilitate the filling of a data capture spreadsheet and to record the application of the inclusion and exclusion criteria to each search result. A PRISMA flowchart is required to provide an overview of the processes of search and selection of papers. A separate table condenses the data collected during the Systematic Review, appraised according to their level of evidence. Conclusions: This paper provides a template that includes the instructions for writing FAIR-compliant systematic reviews of rare diseases' treatments that enables the assembly of a Treatabolome database that complement existing diagnostic and management support tools with treatment awareness data

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Personalized Medicine: the Future of Health Care

BACKGROUND: Most medical treatments have been designed for the “average patients”. As a result of this “one-size-fits-all-approach”, treatments can be very successful for some patients but not for others. The issue is shifting by the new innovation approach in diseases treatment and prevention, precision medicine, which takes into account individual differences in people\u27s genes, environments, and lifestyles. This review was aimed to describe a new approach of healthcare performance strategy based on individual genetic variants.CONTENT: Researchers have discovered hundreds of genes that harbor variations contributing to human illness, identified genetic variability in patients\u27 responses to different of treatments, and from there begun to target the genes as molecular causes of diseases. In addition, scientists are developing and using diagnostic tests based on genetics or other molecular mechanisms to better predict patients\u27 responses to targeted therapy.SUMMARY: Personalized medicine seeks to use advances in knowledge about genetic factors and biological mechanisms of disease coupled with unique considerations of an individual\u27s patient care needs to make health care more safe and effective. As a result of these contributions to improvement in the quality of care, personalized medicine represents a key strategy of healthcare reform

DNA Unicorn: An N-of-1 Community Advocacy Resource

With the wider use of genetic testing, an increasing number of people are receiving molecular diagnoses of ultra-rare or N-of-1 diseases. The medical and psychosocial challenges of these individuals are compounded by a lack of support and advice from disease-specific communities. A website ( www.dnaunicorn.org) was developed to help N-of-1 families connect with caregivers, researchers, and patients with the same or related medical conditions. The site provides directions and links to resources to facilitate data-sharing through access to databases, and aids in the construction of social media campaigns to connect genotypically- or phenotypically-related patients and families to each other. Furthermore, the website provides step-by-step instructions and templates for users to optimize their use of Twitter, Facebook, GenomeConnect, MyGene2 and other potential avenues to find and build a community. Fourteen genetic counselors provided feedback by answering seven questions on the usefulness of an early version of the web-based tool kit. Free text responses were also elicited. Five themes emerged in qualitative analysis of their responses: aesthetics, language, resource choice, how-to guide utility, and overall clinical utility. Aesthetics was mentioned most frequently, with eight genetic counselors commenting on font size and text placement. Responses to the website were overwhelmingly positive; 100% of participants agreed that it would be useful in clinical practice and would refer patients to the website. Counselors also described a need for more resources for families with N-of-1 or ultra-rare molecular diagnoses, which our site attempts to address

Neverland: A Critical Autoethnography of Aging with Cystic Fibrosis

In this autoethnography, I analyze stereotypes and misconceptions about people with cystic fibrosis (CF). I examine these illness representations and their social underpinnings through critical analysis of my journey to conclusive diagnosis with CF after first being tested for the disease in early life, and the events that have followed from that turning point. Using experiential data and prior research, I explore and refute harmful misconceptions about life with CF. I challenge the notion that people with CF never grow old. I also contest the idea that people who receive conclusive diagnoses during adulthood only then transition into patient identities. In doing so, I compare and contrast my own experiences with evidence from other patient narratives. I engage lived experiences from both outside and within the CF community to explore intersectional perceptions of aging. By giving voice to the diverse realities of aging with CF, I illuminate larger gaps in the illness management literature and the health care services it informs. I conclude that narrow representations of illness experience can ultimately impede quality health care and social support for people aging with CF, and that centering diverse patient voices can positively transform both clinical and community experiences

European lipodystrophy registry: Background and structure

Background: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. Results: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, M\ufcnster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. Conclusions: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. Study registration: ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered

How can clinical ethics guide the management of comorbidities in the child with Rett syndrome?

Rett syndrome is a rare disorder caused by a mutation in the MECP2 gene. Those affected generally have severe functional impairments, and medical comorbidities such as scoliosis and poor growth are common. There is a paucity of information on the natural history of many rare disorders and an even greater deficit of evidence to guide best practice. The population-based and longitudinal Australian Rett Syndrome Database established in 1993 has supported investigations of the natural history of Rett syndrome and effectiveness of treatments. This paper reviews the disorder Rett syndrome and evidence for the management of scoliosis and poor growth within a clinical ethics framework. Compared with conservative management, we have shown that spinal fusion is associated with reduced mortality and better respiratory health. We have also shown that gastrostomy insertion is associated with subsequent weight gain. Family counselling for both procedures necessarily must include family perspectives and careful clinical attention to their needs and wishes. Vignettes describing family decision-making and experiences are presented to illustrate the principals of beneficence and autonomy in determining the best interests of the child and family. A blend of evidence-based practice with a strong clinical ethics framework has capacity to build existing strengths in families and reduce the negative impacts of disability and in so doing, optimise the health and wellbeing of those with Rett syndrome

Genetic Evaluation of Cardiomyopathy - a Heart Failure Society of America Practice Guideline

This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), this guidance has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, as high throughput sequencing is now feasible for clinical testing, and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to manage secondary and incidental sequence findings as recommended by the ACMG is provided

Impact of Biobanks on Research Outcomes in Rare Diseases：A Systematic Review

Rare diseases (RDs) are a global priority yet are still under researched. When combined, RDs are common, with individual diseases numbering approximately 5,000-8,000, equating to approximately 7% of the population in Europe. Extrapolating this figure for Australia suggests that about 1.2 million people are affected by RDs, with about 400,000 of those being children. The WA Rare Diseases Strategic Framework 2015-2018, the first strategy for rare diseases in Australia, recognises that in order to alleviate the significant burden of rare diseases, innovative translational tools that facilitate research into new diagnostic and therapeutic strategies should be given priority. Registries facilitate clinical, epidemiological, and post-marketing surveillance research for RD, collecting information from individuals with a particular disease, and storing these data in an organised system. Registries can lead to a greater understanding of the natural history of disease, consensus-driven treatment protocols, informed policy making and, in turn, improved patient outcomes. Despite these benefits, registries are limited in their capacity to conduct basic research, attributed to the fact that most registries do not collect and store patient and donor specimens appropriately to capture or preserve important biological information (such as DNA, RNA and proteins) for basic research, a prerequisite for translating scientific discoveries into diagnostic tools and therapies for clinical practice. Biobanks (BB) are gradually becoming more recognised as invaluable tools to drive basic and translational research for RDs. BBs collect and store biological specimens with matched clinical data and patient metadata in an organised system, distributing samples and data to the scientific community, enabling “omics” studies. This is especially important considering the field of drug innovation for RDs has, in recent years, become progressively focused on ‘omics-type research, and that more than 80% of RDs have a genetic component RDs have recently been referred to as “fundamental diseases”, highlighting their unique capacity in providing opportunities to investigate the “extremes of human pathology”. For example, research of LDL-receptors in familial hypercholesterolemia, a rare disease, led to the discovery of statins, a drug therapy that is now also routinely used to prevent heart disease. This Masters research thesis examined the research outcomes of two specific research strategies: registries linked to BBs and registries without BBs, and found that whilst registries without BBs had the capacity to uncover the natural history of disease, develop best practice, replace clinical trials, and improve patient outcomes, they were limited in their capacity to conduct basic research. Registries, when annexed to BBs, had the key infrastructure required to make novel Omics discoveries, identify and validate biomarkers, uncover novel genes, and develop new therapeutic strategies. The results of this Masters research thesis suggest that the role of basic research in RD research is vital; scientists must first understand the pathways of disease before they can develop appropriate interventions. Linkage of BBs to RD registries will provide the enhanced resources required for the effective translation of basic research into clinical practice