BACKGROUND:Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely ...tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.
METHODS:Utilizing an evidence-based framework, 3 gene curation teams blinded to each other’s work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.
RESULTS:Of 17 genes reported as being causative for LQTS, 9 (AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (KCNQ1, KCNH2, SCN5A) were curated as definitive genes for typical LQTS. Another 4 genes (CALM1, CALM2, CALM3, TRDN) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (CACNA1C) had moderate level evidence for causing LQTS.
CONCLUSIONS:More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
BACKGROUND:Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and ...statistical evidence. However, in the past 20 years, considerable variability has existed in the study design and quality of evidence supporting reported gene-disease associations, raising concerns of the validity of many published disease-causing genes. Brugada syndrome (BrS) is an arrhythmia syndrome with a risk of sudden death. More than 20 genes have been reported to cause BrS and are assessed routinely on genetic testing panels in the absence of a systematic, evidence-based evaluation of the evidence supporting the causality of these genes.
METHODS:We evaluated the clinical validity of genes tested by diagnostic laboratories for BrS by assembling 3 gene curation teams. Using an evidence-based semiquantitative scoring system of genetic and experimental evidence for gene-disease associations, curation teams independently classified genes as demonstrating limited, moderate, strong, or definitive evidence for disease causation in BrS. The classification of curator teams was reviewed by a clinical domain expert panel that could modify the classifications based on their independent review and consensus.
RESULTS:Of 21 genes curated for clinical validity, biocurators classified only 1 gene (SCN5A) as definitive evidence, whereas all other genes were classified as limited evidence. After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS.
CONCLUSIONS:Our results contest the clinical validity of all but 1 gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations before use in patient care.
A novel ketoreductase isolated from Zygosaccharomyces rouxii catalyzes the asymmetric reduction of selected ketone substrates of commercial importance. The 37.8‐kDa ketoreductase was purified more ...than 300‐fold to > 95% homogeneity from whole cells with a 30% activity yield. The ketoreductase functions as a monomer with an apparent Km for 3,4‐methylenedioxyphenyl acetone of 2.9 mm and a Km for NADPH of 23.5 µm. The enzyme is able to effectively reduce α‐ketolactones, α‐ketolactams, and diketones. Inhibition is observed in the presence of diethyl pyrocarbonate, suggesting that a histidine is crucial for catalysis. The 1.0‐kb ketoreductase gene was cloned and sequenced from a Z. rouxii cDNA library using a degenerate primer to the N‐terminal sequence of the purified protein. Furthermore, it was expressed in both Escherichia coli and Pichia pastoris and shown to be active. Substrate specificity, lack of a catalytic metal, and extent of protein sequence identity to known reductases suggests that the enzyme falls into the carbonyl reductase enzyme class.
Last fall, the Editors of the journal Congestive Heart Failure, Drs. Marc Silver and John Strobeck, asked me to serve as Guest Editor for an issue of the journal. Accepting this honor was linked to ...the requirement that I had to generate a meaningful theme. The thought of delivering another series of articles on CHF trials and their interpretation, bench‐to‐bedside (and vice‐versa) topics in heart failure, and similar efforts did little to excite me and, in fact, it threatened to exacerbate my narcoleptic condition. Besides, we have many colleagues more skilled at delivering this information and they truly enjoy doing so.
We have fortunately entered the era of “evidence‐based medicine” this theme will likely remain with us for the entire lifetime of health care delivery. While most physicians have now joined this movement, it is remarkable how much of the day‐to‐day medical care of the patient with heart failure has not yet been addressed by statistically powered (i.e., evidence‐based) trials. Much (probably most) of what we do to keep patients as healthy and functional as possible is still based on our experience as clinicians and on the information shared by colleagues (personal contact, consultation, conferences, written material). It is not often that data from a large treatment trial assist me in determining the optimal dose of a drug or doses of combinations in an individual patient, in optimizing the immediate care and management of a complexly ill patient, in addressing the emergency phone call at 2 a.m., and so forth.
Until statistically powered trials can address all aspects and details of patient care, “experience‐based medicine” must fill the knowledge void. Unfortunately, much of this information is not available in textbooks, review articles, the Internet and other media. As the passionate fervor of evidence‐based medicine soars to its fever pitch, there will be even less incentive to share in print potentially helpful information based on clinical experience. In his submission to this issue, Thomas D. Giles, MD, wrote, “I am fearful that valuable contributions to patient care will be lost and sacrificed on the altar of ‘evidenced‐based’ medicine (usually referring to data from clinical trials). While I certainly believe that important concepts emanate from clinical trials, I also believe that there are other sources of guidance for the care of patients. The Reverend Bayes reminded us that intuition and prior experience are an integral part of the analysis of data.” Parenthetically, most of the questions addressed by trials and the design of trials are largely based on information gleaned from clinical experience.
It is in this spirit that the Editors, Drs. Silver and Strobeck, CHF, Inc., and I present to you the first installment in a four‐part series. The fuel for this project has both a historical and a pragmatic thrust; “it would be a shame” if we allowed our venerable colleagues to advance into the autumn of their careers or even retire without learning about their insights, thoughts, and passions regarding patient care, which grew out of decades of focused, intense clinical experience. Instead of less, we need to hear more from Drs. Chatterjee, Cohn, Armstrong, and colleagues.
This series is not intended to serve as a comprehensive treatise on the management of heart failure. In fact, the authors assume that the reader is reasonably well versed in this area of study and practice. The content of each author's submission was not substantially altered by the editors and staff. Any disagreements that we and fellow coauthors may have regarding any submission were set aside so as to allow a free and open rendering of views and opinions. We are asking you, the reader, to judge and decide for yourself which of the “nuggets and pearls” are palatable and useful in your practice and in the day‐to‐day care of your patients afflicted with heart failure.
To give you a better sense of the format and content of this series, I am sharing with you the directive I sent to each author in the letter of invitation:
I would like you to contribute a piece on helpful tips, suggestions, maneuvers, and approaches that have been helpful to you (and your patients) over the years in the evaluation, management, and therapy of CHF. Everything is fair game. Much of the material will not have been previously published and is certainly not yet evidence‐based. Basically, much of what we do in our day‐to‐day management of CHF patients is still related to simple clinical experience, doing what works, and our own ‘tricks of the trade.’ It is my intent to get these ideas, experiences, and thoughts into print. The publication should serve as a rich source of clinical insight, experience, and information, and perhaps will serve as a springboard for further studies and evidence‐generating trials. With the exception of the deadline, there are absolutely no rules (referring to the usual editorial instructions for authors) for your submission!
With the hundreds of heart failure experts located across this country and Canada, the selection of authors was a serious challenge. The selection targeted physician‐scientists with at least two decades of heart failure experience, a significant publication record of peer‐reviewed investigation in heart failure, and known, masterful clinical expertise in human heart failure at the bedside. Under the directive of the Guest Editor and taking advantage of my own lack of discretion, I added my name to the list of authors. A few of those invited could not contribute to the manuscript, thus accounting for the absence of certain authors. The Editors and I deeply apologize to those who were not invited to contribute because of our inadvertent oversight. If this venture is successful and well received, you are likely to be part of similar endeavors planned over the coming years.
The coauthors and I dedicate this collection of insights and views to our teachers, who have collectively consisted of our patients, students, colleagues, and mentors. I thank Dr. Silver and Dr. Strobeck for this honor, and I thank my esteemed coauthors and colleagues for making this an educational and enjoyable experience for me.
Purposeful behavior - the control theory approach Marken, Richard S; Runkel, Philip J; Powers, William T ...
The American behavioral scientist (Beverly Hills),
09/1990, Letnik:
34, Številka:
1
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