Human Genetics Society of Australasia Position Statement: Use of Polygenic Scores in Clinical Practice and Population Health.

Considerable progress continues to be made with regards to the value and use of disease associated polygenic scores (PGS). PGS aim to capture a person's genetic liability to a condition, disease, or a trait, combining information across many risk variants and incorporating their effect sizes. They are already available for clinicians and consumers to order in Australasia. However, debate is ongoing over the readiness of this information for integration into clinical practice and population health. This position statement provides the viewpoint of the Human Genetics Society of Australasia (HGSA) regarding the clinical application of disease-associated PGS in both individual patients and population health. The statement details how PGS are calculated, highlights their breadth of possible application, and examines their current challenges and limitations. We consider fundamental lessons from Mendelian genetics and their continuing relevance to PGS, while also acknowledging the distinct elements of PGS. Use of PGS in practice should be evidence based, and the evidence for the associated benefit, while rapidly emerging, remains limited. Given that clinicians and consumers can already order PGS, their current limitations and key issues warrant consideration. PGS can be developed for most complex conditions and traits and can be used across multiple clinical settings and for population health. The HGSA's view is that further evaluation, including regulatory, implementation and health system evaluation are required before PGS can be routinely implemented in the Australasian healthcare system.

Use of coronary computed tomography or polygenic risk scores to prompt action to reduce coronary artery disease risk: the CAPAR-CAD trial.

BACKGROUND: The traditional primary prevention paradigm for coronary artery disease (CAD) centers on population-based algorithms to classify individual risk. However, this approach often misclassifies individuals and leaves many in the 'intermediate' category, for whom there is no clear preferred prevention strategy. Coronary artery calcium (CAC) and polygenic risk scoring (PRS) are 2 contemporary tools for risk prediction to enhance the impact of effective management. AIMS: To determine how these CAC and PRS impact adherence to pharmacotherapy and lifestyle measures in asymptomatic individuals with subclinical atherosclerosis. METHODS: The CAPAR-CAD study is a multicenter, open, randomized controlled trial in Victoria, Australia. Participants are self-selected individuals aged 40 to 70 years with no prior history of cardiovascular disease (CVD), intermediate 10-year risk for CAD as determined by the pooled cohort equation (PCE), and CAC scores >0. All participants will have a health assessment, a full CT coronary angiogram (CTCA), and PRS calculation. They will then be randomized to receive their risk presented either as PCE and CAC, or PCE and PRS. The intervention includes e-Health coaching focused on risk factor management, health education and pharmacotherapy, and follow-up to augment adherence to a statin medication. The primary endpoint is a change in low-density lipoprotein cholesterol (LDL-C) from baseline to 12 months. The secondary endpoint is between-group differences in behavior modification and adherence to statin pharmacotherapy. RESULTS: As of July 31, 2021, we have screened 1,903 individuals. We present the results of the 574 participants deemed eligible after baseline assessment.

Real world outcomes and implementation pathways of exome sequencing in an adult genetic department.

PURPOSE: This study aimed to correlate the indications and diagnostic yield of exome sequencing (ES) in adult patients across various clinical settings. The secondary aim was to examine the clinical utility of ES in adult patients. METHODS: Data on demographics, clinical indications, results, management changes, and cascade testing were collected for 250 consecutive patients who underwent ES through an adult genetics department between 2016 and 2021. Data were analyzed using descriptive and inferential statistics. Testing in which traditional gene panels were in standard use, such as in heritable cancers, was excluded. RESULTS: The average age at testing was 43 years (range = 17-80 years). A molecular diagnosis was identified in 29% of patients. Older age at symptom onset did not pre-exclude a substantial diagnostic yield. Patients with syndromic intellectual disability and multiple system disorders had the highest yield. In >50% of patients with an exome diagnosis, the results changed management. Cascade testing occured in at least one family member for 30% of patients with a diagnosis. Diagnostic results had reproductive implications for 26% of patients and 31% of patients' relatives. CONCLUSION: ES has a robust diagnostic yield and clear clinical utility in adult patients across a range of ages and phenotypes.

A homozygous truncating variant in GDF9 in siblings with primary ovarian insufficiency.

Premature or primary ovarian insufficiency (POI) affects approximately 1% of women and can be due to a variety of causes. Genetic causes include syndromic and non-syndromic POI. There are several promising candidate genes for whom a clear Mendelian association with non-syndromic POI has not yet been conclusively established, including GDF9. GDF9 is an oocyte-secreted factor and is part of the TGF-beta superfamily of morphogens. It has an important role in follicular development and granulosa cell maturation. We report the case of two siblings with primary ovarian insufficiency (POI) and a homozygous truncating variant in GDF9 (c.604C>T; p.(Gln202*). This report helps establish a clear gene-disease association between GDF9 and POI and argues for routine evaluation for GDF9 variants in patients undergoing genomic investigation for POI.

An unusual source of electromagnetic interference.

A 62-year-old male presented to his treating cardiologist for routine interrogation of his implantable cardiac defibrillator on the background of severe ischemic cardiomyopathy and end-stage kidney disease on hemodialysis. The device log revealed multiple paroxysms of atrial fibrillation; however, upon scrutinizing these episodes it was evident that they always corresponded to episodes of hemodialysis while dialyzing through a chronic dialysis catheter, but not while dialyzing via an arteriovenous fistula. We report the novel finding of inappropriate sensing of current leak from the catheter by a lead with a floating atrial dipole.

Aborted sudden cardiac death in a patient with implantable loop recorder.

We discuss a 46-year-old man with history of hypertension and inferior wall myocardial infarction and mild left ventricular dysfunction who presented with aborted sudden cardiac death due to episodes of ventricular tachyarrhythmia detected by a Reveal-LINQ which had been implanted one year prior to presentation.

POLR3A-related disorders: From spastic ataxia to generalised dystonia and long-term efficacy of deep brain stimulation.

While biallelic POLR3A loss-of-function variants are traditionally linked to hypomyelinating leukodystrophy, patients with a specific splice variant c.1909+22G>A manifest as adolescent-onset spastic ataxia without overt leukodystrophy. In this study, we reported eight new cases, POLR3A-related disorder with c.1909+22 variant. One of these patients showed expanded phenotypic spectrum of generalised dystonia and her sister remained asymptomatic except for hypodontia. Two patients with dystonic arm tremor responded to deep brain stimulation. In our systemic literature review, we found that POLR3A-related disorder with c.1909+22 variant has attenuated disease severity but frequency of dystonia and upper limb tremor did not differ among genotypes.

How appropriately is blood ordered in a rural hospital?

BACKGROUND: Blood products are a limited resource particularly in a rural setting and their appropriate use is important to maintain patient safety and minimise costs. OBJECTIVE: To assess the appropriateness of transfusion practices in a rural hospital. DESIGN/DATA SOURCES: A retrospective medical record audit of packed red blood cell (PRBC) use. SETTING: A rural hospital 300 km northwest of Melbourne. PARTICIPANTS: All patients in Wimmera Base Hospital who had a PRBC crossmatch request from October 2010 to March 2011 inclusive. MAIN OUTCOME MEASURES: Proportion of appropriate transfusions and crossmatch to transfusion ratios. RESULTS: A total of 257 patients and 657 PRBC units were cross-matched during the study period. Of these patients, 28.4% had pre-procedure (elective) cross-matches. Of the elective cross-matches, 27.4% were inappropriate, compared with 16.1% of emergency cross-matches. The cross-match to transfusion ratio (C:T) was 1.59 for emergency requests and 5.96 for elective requests. The C:T ratio was high in the surgical and obstetrics and gynaecology departments. 16.3% of all transfusions were single-unit transfusions. CONCLUSIONS: Emergency requests were predominantly appropriate but a significant proportion of elective requests were inappropriate, suggesting changes in elective crossmatch request protocols, and increased education regarding ordering blood in a rural setting.

New Cardiovascular Risk Assessment Techniques for Primary Prevention: JACC Review Topic of the Week.

Risk factor-based models fail to accurately estimate risk in select populations, in particular younger individuals. A sizable number of people are also classified as being at intermediate risk, for whom the optimal preventive strategy could be more precise. Several personalized risk prediction tools, including coronary artery calcium scoring, polygenic risk scores, and metabolic risk scores may be able to improve risk assessment, pending supportive outcome data from clinical trials. Other tools may well emerge in the near future. A multidimensional approach to risk prediction holds the promise of precise risk prediction. This could allow for targeted prevention minimizing unnecessary costs and risks while maximizing benefits. High-risk individuals could also be identified early in life, creating opportunities to arrest the development of nascent coronary atherosclerosis and prevent future clinical events.

Atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is increasingly common among Australia's ageing population and carries significant morbidity and mortality. Its detection through screening, cardiac device interrogation and/or symptoms of AF brings with it a number of significant clinical issues. OBJECTIVE: The aim of this article is to outline a systematic approach to the management of patients with AF, including the initial investigations required, rhythm versus rate control, anticoagulation for stroke prevention, and the interplay between AF and heart failure. DISCUSSION: Most patients with AF can be managed safely and effectively in the primary care setting. Rhythm control is pursued early in certain patients with AF who are at risk of decompensated heart failure. Specialist cardiology input is important in the treatment of AF coinciding with clinical heart failure, and for patients with medically refractory symptoms or slow/rapid heart rates.

Awareness of Familial Hypercholesterolemia Among Healthcare Providers Involved in the Management of Acute Coronary Syndrome in Victoria, Australia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common underdiagnosed autosomal dominant lipid disorder carrying a significant risk of premature coronary artery disease. The aim of this study was to evaluate the awareness and knowledge of heterozygous FH of healthcare providers in coronary care units (CCUs). METHODS: Medical staff working in CCUs in 4 sizable metropolitan health networks in Melbourne, Australia, were requested to complete a structured anonymised questionnaire with regard to FH. The results were tabulated and analysed with the Statistical Package for the Social Sciences version 23 (IBM, New York, NY). RESULTS: A total of 121 participants (67% response rate) completed the survey. Some 76% claimed to be at least modestly familiar with FH, and more than half of them adequately described FH; however, only 16% and 43%, respectively, were aware of the prevalence of FH and existence of lipid guidelines. In regard to epidemiological knowledge and update in the management of FH in CCUs, knowledge was suboptimal. In regard to FH care, General Practitioners were rated by 72% of participants as the first most efficient healthcare provider in the management of FH, and cardiologists were rated by 54% of participants as the second most efficient healthcare provider in the management of FH. Some 36% of respondents advocated a form of alert system in laboratory reports to facilitate the diagnosis of FH. CONCLUSIONS: This survey identified substantial gaps in the knowledge and awareness of FH among healthcare providers involved in the management of acute coronary syndrome. Focused education and clinical training are warranted to raise awareness of FH among healthcare providers working in CCUs.

CONTEXTE: L'hypercholestérolémie familiale (HF) est un trouble lipidique autosomique dominant courant et sous-diagnostiqué, associé à un risque important de coronaropathie prématurée. Le but de cette étude consistait à évaluer la sensibilisation et les connaissances à l'égard de l'HF hétérozygote parmi les professionnels de la santé œuvrant en unité de soins coronariens (USC). MÉTHODOLOGIE: Les membres du personnel médical des USC de quatre réseaux de santé métropolitains relativement importants de Melbourne, en Australie, ont été invités à remplir un questionnaire anonyme structuré sur l'HF. Les résultats ont été mis sous forme de tableaux et analysés à l'aide de la trousse logicielle SPSS (Statistical Package for the Social Sciences, IBM, New York, NY), version 23. RÉSULTATS: Au total, 121 personnes (taux de réponse de 67 %) ont participé à l'enquête. Environ 76 % des répondants ont indiqué posséder à tout le moins quelques connaissances sur l'HF, tandis que plus de la moitié d'entre eux en ont donné une définition adéquate; en revanche, seuls 16 et 43 %, respectivement, connaissaient la prévalence de l'HF et l'existence de lignes directrices sur les lipides. Par rapport aux connaissances épidémiologiques et à l'actualisation des stratégies de prise en charge de l'HF en USC, les connaissances étaient sous-optimales. Soixante-douze pour cent des répondants ont jugé que le médecin généraliste était le professionnel de la santé le plus à même de soigner et de prendre en charge l'HF; le cardiologue a été mentionné en seconde position par 54 % des répondants. Quelque 36 % des répondants ont préconisé la mise en place d'un système d'alerte, dans les rapports de laboratoire, pour faciliter le diagnostic d'HF. CONCLUSIONS: Cette enquête a mis en évidence des lacunes considérables dans la sensibilisation et les connaissances à l'égard de l'HF parmi les professionnels de la santé intervenant dans la prise en charge du syndrome coronarien aigu. Un enseignement et une formation clinique ciblés s'imposent pour accroître la sensibilisation à l'égard de l'HF parmi les professionnels de la santé qui travaillent en USC.

Intravascular ultrasound guidance improves clinical outcomes during implantation of both first- and second-generation drug-eluting stents: a meta-analysis.

AIMS: Our aim was to assess whether intravascular ultrasound (IVUS) improves clinical outcomes during implantation of first- and second-generation drug-eluting stents (DES). IVUS guidance is associated with improved clinical outcomes during DES implantation, but it is unknown whether this benefit is limited to either first- or second-generation devices. METHODS AND RESULTS: MEDLINE, EMBASE and PubMed were searched for studies comparing outcomes between IVUS- and angiography-guided PCI. Among 909 potentially relevant studies, 15 trials met the inclusion criteria. The primary endpoint was MACE, defined as death, myocardial infarction, target vessel/lesion revascularisation (TVR/TLR) or stent thrombosis (ST). Summary estimates were obtained using Peto modelling. In total, 9,313 patients from six randomised trials and nine observational studies were included. First-generation DES were implanted in 6,156 patients (3,064 IVUS-guided and 3,092 angiography-guided) and second-generation in 3,157 patients (1,528 IVUS-guided and 1,629 angiography-guided). IVUS guidance was associated with a significant reduction in MACE (odds ratio [OR] 0.73, 95% CI: 0.64-0.85, p<0.001), across both first- (OR 0.79, 95% CI: 0.67-0.92, p=0.01) and second-generation DES (0.57, 95% CI: 0.43-0.77, p<0.001). For second-generation DES, IVUS guidance was associated with significantly lower rates of cardiac death (OR 0.33, 95% CI: 0.14-0.78, p=0.02), TVR (OR 0.47, 95% CI: 0.28-0.79, p=0.006), TLR (OR 0.61, 95% CI: 0.42-0.90, p=0.01) and ST (OR 0.31, 95% CI: 0.12-0.78, p=0.02). Cumulative meta-analysis highlighted progressive temporal benefit towards IVUS-guided PCI to reduce MACE (OR 0.60, 95% CI: 0.48-0.75, p<0.001). CONCLUSIONS: IVUS guidance is associated with a significant reduction in MACE during implantation of both first- and second-generation DES platforms. These data support the use of IVUS guidance in contemporary revascularisation procedures using second-generation DES.

Percutaneous Coronary Intervention Using Drug-Eluting Stents Versus Coronary Artery Bypass Grafting for Unprotected Left Main Coronary Artery Stenosis: A Meta-Analysis of Randomized Trials.

BACKGROUND: Current guidelines suggest that coronary artery bypass grafting (CABG) should be the preferred revascularization method for unprotected left main coronary artery stenosis. In light of evidence from recent randomized trials, we assessed whether percutaneous coronary intervention (PCI) using drug-eluting stents is as safe and effective as CABG for the treatment of unprotected left main coronary artery disease. METHODS AND RESULTS: Digital databases and manual searches were performed for randomized trials comparing PCI and CABG for unprotected left main coronary artery stenosis. Among 3887 potentially relevant studies, 5 met inclusion criteria. The primary safety end point was defined as the composite of all-cause death, myocardial infarction, or stroke. Secondary end points included a clinical effectiveness composite, which was defined as all-cause death, myocardial infarction, stroke, or repeat revascularization. Summary estimates were obtained using random-effects modeling. In total, 4594 patients were included in the analysis. There was no significant difference in the primary safety end point between the revascularization strategies (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.79-1.17; P=0.73). However, when compared with CABG, PCI was less effective (OR, 1.36; 95% CI, 1.18-1.58; P<0.001) because of significantly higher rates of repeat revascularization (OR, 1.85; 95% CI, 1.53-2.23; P<0.001). The incidence of all-cause death (OR, 1.03; 95% CI, 0.78-1.35; P=0.61), myocardial infarction (OR, 1.46; 95% CI, 0.88-2.45; P=0.08), and stroke (OR, 0.88; 95% CI, 0.39-1.97; P=0.53) did not differ between PCI and CABG. CONCLUSIONS: PCI using drug-eluting stents and CABG are equally safe methods of revascularization for patients at low surgical risk with significant unprotected left main coronary artery stenosis. However, CABG is associated with significantly lower rates of repeat revascularization.