Development of a storytelling communication facilitation tool (SCFT) to facilitate discussion of complex genetic diagnoses between parents and their children: A pilot study using 22q11.2 deletion syndrome as a model condition.

Objective: To develop and evaluate a storytelling communication facilitation tool designed to help parents overcome barriers to discussing a complex multisystem genetic diagnosis with their affected children, using 22q11.2 deletion syndrome (22q11DS) as an exemplar condition. Methods: A story telling communication facilitation tool (SCFT), entitled 22q and Me, was developed for a target audience of children with 22q11DS aged 9 to 12. The SCFT was evaluated by 14 parents to assess usability and utility by comparing responses to survey questions before and after viewing the SCFT, using a Likert scale. Results: After viewing 22q and Me, parents reported that barriers to discussion were mitigated. Participants indicated they felt more comfortable and better prepared to talk to their children about 22q11DS and worried less that the diagnosis would affect their children's self-esteem. Parents described 22q and Me as engaging and able to address parental concerns. Conclusion: 22q and Me was found to be an effective tool for increasing parental comfort and ability to talk to their children about their diagnosis of 22q11DS. Innovation: This novel storytelling communication facilitation tool can serve as a model for the development of other educational tools geared at facilitating disclosure and discussion of other genetic conditions.

Using Facial Micro-Expressions in Combination With EEG and Physiological Signals for Emotion Recognition.

Emotions are multimodal processes that play a crucial role in our everyday lives. Recognizing emotions is becoming more critical in a wide range of application domains such as healthcare, education, human-computer interaction, Virtual Reality, intelligent agents, entertainment, and more. Facial macro-expressions or intense facial expressions are the most common modalities in recognizing emotional states. However, since facial expressions can be voluntarily controlled, they may not accurately represent emotional states. Earlier studies have shown that facial micro-expressions are more reliable than facial macro-expressions for revealing emotions. They are subtle, involuntary movements responding to external stimuli that cannot be controlled. This paper proposes using facial micro-expressions combined with brain and physiological signals to more reliably detect underlying emotions. We describe our models for measuring arousal and valence levels from a combination of facial micro-expressions, Electroencephalography (EEG) signals, galvanic skin responses (GSR), and Photoplethysmography (PPG) signals. We then evaluate our model using the DEAP dataset and our own dataset based on a subject-independent approach. Lastly, we discuss our results, the limitations of our work, and how these limitations could be overcome. We also discuss future directions for using facial micro-expressions and physiological signals in emotion recognition.

Lentivirus-mediated gene therapy for Fabry disease.

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy.

Independent Registries Are Cost-Effective Tools to Provide Mandatory Postauthorization Surveillance for Orphan Medicinal Products.

OBJECTIVES: Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may not be of sufficient quality to answer these questions and may not always be accessible for regulatory review. We propose that a mandatory independent registry is an efficient and cost-effective tool for PAS for OMPs. METHODS: Using data from the Canadian Fabry Disease Initiative, we reviewed costs per unique patient from sites participating in both the independent national registry and IFRs for Fabry disease and compared data completeness from the Canadian Fabry Disease Initiative to that in published documents from IFRs. RESULTS: The costs of data collection through the independent registry were 17% to 36% (depending on site) lower than costs to collect data in the IFRs, and completeness of data collected through the independent registry was higher than that through the IFRs. Data from the independent registry were reviewed annually to guide indications for publicly funded Fabry disease therapy. Even when enrollment ceased to be a requirement to receive therapy, 77% of patients continued to enroll in the registry, suggesting the structure was acceptable to patients. CONCLUSIONS: Independent registries are cost-effective and efficient tools and should be mandated by regulatory agencies as the preferred tool for PAS for OMPs. Countries with publicly funded health systems should consider investment in registry infrastructure for OMPs.

Clinical Significance of Papillary Muscles on Left Ventricular Mass Quantification Using Cardiac Magnetic Resonance Imaging: Reproducibility and Prognostic Value in Fabry Disease.

PURPOSE: Accurate and reproducible assessment of left ventricular mass (LVM) is important in Fabry disease. However, it is unclear whether papillary muscles should be included in LVM assessed by cardiac magnetic resonance imaging (MRI). The purpose of this study was to evaluate the reproducibility and predictive value of LVM in patients with Fabry disease using different analysis approaches. MATERIALS AND METHODS: A total of 92 patients (44±15 y, 61 women) with confirmed Fabry disease who had undergone cardiac MRI at a single tertiary referral hospital were included in this retrospective study. LVM was assessed at end-diastole using 2 analysis approaches, including and excluding papillary muscles. Adverse cardiac events were assessed as a composite end point, defined as ventricular tachycardia, bradycardia requiring device implantation, severe heart failure, and cardiac death. Statistical analysis included Cox proportional hazard models, Akaike information criterion, intraclass correlation coefficients, and Bland-Altman analysis. RESULTS: Left ventricular end-diastolic volume, end-systolic volume, ejection fraction, and LVM all differed significantly between analysis approaches. LVM was significantly higher when papillary muscles were included versus excluded (157±71 vs. 141±62 g, P<0.001). Mean papillary mass was 16±11 g, accounting for 10%±3% of total LVM. LVM with pap illary muscles excluded had slightly better predictive value for the composite end point compared with LVM with papillary muscles included based on the model goodness-of-fit (Akaike information criterion 140 vs. 142). Interobserver agreement was slightly better for LVM with papillary muscles excluded compared with included (intraclass correlation coefficient 0.993 [95% confidence interval: 0.985, 0.996] vs. 0.989 [95% confidence interval: 0.975, 0.995]) with less bias and narrower limits of agreement. CONCLUSIONS: Inclusion or exclusion of papillary muscles has a significant effect on LVM quantified by cardiac MRI, and therefore, a standardized analysis approach should be used for follow-up. Exclusion of papillary muscles from LVM is a reasonable approach in patients with Fabry disease given slightly better predictive value and reproducibility.

Left Ventricular Hypertrophy and Late Gadolinium Enhancement at Cardiac MRI Are Associated with Adverse Cardiac Events in Fabry Disease.

Background Cardiac involvement is the leading cause of mortality in patients with Fabry disease. Identification of imaging findings that predict adverse cardiac events is needed to enable identification of high-risk patients. Purpose To establish the prognostic value of cardiac MRI findings in men and women with Fabry disease. Materials and Methods Consecutive women and men with gene-positive Fabry disease who had undergone cardiac MRI at a single large tertiary referral hospital between March 2008 and January 2019 were included in this retrospective cohort study. Evaluators of cardiac MRI studies were blinded to all clinical information. Adverse cardiac events were assessed as a composite end point, defined as ventricular tachycardia, bradycardia requiring device implantation, severe heart failure, and cardiac death. Statistical analysis included Cox proportional hazard models adjusted for age and Mainz Severity Score Index (a measure of the severity of Fabry disease). Results Ninety patients (mean age, 44 years ± 15 [standard deviation]; 59 women) were evaluated. After a median follow-up period of 3.6 years, the composite end point was reached in 21 patients (incidence rate, 7.6% per year). Left ventricular hypertrophy (LVH) and late gadolinium enhancement (LGE) were independent predictors of the composite end point in adjusted analysis (LVH hazard ratio [HR], 3.0; 95% confidence interval [CI]: 1.1, 8.1; P = .03; and LGE HR, 7.2; 95% CI: 1.5, 34; P = .01). Patients with extensive LGE (≥15% of left ventricular mass) were at highest risk (HR, 12; 95% CI: 2.0, 67; P = .006). Sex did not modify the relationship between the composite end point and any of the cardiac MRI parameters, including LVH (P = .15 for interaction term) and LGE (P = .38 for interaction term). Conclusion Cardiac MRI findings of left ventricular hypertrophy and late gadolinium enhancement can be used to identify patients with Fabry disease who are at high risk of adverse cardiac events. © RSNA, 2019 See also the editorial by Zimmerman in this issue.

Loss of base-to-apex circumferential strain gradient assessed by cardiovascular magnetic resonance in Fabry disease: relationship to T1 mapping, late gadolinium enhancement and hypertrophy.

BACKGROUND: Cardiac involvement is common and is the leading cause of mortality in Fabry disease (FD). We explored the association between cardiovascular magnetic resonance (CMR) myocardial strain, T1 mapping, late gadolinium enhancement (LGE) and left ventricular hypertrophy (LVH) in patients with FD. METHODS: In this prospective study, 38 FD patients (45.0 ± 14.5 years, 37% male) and 8 healthy controls (40.1 ± 13.7 years, 63% male) underwent 3 T CMR including cine balanced steady-state free precession (bSSFP), LGE and modified Look-Locker Inversion recovery (MOLLI) T1 mapping. Global longitudinal (GLS) and circumferential (GCS) strain and base-to-apex longitudinal strain (LS) and circumferential strain (CS) gradients were derived from cine bSSFP images using feature tracking analysis. RESULTS: Among FD patients, 8 had LVH (FD LVH+, 21%) and 17 had LGE (FD LGE+, 45%). Nineteen FD patients (50%) had neither LVH nor LGE (FD LVH- LGE-). None of the healthy controls had LVH or LGE. FD patients and healthy controls did not differ significantly with respect to GLS (- 15.3 ± 3.5% vs. - 16.3 ± 1.5%, p = 0.45), GCS (- 19.4 ± 3.0% vs. -19.5 ± 2.9%, p = 0.84) or base-to-apex LS gradient (7.5 ± 3.8% vs. 9.3 ± 3.5%, p = 0.24). FD patients had significantly lower base-to-apex CS gradient (2.1 ± 3.7% vs. 6.5 ± 2.2%, p = 0.002) and native T1 (1170.2 ± 37.5 ms vs. 1239.0 ± 18.0 ms, p < 0.001). Base-to-apex CS gradient differentiated FD LVH- LGE- patients from healthy controls (OR 0.42, 95% CI: 0.20 to 0.86, p = 0.019), even after controlling for native T1 (OR 0.24, 95% CI: 0.06 to 0.99, p = 0.049). In a nested logistic regression model with native T1, model fit was significantly improved by the addition of base-to-apex CS gradient (χ2(df = 1) = 11.04, p < 0.001). Intra- and inter-observer agreement were moderate to good for myocardial strain parameters: GLS (ICC 0.849 and 0.774, respectively), GCS (ICC 0.831 and 0.833, respectively), and base-to-apex CS gradient (ICC 0.737 and 0.613, respectively). CONCLUSIONS: CMR reproducibly identifies myocardial strain abnormalities in FD. Loss of base-to-apex CS gradient may be an early marker of cardiac involvement in FD, with independent and incremental value beyond native T1.

Copy number variant syndromes are frequent in schizophrenia: Progressing towards a CNV-schizophrenia model.

The genetic underpinnings of schizophrenia (SCZ) remain unclear. SCZ genetic studies thus far have only identified numerous single nucleotide polymorphisms with small effect sizes and a handful of copy number variants (CNVs). This study investigates the prevalence of well-characterized CNV syndromes and candidate CNVs within a cohort of 348 SCZ patients, and explores correlations to their phenotypic findings. There was an enrichment of syndromic CNVs in the cohort, as well as brain-related and immune pathway genes within the detected CNVs. SCZ patients with brain-related CNVs had increased CNV burden, neurodevelopmental features, and types of hallucinations. Based on these results, we propose a CNV-SCZ model wherein specific phenotypic profiles should be prioritized for CNV screening within the SCZ patient population.

Perplexed by PGx? Exploring the impact of pharmacogenomic results on medical management, disclosures and patient behavior.

Pharmacogenomic (PGx) tests represent significant advances in precision medicine. Our aim was to explore perceptions following the return of PGx results, medication management, and disclosure to providers. We surveyed clients who had PGx testing and conducted a chart review of PGx results. Respectively, 84% and 94% of participants found pre- and post-test genetic counseling helpful. There was a significant difference in disclosure, while 6% disclosed results to a pharmacist, 50% disclosed to a physician. Qualitative analysis identified three themes: 1) psychological response; 2) perceived utility; 3) experiences with disclosure. Our study supports the provision of genetic counseling for a non-disease related genetic test. Benefits of PGx testing can be optimized by the collaboration of physicians, pharmacists, genetic counselors and patients.

Use of Myocardial T1 Mapping at 3.0 T to Differentiate Anderson-Fabry Disease from Hypertrophic Cardiomyopathy.

Purpose To compare left ventricular (LV) and right ventricular (RV) 3.0-T cardiac magnetic resonance (MR) imaging T1 values in Anderson-Fabry disease (AFD) and hypertrophic cardiomyopathy (HCM) and evaluate the diagnostic value of native T1 values beyond age, sex, and conventional imaging features. Materials and Methods For this prospective study, 30 patients with gene-positive AFD (37% male; mean age ± standard deviation, 45.0 years ± 14.1) and 30 patients with HCM (57% male; mean age, 49.3 years ± 13.5) were prospectively recruited between June 2016 and September 2017 to undergo cardiac MR imaging T1 mapping with a modified Look-Locker inversion recovery (MOLLI) acquisition scheme at 3.0 T (repetition time msec/echo time msec, 280/1.12; section thickness, 8 mm). LV and RV T1 values were evaluated. Statistical analysis included independent samples t test, receiver operating characteristic curve analysis, multivariable logistic regression, and likelihood ratio test. Results Septal LV, global LV, and RV native T1 values were significantly lower in AFD compared with those in HCM (1161 msec ± 47 vs 1296 msec ± 55, respectively [P < .001]; 1192 msec ± 52 vs 1268 msec ± 55 [P < .001]; and 1221 msec ± 54 vs 1271 msec ± 37 [P = .001], respectively). A septal LV native T1 cutoff point of 1220 msec or lower distinguished AFD from HCM with sensitivity of 97%, specificity of 93%, and accuracy of 95%. Septal LV native T1 values differentiated AFD from HCM after adjustment for age, sex, and conventional imaging features (odds ratio, 0.94; 95% confidence interval: 0.91, 0.98; P = < .001). In a nested logistic regression model with age, sex, and conventional imaging features, model fit was significantly improved by the addition of septal LV native T1 values (χ2 [df = 1] = 33.4; P < .001). Conclusion Cardiac MR imaging native T1 values at 3.0 T are significantly lower in patients with AFD compared with those with HCM and provide independent and incremental diagnostic value beyond age, sex, and conventional imaging features. © RSNA, 2018.

Informed Decision-Making in the Context of Prenatal Chromosomal Microarray.

The introduction of chromosomal microarray (CMA) into the prenatal setting has involved considerable deliberation due to the wide range of possible outcomes (e.g., copy number variants of uncertain clinical significance). Such issues are typically discussed in pre-test counseling for pregnant women to support informed decision-making regarding prenatal testing options. This research study aimed to assess the level of informed decision-making with respect to prenatal CMA and the factor(s) influencing decision-making to accept CMA for the selected prenatal testing procedure (i.e., chorionic villus sampling or amniocentesis). We employed a questionnaire that was adapted from a three-dimensional measure previously used to assess informed decision-making with respect to prenatal screening for Down syndrome and neural tube defects. This measure classifies an informed decision as one that is knowledgeable, value-consistent, and deliberated. Our questionnaire also included an optional open-ended question, soliciting factors that may have influenced the participants' decision to accept prenatal CMA; these responses were analyzed qualitatively. Data analysis on 106 participants indicated that 49% made an informed decision (i.e., meeting all three criteria of knowledgeable, deliberated, and value-consistent). Analysis of 59 responses to the open-ended question showed that "the more information the better" emerged as the dominant factor influencing both informed and uninformed participants' decisions to accept prenatal CMA. Despite learning about the key issues in pre-test genetic counseling, our study classified a significant portion of women as making uninformed decisions due to insufficient knowledge, lack of deliberation, value-inconsistency, or a combination of these three measures. Future efforts should focus on developing educational approaches and counseling strategies to effectively increase the rate of informed decision-making among women offered prenatal CMA.

Does personal genome testing drive service utilization in an adult preventive medicine clinic?

Personal genome testing (PGT) that assesses risk for common diseases may influence the use of preventive health services, but outcome data are limited. We aimed to assess health service utilization following PGT. We conducted a retrospective matched cohort study at an adult health clinic. Medical records of clients who pursued PGT at their comprehensive health assessment (CHA) over a 1-year period (N = 388) were reviewed and compared to age- and sex-matched clients who underwent CHA but not PGT (N = 388). We measured condition-specific health services used post CHA up to two subsequent visits while accounting for confounding factors (e.g., family history, health status, and age). A relatively equal number of post CHA services were used by clients who pursued PGT and those who did not pursue PGT (52% and 48%, respectively). Overall and across the majority of conditions examined, clients' service utilization was significantly associated with health status, e.g., clients identified as "at risk" on CHA for heart attack used 2.86 times more services than clients not at risk. Pursuing PGT was not significantly associated with increased use of services post CHA overall or for most of the conditions examined. Our data demonstrate that health status rather than pursuing PGT is the strongest driver of service utilization in this population. Overall, pursuit of PGT and PGT results does not appear to significantly drive the utilization of downstream health services.

Cardiovascular magnetic resonance demonstration of the spectrum of morphological phenotypes and patterns of myocardial scarring in Anderson-Fabry disease.

BACKGROUND: Although it is known that Anderson-Fabry Disease (AFD) can mimic the morphologic manifestations of hypertrophic cardiomyopathy (HCM) on echocardiography, there is a lack of cardiovascular magnetic resonance (CMR) literature on this. There is limited information in the published literature on the distribution of myocardial fibrosis in patients with AFD, with scar reported principally in the basal inferolateral midwall. METHODS: All patients with confirmed AFD undergoing CMR at our center were included. Left ventricular (LV) volumes, wall thicknesses and scar were analyzed offline. Patients were categorized into 4 groups: (1) no wall thickening; (2) concentric hypertrophy; (3) asymmetric septal hypertrophy (ASH); and (4) apical hypertrophy. Charts were reviewed for clinical information. RESULTS: Thirty-nine patients were included (20 males [51%], median age 45.2 years [range 22.3-64.4]). Almost half (17/39) had concentric wall thickening. Almost half (17/39) had pathologic LV scar; three quarters of these (13/17) had typical inferolateral midwall scar. A quarter (9/39) had both concentric wall thickening and typical inferolateral scar. A subgroup with ASH and apical hypertrophy (n = 5) had greater maximum wall thickness, total LV scar, apical scar and mid-ventricular scar than those with concentric hypertrophy (n = 17, p < 0.05). Patients with elevated LVMI had more overall arrhythmia (p = 0.007) more ventricular arrhythmia (p = 0.007) and sustained ventricular tachycardia (p = 0.008). CONCLUSIONS: Concentric thickening and inferolateral mid-myocardial scar are the most common manifestations of AFD, but the spectrum includes cases morphologically identical to apical and ASH subtypes of HCM and these have more apical and mid-ventricular LV scar. Significant LVH is associated with ventricular arrhythmia.

Psychiatric disorders in Ehlers-Danlos syndrome are frequent, diverse and strongly associated with pain.

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial impairment are common, yet poorly characterized, findings in EDS patients. We investigated the frequency and types of psychiatric disorders and their relationship to systemic manifestations in a cohort of 106 classic and hypermobility type EDS patients. In this retrospective study, extensive medical chart review was performed for patients referred at two genetics clinics who were diagnosed with EDS. Statistical analysis was undertaken to determine the frequency of psychiatric disorders and association with systemic findings. Psychiatric disorders were found in 42.5% of the EDS cohort, with 22.7% of patients affected with 2 or more psychiatric diagnoses. Anxiety and depression were most commonly reported, with frequencies of 23.6 and 25.5%, respectively. A variety of other psychiatric diagnoses were also identified. Abdominal pain [odds ratio (OR) 7.38], neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR 2.85) and fatigue (OR 5.55) were significantly associated with the presence of a psychiatric disorder. The presence of any pain symptom was significantly associated with having a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR 5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were significantly associated with having an anxiety or mood disorder. Joint hypermobility and the classic dermatological features of EDS showed no significant association with having a psychiatric disorder. Our findings demonstrate a high frequency of psychiatric disorders and an association with pain symptoms in EDS.