Predictive processing of music and language in autism: Evidence from Mandarin and English speakers.

Atypical predictive processing has been associated with autism across multiple domains, based mainly on artificial antecedents and consequents. As structured sequences where expectations derive from implicit learning of combinatorial principles, language and music provide naturalistic stimuli for investigating predictive processing. In this study, we matched melodic and sentence stimuli in cloze probabilities and examined musical and linguistic prediction in Mandarin- (Experiment 1) and English-speaking (Experiment 2) autistic and non-autistic individuals using both production and perception tasks. In the production tasks, participants listened to unfinished melodies/sentences and then produced the final notes/words to complete these items. In the perception tasks, participants provided expectedness ratings of the completed melodies/sentences based on the most frequent notes/words in the norms. While Experiment 1 showed intact musical prediction but atypical linguistic prediction in autism in the Mandarin sample that demonstrated imbalanced musical training experience and receptive vocabulary skills between groups, the group difference disappeared in a more closely matched sample of English speakers in Experiment 2. These findings suggest the importance of taking an individual differences approach when investigating predictive processing in music and language in autism, as the difficulty in prediction in autism may not be due to generalized problems with prediction in any type of complex sequence processing.

Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score.

BACKGROUND: The extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD. METHODS: Participants were of European ancestry from the UK Biobank without prevalent CAD. An externally trained genome-wide CAD PRS was generated and then applied. Clinical risk factors were ascertained at baseline. Cox proportional hazards models were fitted to examine the incident CAD effects of CAD PRS, risk factors, and their interactions. Next, the PRS and risk factors were stratified to investigate the attributable risk of clinical risk factors. FINDINGS: A total of 357,144 individuals of European ancestry without prevalent CAD were included. During a median of 11.1 years of follow-up (interquartile range 10.4-14.1 years), CAD PRS was associated with 1.35-fold (95% confidence interval [CI] 1.332-1.368) risk per SD for incident CAD. The prognostic relevance of the following risk factors was relatively diminished for those with high CAD PRS on a continuous scale: type 2 diabetes (hazard ratio [HR]interaction 0.91, 95% CIinteraction 0.88-0.94), increased body mass index (HRinteraction 0.97, 95% CIinteraction 0.96-0.98), and increased C-reactive protein (HRinteraction 0.98, 95% CIinteraction 0.96-0.99). However, a high CAD PRS yielded joint risk increases with low-density lipoprotein cholesterol (HRinteraction 1.05, 95% CIinteraction 1.04-1.06) and total cholesterol (HRinteraction 1.05, 95% CIinteraction 1.03-1.06). CONCLUSION: The CAD PRS is associated with incident CAD, and its application improves the prognostic relevance of several clinical risk factors. FUNDING: P.N. (R01HL127564, R01HL151152, and U01HG011719) is supported by the National Institutes of Health.

Polygenic Scores and Preclinical Cardiovascular Disease in Individuals With HIV: Insights From the REPRIEVE Trial.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of death among the 38.4 million people with HIV globally. The extent to which cardiovascular polygenic risk scores (PRSs) derived in non-HIV populations generalize to people with HIV is not well understood. METHODS AND RESULTS: PRSs for CAD (GPSMult) and lipid traits were calculated in a global cohort of people with HIV treated with antiretroviral therapy with low-to-moderate atherosclerotic cardiovascular disease risk enrolled in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV). The PRSs were associated with baseline lipid traits in 4495 genotyped participants, and with subclinical CAD in a subset of 662 who underwent coronary computed tomography angiography. Among participants who underwent coronary computed tomography angiography (mean age, 50.9 [SD, 5.8] years; 16.1% women; 41.8% African, 57.3% European, 1.1% Asian), GPSMult was associated with plaque presence with odds ratio (OR) per SD in GPSMult of 1.42 (95% CI, 1.20-1.68; P=3.8×10-5), stenosis >50% (OR, 2.39 [95% CI, 1.48-3.85]; P=3.4×10-4), and noncalcified/vulnerable plaque (OR, 1.45 [95% CI, 1.23-1.72]; P=9.6×10-6). Effects were consistent in subgroups of age, sex, 10-year atherosclerotic cardiovascular disease risk, ancestry, and CD4 count. Adding GPSMult to established risk factors increased the C-statistic for predicting plaque presence from 0.718 to 0.734 (P=0.02). Furthermore, a PRS for low-density lipoprotein cholesterol was associated with plaque presence with OR of 1.21 (95% CI, 1.01-1.44; P=0.04), and partially calcified plaque with OR of 1.21 (95% CI, 1.01-1.45; P=0.04) per SD. CONCLUSIONS: Among people with HIV treated with antiretroviral therapy without documented atherosclerotic cardiovascular disease and at low-to-moderate calculated risk in REPRIEVE, an externally developed CAD PRS was predictive of subclinical atherosclerosis. PRS for low-density lipoprotein cholesterol was also associated with subclinical atherosclerosis, supporting a role for low-density lipoprotein cholesterol in HIV-associated CAD. REGISTRATION: URL: https://www.reprievetrial.org; Unique identifier: NCT02344290.

Weighting of cues to categorization of song versus speech in tone-language and non-tone-language speakers.

One of the most important auditory categorization tasks a listener faces is determining a sound's domain, a process which is a prerequisite for successful within-domain categorization tasks such as recognizing different speech sounds or musical tones. Speech and song are universal in human cultures: how do listeners categorize a sequence of words as belonging to one or the other of these domains? There is growing interest in the acoustic cues that distinguish speech and song, but it remains unclear whether there are cross-cultural differences in the evidence upon which listeners rely when making this fundamental perceptual categorization. Here we use the speech-to-song illusion, in which some spoken phrases perceptually transform into song when repeated, to investigate cues to this domain-level categorization in native speakers of tone languages (Mandarin and Cantonese speakers residing in the United Kingdom and China) and in native speakers of a non-tone language (English). We find that native tone-language and non-tone-language listeners largely agree on which spoken phrases sound like song after repetition, and we also find that the strength of this transformation is not significantly different across language backgrounds or countries of residence. Furthermore, we find a striking similarity in the cues upon which listeners rely when perceiving word sequences as singing versus speech, including small pitch intervals, flat within-syllable pitch contours, and steady beats. These findings support the view that there are certain widespread cross-cultural similarities in the mechanisms by which listeners judge if a word sequence is spoken or sung.

Risk factors for clonal hematopoiesis of indeterminate potential in people with HIV: a report from the REPRIEVE trial.

ABSTRACT: Clonal hematopoiesis of indeterminate potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH), but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole-exome sequencing. Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4486 PWH, mean age was 49.9 (standard deviation [SD], 6.4) years; 1650 (36.8%) were female; and 3418 (76.2%) were non-White. CHIP was identified in 223 of 4486 (4.97%) and in 38 of 373 (10.2%) among those aged ≥60 years. Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.05-1.09; P < .0001) and smoking (OR, 1.37; 95% CI, 1.14-1.66; P < .001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including sub-Saharan Africa (OR, 0.57; 95% CI, 0.4-0.81; P = .0019), South Asia (OR, 0.45; 95% CI, 0.23-0.80; P = .01), and Latin America/Caribbean (OR, 0.56; 95% CI, 0.34-0.87; P = .014). Hispanic/Latino ethnicity (OR, 0.38; 95% CI, 0.23-0.54; P = .002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI, 1.21-3.05; P = .006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART; OR, 4.15; 95% CI, 1.51-11.1; P = .005) (Pinteraction= .0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. This trial was registered at www.ClinicalTrials.gov as NCT02344290.

Musical anhedonia, timbre, and the rewards of music listening.

Pleasure in music has been linked to predictive coding of melodic and rhythmic patterns, subserved by connectivity between regions in the brain's auditory and reward networks. Specific musical anhedonics derive little pleasure from music and have altered auditory-reward connectivity, but no difficulties with music perception abilities and no generalized physical anhedonia. Recent research suggests that specific musical anhedonics experience pleasure in nonmusical sounds, suggesting that the implicated brain pathways may be specific to music reward. However, this work used sounds with clear real-world sources (e.g., babies laughing, crowds cheering), so positive hedonic responses could be based on the referents of these sounds rather than the sounds themselves. We presented specific musical anhedonics and matched controls with isolated short pleasing and displeasing synthesized sounds of varying timbres with no clear real-world referents. While the two groups found displeasing sounds equally displeasing, the musical anhedonics gave substantially lower pleasure ratings to the pleasing sounds, indicating that their sonic anhedonia is not limited to musical rhythms and melodies. Furthermore, across a large sample of participants, mean pleasure ratings for pleasing synthesized sounds predicted significant and similar variance in six dimensions of musical reward considered to be relatively independent, suggesting that pleasure in sonic timbres play a role in eliciting reward-related responses to music. We replicate the earlier findings of preserved pleasure ratings for semantically referential sounds in musical anhedonics and find that pleasure ratings of semantic referents, when presented without sounds, correlated with ratings for the sounds themselves. This association was stronger in musical anhedonics than in controls, suggesting the use of semantic knowledge as a compensatory mechanism for affective sound processing. Our results indicate that specific musical anhedonia is not entirely specific to melodic and rhythmic processing, and suggest that timbre merits further research as a source of pleasure in music.

Pragmatic Approach to Applying Polygenic Risk Scores to Diverse Populations.

Polygenic risk scores (PRS) estimate genetic susceptibility of an individual to disease and have the potential of providing utility in multiple clinical contexts. However, their performance, computation, and reporting in diverse populations remain challenging. Here, we present a pragmatic approach to optimize a PRS for a population of interest that leverages publicly available data and methods and consists of seven steps that are easily implemented without the requirement of expertise in complex genetics: step 1, selecting source genome-wide association studies (GWAS) and imputation; step 2, selecting methods to compute polygenic score; step 3, adjusting scores using principal components of genetic ancestry; step 4, selecting the best performing score; step 5, defining percentiles of a population distribution; step 6, validating performance of the optimized polygenic score; and step 7, implementing the optimized polygenic score in clinical practice. © 2023 Wiley Periodicals LLC.

Concordance of a High Lipoprotein(a) Concentration Among Relatives.

Importance: Lipoprotein(a) (Lp[a]) concentrations are a highly heritable and potential causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent consensus statements by the European Atherosclerosis Society and American Heart Association recommend screening of relatives of individuals with high Lp(a) concentrations, but the expected yield of this approach has not been quantified in large populations. Objective: To measure the prevalence of high Lp(a) concentrations among first- and second-degree relatives of individuals with high Lp(a) concentrations compared with unrelated participants. Design, Setting, and Participants: In this cross-sectional analysis, pairs of first-degree (n = 19 899) and second-degree (n = 9715) relatives with measured Lp(a) levels from the UK Biobank study and random pairs of unrelated individuals (n = 184 764) were compared. Data for this study were collected from March 2006 to August 2010 and analyzed from December 2021 to August 2023. Exposure: Serum Lp(a) levels, with a high Lp(a) level defined as at least 125 nmol/L. Main Outcome and Measure: Concordance of clinically relevant high Lp(a) levels in first- and second-degree relatives of index participants with high Lp(a) levels. Results: A total of 52 418 participants were included in the analysis (mean [SD] age, 57.3 [8.0] years; 29 825 [56.9%] women). Levels of Lp(a) were correlated among pairs of first-degree (Spearman ρ = 0.45; P < .001) and second-degree (Spearman ρ = 0.22; P < .001) relatives. A total of 1607 of 3420 (47.0% [95% CI, 45.3%-48.7%]) first-degree and 514 of 1614 (31.8% [95% CI, 29.6%-34.2%]) second-degree relatives of index participants with high Lp(a) levels also had elevated concentrations compared with 4974 of 30 258 (16.4% [95% CI, 16.0%-16.9%]) pairs of unrelated individuals. The concordance in high Lp(a) levels was generally consistent among subgroups (eg, those with prior ASCVD, postmenopausal women, and statin users). The odds ratios for relatives to have high Lp(a) levels if their index relative had a high Lp(a) level compared with those whose index relatives did not have high Lp(a) levels were 7.4 (95% CI, 6.8-8.1) for first-degree relatives and 3.0 (95% CI, 2.7-3.4) for second-degree relatives. Conclusions and Relevance: The findings of this cross-sectional study suggest that the yield of cascade screening of first-degree relatives of individuals with high Lp(a) levels is over 40%. These findings support recent recommendations to use this approach to identify additional individuals at ASCVD risk based on Lp(a) concentrations.

Sex differences in vocal learning ability in songbirds are linked with differences in flexible rhythm pattern perception.

Humans readily recognize familiar rhythmic patterns, such as isochrony (equal timing between events) across a wide range of rates. This reflects a facility with perceiving the relative timing of events, not just absolute interval durations. Several lines of evidence suggest this ability is supported by precise temporal predictions arising from forebrain auditory-motor interactions. We have shown previously that male zebra finches, Taeniopygia guttata, which possess specialized auditory-motor networks and communicate with rhythmically patterned sequences, share our ability to flexibly recognize isochrony across rates. To test the hypothesis that flexible rhythm pattern perception is linked to vocal learning, we ask whether female zebra finches, which do not learn to sing, can also recognize global temporal patterns. We find that females can flexibly recognize isochrony across a wide range of rates but perform slightly worse than males on average. These findings are consistent with recent work showing that while females have reduced forebrain song regions, the overall network connectivity of vocal premotor regions is similar to males and may support predictions of upcoming events. Comparative studies of male and female songbirds thus offer an opportunity to study how individual differences in auditory-motor connectivity influence perception of relative timing, a hallmark of human music perception.

A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease.

Identification of individuals at highest risk of coronary artery disease (CAD)-ideally before onset-remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPSMult, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPSMult strongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10-2.19, P < 0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPSMult was also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70-1.76, P < 0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPSMult demonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPSMult for CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction.

Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study.

AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence. METHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686). CONCLUSION: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.

Polygenic prediction of preeclampsia and gestational hypertension.

Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR-CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.

Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease.

Importance: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies. Objective: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk. Design, Setting, and Participants: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022. Exposures: PTVs in APOB and PCSK9. Main Outcomes and Measures: Estimated untreated LDL cholesterol levels and CHD. Results: Among 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004). Conclusions and Relevance: Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.

Advances and Applications of Polygenic Scores for Coronary Artery Disease.

Polygenic scores quantify inherited risk by integrating information from many common sites of DNA variation into a single number. Rapid increases in the scale of genetic association studies and new statistical algorithms have enabled development of polygenic scores that meaningfully measure-as early as birth-risk of coronary artery disease. These newer-generation polygenic scores identify up to 8% of the population with triple the normal risk based on genetic variation alone, and these individuals cannot be identified on the basis of family history or clinical risk factors alone. For those identified with increased genetic risk, evidence supports risk reduction with at least two interventions, adherence to a healthy lifestyle and cholesterol-lowering therapies, that can substantially reduce risk. Alongside considerable enthusiasm for the potential of polygenic risk estimation to enable a new era of preventive clinical medicine is recognition of a need for ongoing research into how best to ensure equitable performance across diverse ancestries, how and in whom to assess the scores in clinical practice, as well as randomized trials to confirm clinical utility.

Music and Brain Circuitry: Strategies for Strengthening Evidence-Based Research for Music-Based Interventions.

The neuroscience of music and music-based interventions (MBIs) is a fascinating but challenging research field. While music is a ubiquitous component of every human society, MBIs may encompass listening to music, performing music, music-based movement, undergoing music education and training, or receiving treatment from music therapists. Unraveling the brain circuits activated and influenced by MBIs may help us gain better understanding of the therapeutic and educational values of MBIs by gathering strong research evidence. However, the complexity and variety of MBIs impose unique research challenges. This article reviews the recent endeavor led by the National Institutes of Health to support evidence-based research of MBIs and their impact on health and diseases. It also highlights fundamental challenges and strategies of MBI research with emphases on the utilization of animal models, human brain imaging and stimulation technologies, behavior and motion capturing tools, and computational approaches. It concludes with suggestions of basic requirements when studying MBIs and promising future directions to further strengthen evidence-based research on MBIs in connections with brain circuitry.SIGNIFICANCE STATEMENT Music and music-based interventions (MBI) engage a wide range of brain circuits and hold promising therapeutic potentials for a variety of health conditions. Comparative studies using animal models have helped in uncovering brain circuit activities involved in rhythm perception, while human imaging, brain stimulation, and motion capture technologies have enabled neural circuit analysis underlying the effects of MBIs on motor, affective/reward, and cognitive function. Combining computational analysis, such as prediction method, with mechanistic studies in animal models and humans may unravel the complexity of MBIs and their effects on health and disease.