Mixture multilevel vector-autoregressive modeling.

With the rising popularity of intensive longitudinal research, the modeling techniques for such data are increasingly focused on individual differences. Here we present mixture multilevel vector-autoregressive modeling, which extends multilevel vector-autoregressive modeling by including a mixture, to identify individuals with similar traits and dynamic processes. This exploratory model identifies mixture components, where each component refers to individuals with similarities in means (expressing traits), autoregressions, and cross-regressions (expressing dynamics), while allowing for some interindividual differences in these attributes. Key issues in modeling are discussed, where the issue of centering predictors is examined in a small simulation study. The proposed model is validated in a simulation study and used to analyze the affective data from the COGITO study. These data consist of samples for two different age groups of over 100 individuals each who were measured for about 100 days. We demonstrate the advantage of exploratory identifying mixture components by analyzing these heterogeneous samples jointly. The model identifies three distinct components, and we provide an interpretation for each component motivated by developmental psychology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A comprehensive model framework for between-individual differences in longitudinal data.

Across different fields of research, the similarities and differences between various longitudinal models are not always eminently clear due to differences in data structure, application area, and terminology. Here we propose a comprehensive model framework that will allow simple comparisons between longitudinal models, to ease their empirical application and interpretation. At the within-individual level, our model framework accounts for various attributes of longitudinal data, such as growth and decline, cyclical trends, and the dynamic interplay between variables over time. At the between-individual level, our framework contains continuous and categorical latent variables to account for between-individual differences. This framework encompasses several well-known longitudinal models, including multilevel regression models, growth curve models, growth mixture models, vector-autoregressive models, and multilevel vector-autoregressive models. The general model framework is specified and its key characteristics are illustrated using famous longitudinal models as concrete examples. Various longitudinal models are reviewed and it is shown that all these models can be united into our comprehensive model framework. Extensions to the model framework are discussed. Recommendations for selecting and specifying longitudinal models are made for empirical researchers who aim to account for between-individual differences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Feasibility and early clinical impact of precision medicine for late-stage cancer patients in a regional public academic hospital.

AIM: Our goal was to describe a precision medicine program in a regional academic hospital, characterize features of included patients and present early data on clinical impact. MATERIALS AND METHODS: We prospectively included 163 eligible patients with late-stage cancer of any diagnosis from June 2020 to May 2022 in the Proseq Cancer trial. Molecular profiling of new or fresh frozen tumor biopsies was done by WES and RNAseq with parallel sequencing of non-tumoral DNA as individual reference. Cases were presented at a National Molecular Tumor Board (NMTB) for discussion of targeted treatment. Subsequently, patients were followed for at least 7 months. RESULTS: 80% (N = 131) of patients had a successful analysis done, disclosing at least one pathogenic or likely pathogenic variant in 96%. A strongly or potentially druggable variant was found in 19% and 73% of patients, respectively. A germline variant was identified in 2.5%. Median time from trial inclusion to NMTB decision was one month. One third (N = 44) of patients who underwent molecularly profiling were matched with a targeted treatment, however, only 16% were either treated (N = 16) or are waiting for treatment (N = 5), deteriorating performance status being the primary cause of failure. A history of cancer among 1st degree relatives, and a diagnosis of lung or prostate cancer correlated with greater chance of targeted treatment being available. The response rate of targeted treatments was 40%, the clinical benefit rate 53%, and the median time on treatment was 3.8 months. 23% of patients presented at NMTB were recommended clinical trial participation, not dependent on biomarkers. CONCLUSIONS: Precision medicine in end-stage cancer patients is feasible in a regional academic hospital but should continue within the frame of clinical protocols as few patients benefit. Close collaboration with comprehensive cancer centers ensures expert evaluations and equality in access to early clinical trials and modern treatment.

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease.

TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants-one nonsense variant and six missense variants-that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

A phylogeny of the genus Limia (Teleostei: Poeciliidae) suggests a single-lake radiation nested in a Caribbean-wide allopatric speciation scenario.

OBJECTIVE: The Caribbean is an important global biodiversity hotspot. Adaptive radiations there lead to many speciation events within a limited period and hence are particularly prominent biodiversity generators. A prime example are freshwater fish of the genus Limia, endemic to the Greater Antilles. Within Hispaniola, nine species have been described from a single isolated site, Lake Miragoâne, pointing towards extraordinary sympatric speciation. This study examines the evolutionary history of the Limia species in Lake Miragoâne, relative to their congeners throughout the Caribbean. RESULTS: For 12 Limia species, we obtained almost complete sequences of the mitochondrial cytochrome b gene, a well-established marker for lower-level taxonomic relationships. We included sequences of six further Limia species from GenBank (total N = 18 species). Our phylogenies are in concordance with other published phylogenies of Limia. There is strong support that the species found in Lake Miragoâne in Haiti are monophyletic, confirming a recent local radiation. Within Lake Miragoâne, speciation is likely extremely recent, leading to incomplete lineage sorting in the mtDNA. Future studies using multiple unlinked genetic markers are needed to disentangle the relationships within the Lake Miragoâne clade.

Cell-based non-invasive prenatal testing for monogenic disorders: confirmation of unaffected fetuses following preimplantation genetic testing.

PURPOSE: Proof of concept of the use of cell-based non-invasive prenatal testing (cbNIPT) as an alternative to chorionic villus sampling (CVS) following preimplantation genetic testing for monogenic disorders (PGT-M). METHOD: PGT-M was performed by combined testing of short tandem repeat (STR) markers and direct mutation detection, followed by transfer of an unaffected embryo. Patients who opted for follow-up of PGT-M by CVS had blood sampled, from which potential fetal extravillous throphoblast cells were isolated. The cell origin and mutational status were determined by combined testing of STR markers and direct mutation detection using the same setup as during PGT. The cbNIPT results with respect to the mutational status were compared to those of genetic testing of the CVS. RESULTS: Eight patients had blood collected between gestational weeks 10 and 13, from which 33 potential fetal cell samples were isolated. Twenty-seven out of 33 isolated cell samples were successfully tested (82%), of which 24 were of fetal origin (89%). This corresponds to a median of 2.5 successfully tested fetal cell samples per case (range 1-6). All fetal cell samples had a genetic profile identical to that of the transferred embryo confirming a pregnancy with an unaffected fetus, in accordance with the CVS results. CONCLUSION: These findings show that although measures are needed to enhance the test success rate and the number of cells identified, cbNIPT is a promising alternative to CVS. TRIAL REGISTRATION NUMBER: N-20180001.

Insight Into Individual Differences in Emotion Dynamics With Clustering.

Studying emotion dynamics through time series models is becoming increasingly popular in the social sciences. Across individuals, dynamics can be rather heterogeneous. To enable comparisons and generalizations of dynamics across groups of individuals, one needs sophisticated tools that express the essential similarities and differences. A way to proceed is to identify subgroups of people who are characterized by qualitatively similar emotion dynamics through dynamic clustering. So far, these methods assume equal generating processes for individuals per cluster. To avoid this overly restrictive assumption, we outline a probabilistic clustering approach based on a mixture model that clusters on individuals' vector autoregressive coefficients. We evaluate the performance of the method and compare it with a nonprobabilistic method in a simulation study. The usefulness of the methods is illustrated using 366 ecological momentary assessment time series with external measures of depression and anxiety.

National data on the early clinical use of non-invasive prenatal testing in public and private healthcare in Denmark 2013-2017.

INTRODUCTION: In Denmark, non-invasive prenatal testing (NIPT) has been used since 2013. We aimed to evaluate the early clinical use of NIPT in Danish public and private healthcare settings before NIPT became an integrated part of the national guidelines on prenatal screening and diagnosis in 2017. MATERIAL AND METHODS: NIPT data were collected between March 2013 and June 2017 from national public registries and private providers. Results from follow-up samples (chorionic villi, amniotic fluid, postnatal blood or fetal tissue) were included from The Danish Cytogenetics Central Registry and indications and outcome from The Danish Fetal Medicine Database. RESULTS: A total of 3936 NIPT results were included in the study from public hospitals (n = 3463, 88.0%) and private clinics (n = 473, 12.0%). The total number of prenatal tests was 19 713 during the study period: 20% were NIPT analyses (n = 3936) and 80% invasive procedures (n = 15 777). Twenty-five percent of NIPTs in the private clinics were performed before gestational week 11+0 , whereas NIPT in public settings was used only after combined first trimester screening (P < .001). Regardless of indication, the national public sensitivity was 96.9% (95% CI 82.0%-99.8%) for trisomy 21, 100% (95% CI 46.3%-100%) for trisomy 18, 100% (95% CI 5.5%-100%) for trisomy 13, and 87.0% (95% CI 74.5%-92.4%) for any fetal chromosomal aberration. Forty-seven true-positive NIPT results included cases of common aneuplodies (trisomy 21, n = 31; trisomy 18, n = 5; and trisomy 13, n = 1), sex chromosomal aberrations (n = 7) and atypical chromosomal aberrations (n = 3). One false-negative NIPT result occurred (trisomy 21). Of 47 cases, 21 (45%) cases with a true-positive NIPT result resulted in live births by choice; 11 of these children had Down and 4 had Edwards syndrome. CONCLUSIONS: The total number of NIPT analyses was low compared with the number of invasive procedures in the implementation period. In contrast to the generally high termination rate after a positive result following invasive testing in Denmark, a high proportion of true-positive NIPT results from the public setting resulted in live births. NIPT may be an important risk-free alternative to invasive testing for a minority of women in the public setting who wish to use prenatal genetic testing for information only and not for reproductive decision-making.

Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome.

Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p = .0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.

Use of genetic testing for hypolactasia trait in the North Denmark Region.

OBJECTIVE: Lactose intolerance (LI) may be considered in patients with unspecific gastrointestinal symptoms, but there is no clear consensus on when and how to diagnose the disorder. The LCT-13910 CC genotype is associated with acquired primary lactase deficiency (adult-type hypolactasia; ATH). We aimed to describe the number of tests and test results in the North Denmark Region considering patient age, geographical origin and repeated testing. METHODS: Retrospective evaluation of the polymerase chain reaction-based LCT-13910 genotype tests registered in the clinical laboratory information system (LABKA II) with data linkage to Danish nationwide registers. RESULTS: Between 18 May 2007 and 31 December 2018, a total of 23,560 individuals were tested. There was a sevenfold increase in the number of tests performed during the study period. About 9.8% of the tests performed in 2018 were repeated testing in the same individuals. Overall, 8.8% of tested individuals were younger than 5 years, 90.7% were of Danish origin and 5.5% originated from outside of Europe. The LCT-13910 CC genotype was identified in 13.3% of all tested individuals, in 16.0% of children younger than 5 years, in 6.8% of Danish individuals and in 90.9% originating from outside of Europe. CONCLUSIONS: In the North Denmark Region, a marked increase in the use of genetic testing for hypolactasia was observed and repeated testing was frequent. Furthermore, the use of the test and the test results were dependent on patient age and geographical origin. Results inform the debate on when and how to use genetic testing in the diagnosing of LI.

The effect of preregistration on trust in empirical research findings: results of a registered report.

The crisis of confidence has undermined the trust that researchers place in the findings of their peers. In order to increase trust in research, initiatives such as preregistration have been suggested, which aim to prevent various questionable research practices. As it stands, however, no empirical evidence exists that preregistration does increase perceptions of trust. The picture may be complicated by a researcher's familiarity with the author of the study, regardless of the preregistration status of the research. This registered report presents an empirical assessment of the extent to which preregistration increases the trust of 209 active academics in the reported outcomes, and how familiarity with another researcher influences that trust. Contrary to our expectations, we report ambiguous Bayes factors and conclude that we do not have strong evidence towards answering our research questions. Our findings are presented along with evidence that our manipulations were ineffective for many participants, leading to the exclusion of 68% of complete datasets, and an underpowered design as a consequence. We discuss other limitations and confounds which may explain why the findings of the study deviate from a previously conducted pilot study. We reflect on the benefits of using the registered report submission format in light of our results. The OSF page for this registered report and its pilot can be found here: http://dx.doi.org/10.17605/OSF.IO/B3K75.

A systematic review on concurrent aneuploidy screening and preimplantation genetic testing for hereditary disorders: What is the prevalence of aneuploidy and is there a clinical effect from aneuploidy screening?

INTRODUCTION: In assisted reproductive technology, aneuploidy is considered a primary cause of failed embryo implantation. This has led to the implementation of preimplantation genetic testing for aneuploidy in some clinics. The prevalence of aneuploidy and the use of aneuploidy screening during preimplantation genetic testing for inherited disorders has not previously been reviewed. Here, we systematically review the literature to investigate the prevalence of aneuploidy in blastocysts derived from patients carrying or affected by an inherited disorder, and whether screening for aneuploidy improves clinical outcomes. MATERIAL AND METHODS: PubMed and Embase were searched for articles describing preimplantation genetic testing for monogenic disorders and/or structural rearrangements in combination with preimplantation genetic testing for aneuploidy. Original articles reporting aneuploidy rates at the blastocyst stage and/or clinical outcomes (positive human chorionic gonadotropin, gestational sacs/implantation rate, fetal heartbeat/clinical pregnancy, ongoing pregnancy, miscarriage, or live birth/delivery rate on a per transfer basis) were included. Case studies were excluded. RESULTS: Of the 26 identified studies, none were randomized controlled trials, three were historical cohort studies with a reference group not receiving aneuploidy screening, and the remaining were case series. In weighted analysis, 34.1% of 7749 blastocysts were aneuploid. Screening for aneuploidy reduced the proportion of embryos suitable for transfer, thereby increasing the risk of experiencing a cycle without transferable embryos. In pooled analysis the percentage of embryos suitable for transfer was reduced from 57.5% to 37.2% following screening for aneuploidy. Among historical cohort studies, one reported significantly improved pregnancy and birth rates but did not control for confounding, one did not report any statistically significant difference between groups, and one properly designed study concluded that preimplantation genetic testing for aneuploidy enhanced the chance of achieving a pregnancy while simultaneously reducing the chance of miscarriage following single embryo transfer. CONCLUSIONS: On average, aneuploidy is detected in 34% of embryos when performing a single blastocyst biopsy derived from patients carrying or affected by an inherited disorder. Accordingly, when screening for aneuploidy, the risk of experiencing a cycle with no transferable embryos increases. Current available data on the clinical effect of preimplantation genetic testing for aneuploidy performed concurrently with preimplantation genetic testing for inherited disorders are sparse, rendering the clinical effect from preimplantation genetic testing for aneuploidy difficult to access.

Whole-exome sequencing identifies a GREB1L variant in a three-generation family with Müllerian and renal agenesis: a novel candidate gene in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. A case report.

The aetiology of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD = 33) c.705G>T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.

Mitochondrial Disease Caused by a Novel Homozygous Mutation (Gly106del) in the SCO1 Gene.

The cytochrome C oxidase assembly protein SCO1 gene encodes a mitochondrial protein essential for the mammalian energy metabolism. Only three pedigrees of SCO1mutations have thus far been reported. They all presented with lactate acidosis and encephalopathy. Two had hepatopathy and hypotonia, and the other presented with intrauterine growth retardation and hypertrophic cardiomyopathy leading to cardiac failure. Mitochondrial disease may manifest in neonates, but early diagnosis has so far been difficult. Here, we present a novel mutation in the SCO1 gene: in-frame deletion (Gly106del)with a different phenotype without encephalopathy, hepatopathy, hypotonia, or cardiac involvement. Within the first 2 h the girl developed hypoglycemia and severe chronic lactate acidosis. Because of the improved technique in whole exome sequencing, an early diagnosis was made when the girl was only 9 days old, which enabled the prediction of prognosis as well as level of treatment. She died at 1 month of age.

[Preimplantation genetic testing for aneuploidy].

This review summarises the current knowledge on preimplantation genetic testing for aneuploidy (PGT-A). Selection and transfer of euploid embryos aim to improve live birth rate (LBR) per embryo transfer, but fluorescence in situ hybridisation-based PGT-A and biopsy of cleavage stage embryos in the 2000s was a disappointment, as studies revealed a reduced LBR. Today, PGT-A includes comprehensive chromosome screening primarily of blastocyst biopsies. The benefit of PGT-A is highly debated: some suggest improved treatment outcome, while others claim, that the procedure is not cost-effective.

Do Researchers Anchor Their Beliefs on the Outcome of an Initial Study?

As a research field expands, scientists have to update their knowledge and integrate the outcomes of a sequence of studies. However, such integrative judgments are generally known to fall victim to a primacy bias where people anchor their judgments on the initial information. In this preregistered study we tested the hypothesis that people anchor on the outcome of a small initial study, reducing the impact of a larger subsequent study that contradicts the initial result. Contrary to our expectation, undergraduates and academics displayed a recency bias, anchoring their judgment on the research outcome presented last. This recency bias is due to the fact that unsuccessful replications decreased trust in an effect more than did unsuccessful initial experiments. We recommend the time-reversal heuristic to account for temporal order effects during integration of research results.

Direct acting antiviral treatment of chronic hepatitis C in Denmark: factors associated with and barriers to treatment initiation.

OBJECTIVES: We describe factors associated with and barriers to initiation of Direct Acting Antiviral (DAA) treatment in patients with chronic hepatitis C, who fulfill national fibrosis treatment guidelines in Denmark. MATERIALS AND METHODS: In this nationwide cohort study, we included patients with chronic hepatitis C from The Danish Database for Hepatitis B and C (DANHEP) who fulfilled fibrosis treatment criteria. Factors associated with treatment initiation and treatment failure were determined by logistic regression analyses. Medical records were reviewed from patients who fulfilled fibrosis treatment criteria, but did not initiate DAA treatment to determine the cause. RESULTS: In 344 (49%) of 700 patients, who fulfilled treatment criteria, factors associated with DAA treatment initiation were transmission by other routes than injecting drug use odds ratio (OR) 2.13 (CI: 1.38-3.28), previous treatment failure OR 2.58 (CI: 1.84-3.61) and ALT above upper limit of normal OR 1.60 (CI: 1.18-2.17). The most frequent reasons for not starting treatment among 356 (51%) patients were non-adherence to medical appointments (n = 107/30%) and ongoing substance use (n = 61/17%). Treatment failure with viral relapse occurred in 19 (5.5%) patients, who were more likely to have failed previous treatment OR 4.53 (CI: 1.59-12.91). CONCLUSIONS: In this nationwide cohort study, we found non-adherence to medical appointments and active substance use to be major obstacles for DAA treatment initiation. Our findings highlight the need for interventions that can overcome these barriers and increase the number of patients who can initiate and benefit from curative DAA treatment.

Individual differences in satisfaction with activity-based work environments.

Satisfaction with activity-based work environments (ABW environments) often falls short of expectations, with striking differences among individual workers. A better understanding of these differences may provide clues for optimising satisfaction with ABW environments and associated organisational outcomes. The current study was designed to examine how specific psychological needs, job characteristics, and demographic variables relate to satisfaction with ABW environments. Survey data collected at seven organizations in the Netherlands (N = 551) were examined using correlation and regression analyses. Significant correlates of satisfaction with ABW environments were found: need for relatedness (positive), need for privacy (negative), job autonomy (positive), social interaction (positive), internal mobility (positive), and age (negative). Need for privacy appeared to be a powerful predictor of individual differences in satisfaction with ABW environments. These findings underline the importance of providing work environments that allow for different work styles, in alignment with different psychological need strengths, job characteristics, and demographic variables. Improving privacy, especially for older workers and for workers high in need for privacy, seems key to optimizing satisfaction with ABW environments.