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Topics in design of computer experiments
No full textComputer models are used in many fields to simulate real-world processes. One of the goals is to optimise the value of the computer model. Due to the fact that the computer model is usually expensive to evaluate, one can only make a limited number of evaluations of this computer model. Using Gaussian processes in sequential design through the use of acquisition functions is a common approach for sample-efficient optimisation in such cases. Despite many recent successes, there are still a number of outstanding problems in that field. In this work, we address some of these problems. We first give a brief overview of Bayesian optimisation and the common techniques used. After that, we focus on scenarios where one is interested in finding both the minimum and the maximum of the computer model simultaneously. We use the entropy of the location of the optima to define a sequential design algorithm. The design is then created in a way that would minimise the entropy. Monte Carlo methods are used to approximate a number of probability distributions. The resulting algorithm is then compared against a baseline algorithm to demonstrate its superior performance. In the second part of this paper, we are interested in optimising high-dimensional computer models. This is a complicated task and comes with a number of additional challenges compared to the standard problems. Our focus is on computer models whose accuracy we can control by changing the amount of computational resources allocated to them. This is also often referred to as multi-fidelity optimisation. We then use a number of techniques from mathematical optimisation to define a multi-fidelity optimisation algorithm that can be used in high-dimensional settings and scaled to large number of evaluations. Its performance is then compared to that of another state-of-the-art optimisation algorithm. In the final part of this paper, we explore computer models that are non-stationary. These are computer models whose properties change depending on which part of the design space it is evaluated. For example, a computer model that changes rapidly in one area and is completely flat in a different area is non-stationary. Such computer models can accurately be modelled with a non-stationary Gaussian process. However, fitting non-stationary Gaussian processes can be computationally very expensive and a large number of computer model evaluations is often needed to model the process accurately. This makes sequential design difficult. We create a novel acquisition function that allows us to create accurate sequential designs by using regular stationary Gaussian processes that are far easier to fit. Our acquisition function puts more emphasis on more interesting regions and less emphasis on less interesting regions. We then create sequential designs created by our novel acquisition function combined with stationary Gaussian processes and compare it with designs found by non-stationary Gaussian processes
The roles of extreme and rising temperatures on individual, population and biogeographic responses of intertidal gastropods in the northeast Atlantic
No full textAnthropogenic climate change (ACC) is thermally altering atmospheric and marine ecosystems. Within intertidal environments, ACC exacerbates both emersed and immersed natural stressors experienced by organisms during daily tidal and seasonal cycles. Intertidal ectothermic gastropods are indicators of thermal change, as they occupy varying vertical levels of rocky shores, exist across multiple latitudes depending on thermal affinities, and are subject to extensive physiological and biogeographical research. Studies tracking biogeographic responses of intertidal species to rising sea surface temperatures (SSTs) around northeast Atlantic coastlines have shown poleward shifts of both leading and trailing range edges. Much less is known of species-specific biological mechanisms driving changes through life stages. In this thesis, an observational study investigated current temperature regimes on northeast Atlantic rocky shores and how they were modulated by microhabitats serving as nursery grounds or providing refuges (Chapter 2). Temperature loggers were placed into multiple microhabitats at rocky shore sites throughout the coastal northeast Atlantic from northern Scotland to southern Portugal. Up to five years of collected in situ data was then compared with long-term satellite data to assess if calculated broad-scale extreme thermal events are reflected at fine scales. The results confirmed that rocky shore microhabitats are experiencing lethally extreme temperatures at higher frequencies, mostly reflecting broad-scale extreme temperature events in the northeast Atlantic. Refugia such as rockpools are currently providing the greatest thermal stability throughout all seasons in most regions, although will provide limited thermal protection as the planet progresses towards extreme ACC scenarios by 2100. Laboratory experiments tested physiological responses of intertidal species to both current and end-of-the-century extreme atmospheric and marine temperatures (Chapter 3 and Chapter 4). Short-term laboratory experiments used locally-derived atmospheric and marine thermal extremes to explore lethal and sub-lethal (coma) responses of juvenile gastropod species, the trochids, Phorcus lineatus, Steromphala umbilicalis, Steromphala cineraria, and the littorinid, Littorina littorea (Chapter 3). A longer-term mesocosm experiment investigated lethal and sub-lethal (growth, gametogenesis) responses of northern and mid-range populations of the warm temperate species, S. umbilicalis, to variable SSTs under differing future ACC scenarios (Chapter 4). Boreal (cold temperate) mid to low-shore intertidal gastropod species may experience population declines, either through subtidal retreat or localised extinctions where thermal extremes are highest and differ most from localised seasonal conditions. Conversely, Lusitanian (warm temperate) intertidal populations at mid and northern biogeographic range limits will benefit under warming conditions from declining winter cold spells aiding survival. Milder winter SSTs are already enabling the early onset of spring growth and reproductive output rate. Considered together, these observational and experimental approaches have provided additional levels of detail to predict intertidal rocky shore gastropod population responses in a warming world
A systematic analysis of contemporary whole exome sequencing capture kits to optimise high-coverage capture of CCDS regions
No full textWhole Exome Sequencing (WES) is a well-established tool for clinical diagnostics, is more cost-effective and faster to analyse than Whole Genome Sequencing (WGS) and has been implemented to uplift diagnostic rates in human disease. However, challenges remain to achieve comprehensive and uniform coverage of targets, and high sensitivity and specificity. Differences in genomic target regions and exome capture mechanism between kits may lead to differences in overall coverage uniformity and capture efficiency. Here, we analyse the efficiency of a range of off-the-shelf exome sequencing (ES) kits in capturing their reported targets and the Consensus Coding Sequence (CCDS) regions. Our results show Twist Custom Exome, Twist Human Comprehensive Exome, and Roche KAPA HyperExome V1 perform particularly well at capturing their target regions at 10X and 20X coverage and achieve the highest capture efficiency of CCDS regions, upon read downsampling. This was the case despite both Twist kits targeting less than 37Mb in the genome. Our analysis highlights the impact of kit target design on capture efficiency in WES, with kit target size and uniformity of coverage impacting the capture efficiency of CCDS regions. This benchmark will help researchers to make an informed decision based on their needs
The landscape of microbial associations in human cancer
No full textOncomicrobes are estimated to cause 15% of cancers worldwide. When cancer whole-genome sequencing (WGS) data are collected, the microbes present are also sequenced, allowing the investigation of potential etiological and clinical associations. Interrogating the microbial community for 8908 patients encompassing 22 cancer types from the Genomics England WGS dataset revealed that only colorectal tumors exhibited unmistakably distinct microbial communities that can reliably be used to distinguish anatomical site [positive predictive value (PPV) = 0.95]. This pattern was validated in two independent datasets. Potential clinical relevance uncovered by our analyses included accurate detection of alphapapillomaviruses [human papillomavirus (HPV)] in oral cancers, when compared with current clinical standards, and the detection of rare, highly pathogenic viruses such as human T-lymphotropic virus-1. Biomarker investigations demonstrated statistically significant associations (
P < 0.05) between a subset of anaerobic bacteria and survival in certain subtypes of sarcoma. Our results contradict previous claims that each cancer type has a distinct microbiological signature but highlight the potential value of microbial analysis for certain cancers as WGS of tumor samples becomes common in the clinic.
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A standardised saffron extract improves subjective and objective sleep quality in healthy older adults with sleep complaints: results from the Gut-Sleep-Brain Axis randomised, double-blind, placebo-controlled pilot study
No full textSleep disturbances are associated with an increased risk of neurodegenerative diseases and alterations in gut microbiota composition. Saffron (Crocus sativus) has been shown to improve sleep and modulate the gut microbiome, but its effect on sleep quality via the gut microbiota-brain axis remains largely unexplored. This randomised, placebo-controlled pilot study investigated the impact of four weeks of saffron supplementation (30 mg day −1) on sleep quality and gut microbiota in older adults (ages 55-85) with self-reported sleep complaints (N = 52). Subjective sleep quality was assessed using validated questionnaires, while objective measures were captured via an electroencephalography-based sleep tracker. Gut microbiota composition was analysed in a subgroup (N = 26). Saffron supplementation significantly improved subjective sleep quality (p = 0.02) and sleep efficiency (p = 0.04). Objective outcomes included reduced latency to persistent sleep (p = 0.003) and shorter sleep onset latency (p = 0.03). Microbiome analysis using linear discriminant analysis effect size (LEfSe) revealed significant increases in Faecalibacterium (q = 0.013), Lachnoclostridium (q = 0.045), Prevotella (q = 0.022), UBA1819 (q = 0.020) and Oscillibacter (q = 0.045), alongside a decrease in Dialister (q = 0.028). Univariate analysis further identified increases in Lachnospiraceae-UGC-001 (p = 0.020) and Roseburia (p = 0.03), with a reduction in Turicibacter (p = 0.045) in the saffron group. Correlational analyses revealed that Oscillibacter and UBA1819 were positively associated with subjective sleep efficiency (r = 0.63, p = 0.0007) and inversely associated with sleep latency (r = −0.39, p = 0.04). Alterations in in Dialister, Turicibacter and UBA1819 correlated with objective sleep quality parameters including wake duration, latency to persistent sleep and wake-after-sleep-onset. In summary, four-weeks saffron supplementation improved both subjective and objective sleep quality in older adults with sleep complaints, and modulated gut microbiota composition, particularly increasing short-chain fatty acids producing bacteria. These findings pave the way for further randomised controlled trials exploring the links between sleep quality and gut health and may help in devising new preventative strategies for age-related brain disorders
Spatial navigation deficits in early Alzheimer's disease: the role of biomarkers and APOE genotype
No full textBACKGROUND: Spatial navigation deficits are early symptoms of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for AD. This study investigated effects of APOE genotype on spatial navigation in biomarker-defined individuals with amnestic mild cognitive impairment (aMCI) and associations of AD biomarkers and atrophy of AD-related brain regions with spatial navigation.METHODS: 107 participants, cognitively normal older adults (CN, n = 48) and aMCI individuals stratified into AD aMCI (n = 28) and non-AD aMCI (n = 31) groups, underwent cognitive assessment, brain MRI, and spatial navigation assessment using the Virtual Supermarket Test with egocentric and allocentric tasks and a self-report questionnaire. Cerebrospinal fluid (CSF) biomarkers (amyloid-β1-42, phosphorylated tau181 and total tau) and amyloid PET imaging were assessed in aMCI participants.RESULTS: AD aMCI participants had the highest prevalence of APOE ε4 carriers and worst allocentric navigation. CSF levels of AD biomarkers and atrophy in AD-related brain regions were associated with worse allocentric navigation. Between-group differences in spatial navigation and associations with AD biomarkers and regional brain atrophy were not influenced by APOE genotype. Self-reported navigation ability was similar across groups and unrelated to spatial navigation performance.CONCLUSIONS: These findings suggest that allocentric navigation deficits in aMCI individuals are predominantly driven by AD pathology, independent of APOE genotype. This highlights the role of AD pathology as measured by biomarkers, rather than genetic status, as a major factor in navigational impairment in aMCI, and emphasizes the assessment of spatial navigation as a valuable tool for early detection of AD.</p
Reliability of online, remote neuropsychological assessment in people with and without subjective cognitive decline
No full textOnline, remote neuropsychological assessment paradigms may offer a cost-effective alternative to in-person assessment for people who experience subjective cognitive decline (SCD). However, it is vital to establish the psychometric properties of such paradigms. The present study (i) evaluates test-retest reliability of remote, online neuropsychological tests from the NeurOn software platform in people with and without SCD (Non-SCD) recruited from the general population; and (ii) investigates potential group differences in baseline performance and longitudinal change. Ninety-nine participants (SCD N = 44, Non-SCD N = 55) completed seven tests from the NeurOn battery, covering visual and verbal memory, working memory, attention and psychomotor speed. Sixty-nine participants (SCD N = 34, Non-SCD N = 35) repeated the assessment six (+/- one) months later. SCD was classified using the Cognitive Change Index questionnaire. Test-retest reliability of the NeurOn test outcome measures ranged from poor to good, with the strongest evidence of reliability shown for the Sustained Attention to Response Test and Picture Recognition. The SCD group was significantly older than the Non-SCD group so group differences were investigated using analysis of covariance whilst controlling for the effect of age. SCD scored significantly better than Non-SCD for Digit Span Backwards (maximum sequence length) and Picture Recognition (recall of object position) at baseline. However, these were not significant when using the Bonferroni-adjusted alpha level. There were no differences between SCD and Non-SCD in longitudinal change. The results suggest online, remote neuropsychological assessment is a promising option for assessing and monitoring SCD, however more research is needed to determine the most suitable tests in terms of reliability and sensitivity to SCD.</p
Incidence and nature of antidepressant discontinuation symptoms: a systematic review and meta-analysis
No full textImportance: the incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear.Objective: to examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants.Data Sources: the databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023.Study selection: randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included.Data extraction and synthesis : data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024.Main outcomes and measures: the primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales.Results: a total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5).Conclusions and relevance : this systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse
Neural correlates of human fear conditioning and sources of variability in 2199 individuals
No full textPavlovian fear conditioning is a fundamental process in both health and disease. We investigate its neural correlates and sources of variability using harmonized functional magnetic resonance imaging data from 2199 individuals across nine countries, including 1888 healthy individuals and 311 with anxiety-related or depressive disorders. Using mega-analysis and normative modeling, we show that fear conditioning consistently engages brain regions within the "central autonomic-interoceptive" or "salience" network. Several task variables strongly modulate activity in these regions, contributing to variability in neural responses. Additionally, brain activation patterns differ between healthy individuals and those with anxiety-related or depressive disorders, with distinct profiles characterizing specific disorders such as post-traumatic stress disorder and obsessive-compulsive disorder. While the neural correlates of fear conditioning are highly generalizable at the population level, variability arises from differences in task design and clinical status, highlighting the importance of methodological diversity in capturing fear learning mechanisms.</p
Observational cohort study exploring MediEmo smartphone application use, live birth, and in vitro fertilization treatment return rates
No full textObjective: to explore the associations between the use of the MediEmo smartphone application and in vitro fertilization (IVF) live birth and treatment return rates.Design: a 3-year observational cohort studySubjects: patients undergoing IVF were classified as users if they used the medication or emotion features of the MediEmo. Patients who did not use the two key features or declined to use the application were classified as nonusers.ExposureThe use of the MediEmo smartphone application.Main outcome measuresOutcomes of interest were the rate of live birth per fresh index cycle, live birth per complete cycle, and treatment return for a stimulated cycle of treatment within 12 months of the unsuccessful stimulated index cycle.Results: a total of 1,081 patients were eligible to use the MediEmo application, 863 were categorized as users and 218 as nonusers. MediEmo use was associated with a higher live birth rate per index cycle than nonusers (27.81% [n = 240/863] vs. 19.26% [n = 42/218], respectively, OR, 1.248; 95% CI, 1.041–1.509) and treatment return rate compared with nonusers (46.00% [n = 169/363] vs. 31.37% [n = 32/102], respectively, OR, 1.339; 95% CI, 1.092–1.656). It was not associated with the live birth rate per complete cycle.Conclusion: the observed positive association between MediEmo use and live birth and treatment return rates suggests benefits to patients and clinics. Further research and replication using a randomized controlled trial design are warranted, as is investment in the development of digital tools for use during IVF treatment
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