Predicting short- to medium-term care home admission risk in older adults: a systematic review of externally validated models.

INTRODUCTION: Predicting risk of care home admission could identify older adults for early intervention to support independent living but require external validation in a different dataset before clinical use. We systematically reviewed external validations of care home admission risk prediction models in older adults. METHODS: We searched Medline, Embase and Cochrane Library until 14 August 2023 for external validations of prediction models for care home admission risk in adults aged ≥65 years with up to 3 years of follow-up. We extracted and narratively synthesised data on study design, model characteristics, and model discrimination and calibration (accuracy of predictions). We assessed risk of bias and applicability using Prediction model Risk Of Bias Assessment Tool. RESULTS: Five studies reporting validations of nine unique models were included. Model applicability was fair but risk of bias was mostly high due to not reporting model calibration. Morbidities were used as predictors in four models, most commonly neurological or psychiatric diseases. Physical function was also included in four models. For 1-year prediction, three of the six models had acceptable discrimination (area under the receiver operating characteristic curve (AUC)/c statistic 0.70-0.79) and the remaining three had poor discrimination (AUC < 0.70). No model accounted for competing mortality risk. The only study examining model calibration (but ignoring competing mortality) concluded that it was excellent. CONCLUSIONS: The reporting of models was incomplete. Model discrimination was at best acceptable, and calibration was rarely examined (and ignored competing mortality risk when examined). There is a need to derive better models that account for competing mortality risk and report calibration as well as discrimination.

Frailty before and during austerity: A time series analysis of the English Longitudinal Study of Ageing 2002-2018.

BACKGROUND: Frailty is characterised by a reduced resilience to adversity. In this analysis we examined changes in frailty in people aged 50+ before and during a period of austere public spending in England. METHODS: Data from the English Longitudinal Study of Ageing 2002-2018 were analysed. Associations between austerity and frailty were examined using (1) Multilevel interrupted times series analysis (ITSA); and (2) Accelerated longitudinal modelling comparing frailty trajectories in people of the same age in 2002 and 2012. RESULTS: The analysis included 16,410 people (mean age 67 years, 55% women), with mean frailty index score of 0.16. Mean scores in women (0.16) where higher than in men (mean 0.14), and higher in the poorest tertile (mean 0.20) than the richest (mean 0.12). In the ITSA, frailty index scores increased more quickly during austerity than before, with the additional increase in frailty 2012-2018 being similar in magnitude to the difference in mean frailty score between people aged 65-69 and 70-74 years. Steeper increases in frailty after 2012 were experienced across the wealth-spectrum and in both sexes but were greater in the very oldest (80+). In the accelerated longitudinal analysis, frailty was lower in 2012 than 2002, but increased more rapidly in the 2012 cohort compared to the 2002 cohort; markedly so in people aged 80+. CONCLUSION: The period of austerity politics was associated with steeper increases in frailty with age compared to the pre-austerity period, consistent with previously observed increases in mortality.

Performance of models for predicting 1-year to 3-year mortality in older adults: a systematic review of externally validated models.

Mortality prediction models support identifying older adults with short life expectancy for whom clinical care might need modifications. We systematically reviewed external validations of mortality prediction models in older adults (ie, aged 65 years and older) with up to 3 years of follow-up. In March, 2023, we conducted a literature search resulting in 36 studies reporting 74 validations of 64 unique models. Model applicability was fair but validation risk of bias was mostly high, with 50 (68%) of 74 validations not reporting calibration. Morbidities (most commonly cardiovascular diseases) were used as predictors by 45 (70%) of 64 of models. For 1-year prediction, 31 (67%) of 46 models had acceptable discrimination, but only one had excellent performance. Models with more than 20 predictors were more likely to have acceptable discrimination (risk ratio [RR] vs <10 predictors 1·68, 95% CI 1·06-2·66), as were models including sex (RR 1·75, 95% CI 1·12-2·73) or predicting risk during comprehensive geriatric assessment (RR 1·86, 95% CI 1·12-3·07). Development and validation of better-performing mortality prediction models in older people are needed.

Cohort profile: The Scottish SHARE Mental Health (SHARE-MH) cohort - linkable survey, genetic and routinely collected data for mental health research.

PURPOSE: The SHARE Mental Health (SHARE-MH) cohort was established to address the paucity of clinical and genetic data available for mental health research. The cohort brings together detailed mental health questionnaire responses, routinely collected electronic health data and genetic data to provide researchers with an unprecedented linkable dataset. This combination of data sources allows researchers to track mental health longitudinally, across multiple settings. It will be of interest to researchers investigating the genetic and environmental determinants of mental health, the experiences of those interacting with healthcare services, and the overlap between self-reported and clinically derived mental health outcomes. PARTICIPANTS: The cohort consists of individuals sampled from the Scottish Health Research Register (SHARE). To register for SHARE, individuals had to be over the age of 16 years and living in Scotland. Cohort participants were recruited by email and invited to take part in an online mental health survey. When signing up for SHARE, participants also provided written consent to the use of their electronic health records and genetic data-derived from spare blood samples-for research purposes. FINDINGS TO DATE: From 5 February 2021 to 27 November 2021, 9829 individuals completed a survey of various mental health topics, capturing information on symptoms, diagnoses, impact and treatment. Survey responses have been made linkable to electronic health records and genetic data using a single patient identifier. Linked data have been used to describe the cohort in terms of their demographics, self-reported mental health, inpatient and outpatient hospitalisations and dispensed prescriptions. FUTURE PLANS: The cohort will be improved through linkage to a broader variety of routinely collected data and to increasing amounts of genetic data obtained through blood sample diversion. We see the SHARE-MH cohort being used to drive forward novel areas of mental health research and to contribute to global efforts in psychiatric genetics.

Loss-of-Function Mutations in the ALPL Gene Presenting with Adult Onset Osteoporosis and Low Serum Concentrations of Total Alkaline Phosphatase.

Hypophosphatasia (HPP) is a rare inherited disorder characterized by rickets and low circulating concentrations of total alkaline phosphatase (ALP) caused by mutations in ALPL. Severe HPP presents in childhood but milder forms can present in adulthood. The prevalence and clinical features of adult HPP are poorly defined. The aim of this study was to evaluate the prevalence and clinical significance of low serum total alkaline phosphatase (ALP) levels in a clinic-based population of adult osteoporotic patients. We searched for patients with low ALP in a cohort of 3285 patients referred to an osteoporosis clinic over a 10-year period and performed mutation screening of ALPL in those with low ALP (≤40 U/L) on two or more occasions. These individuals were matched with four clinic controls with a normal ALP. We also evaluated the prevalence of low ALP and ALPL mutations in 639 individuals from the general population from the same region. We identified 16/3285 (0.49%) clinic patients with low ALP and 14 (87.5%) had potentially pathogenic variants in ALPL. Eight of these individuals were heterozygous for mutations previously described in HPP and 2 were heterozygous for novel mutations (p.Arg301Trp and p.Tyr101X). These mutations were not found in clinic controls or in the general population. Eight patients with low ALP, including 4 with ALPL mutations, were treated with bisphosphonates for an average of 6.5 years. In these individuals, the rate of fractures during treatment was comparable to that in normal ALP clinic controls who were treated with bisphosphonates. We conclude that heterozygous loss-of-function mutations in ALPL are common in osteoporosis patients with low ALP. Further studies are required to determine how best these individuals should be treated. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions.

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates.

Arginine to Glutamine Variant in Olfactomedin Like 3 (OLFML3) Is a Candidate for Severe Goniodysgenesis and Glaucoma in the Border Collie Dog Breed.

Goniodysgenesis is a developmental abnormality of the anterior chamber of the eye. It is generally considered to be congenital in dogs (Canis lupus familiaris), and has been associated with glaucoma and blindness. Goniodysgenesis and early-onset glaucoma initially emerged in Border Collies in Australia in the late 1990s and have subsequently been found in this breed in Europe and the USA. The objective of the present study was to determine the genetic basis of goniodysgenesis in Border Collies. Clinical diagnosis was based on results of examinations by veterinary ophthalmologists of affected and unaffected dogs from eleven different countries. Genotyping using the Illumina high density canine single nucleotide variant genotyping chip was used to identify a candidate genetic region. There was a highly significant peak of association over chromosome 17, with a p-value of 2 × 10-13 Expression profiles and evolutionary conservation of candidate genes were assessed using public databases. Whole genome sequences of three dogs with glaucoma, three severely affected by goniodysgenesis and three unaffected dogs identified a missense variant in the olfactomedin like 3 (OLFML3) gene in all six affected animals. This was homozygous for the risk allele in all nine cases with glaucoma and 12 of 14 other severely affected animals. Of 67 reportedly unaffected animals, only one was homozygous for this variant (offspring of parents both with goniodysgenesis who were also homozygous for the variant). Analysis of pedigree information was consistent with an autosomal recessive mode of inheritance for severe goniodysgenesis (potentially leading to glaucoma) in this breed. The identification of a candidate genetic region and putative causative variant will aid breeders to reduce the frequency of goniodysgenesis and the risk of glaucoma in the Border Collie population.

Linked Mutations at Adjacent Nucleotides Have Shaped Human Population Differentiation and Protein Evolution.

Despite the fundamental importance of single nucleotide polymorphisms (SNPs) to human evolution, there are still large gaps in our understanding of the forces that shape their distribution across the genome. SNPs have been shown to not be distributed evenly, with directly adjacent SNPs found unusually frequently. Why this is the case is unclear. We illustrate how neighboring SNPs that cannot be explained by a single mutation event (that we term here sequential dinucleotide mutations [SDMs]) are driven by distinct processes to SNPs and multinucleotide polymorphisms (MNPs). By studying variation across populations, including a novel cohort of 1,358 Scottish genomes, we show that, SDMs are over twice as common as MNPs and like SNPs display distinct mutational spectra across populations. These biases are not only different to those observed among SNPs and MNPs but are also more divergent between human population groups. We show that the changes that make up SDMs are not independent and identify a distinct mutational profile, CA → CG → TG, that is observed an order of magnitude more often than expected from background SNP rates and the numbers of other SDMs involving the gain and deamination of CpG sites. Intriguingly particular pathways through the amino acid code appear to have been favored relative to that expected from intergenic SDM rates and the occurrences of coding SNPs, and in particular those that lead to the creation of single codon amino acids. We finally present evidence that epistatic selection has potentially disfavored sequential nonsynonymous changes in the human genome.

Incidence rates and risk factor analyses for owner reported vomiting and diarrhoea in Labrador Retrievers - findings from the Dogslife Cohort.

Dogslife collects data directly from owners of Labrador Retrievers across the UK including information regarding signs of illness irrespective of whether the signs precipitated a veterinary visit. In December 2015, the cohort comprised 6084 dogs aged up to six years and their owners had made 2687 and 2601 reports of diarrhoea and vomiting respectively. The co-occurrence of vomiting and diarrhoea with other signs was described and the frequencies and durations of the two signs were examined with reference to veterinary visitation. Age-specific illness rates were described and Cox Proportional Hazards models were used to estimate risk factors. Just 37% of diarrhoea reports were associated with a veterinary visit and the proportion was even lower for vomiting at 28%; indicating that studies of veterinary practice data miss the majority of signs of gastrointestinal upset. In terms of frequency and duration, diarrhoea typically needed to last two days before the dog would be taken to the vet but if the dog vomited at least every six hours, the owner would be more likely to take the dog to the vet after one day. The illness rates of both signs peaked when the dogs were aged between three and six months. There was also a seasonal pattern to the incidents with the lowest hazards for both in May. Diarrhoea incidents peaked in August-September each year but, while vomiting appeared to be higher in September, it peaked in February. Having another dog in the household was associated with a lower hazard for both vomiting and diarrhoea but having a cat was only associated with a reduced hazard of vomiting. In addition to the distinct seasonal patterns of reporting, there were clear differences in the geographic risks for the two signs. The hazard of diarrhoea was positively associated with human population density within Great Britain (according to home post code) whereas no significant geographical association was found with vomiting. This study is particularly relevant for dog owners because it highlights the wealth of gastrointestinal illnesses in dogs that are dealt with by owners but never seen by veterinarians. The risk factor analyses make use of owner-reported demographic information, highlighting the differences between vomiting and diarrhoea. The analyses give rise to the possibility that the presence of other pets in households may affect rates of illness and indicate new avenues for investigations of these distinct, and oft-suffered conditions.

Validity of Internet-based longitudinal study data: the elephant in the virtual room.

BACKGROUND: Internet-based data collection relies on well-designed and validated questionnaires. The theory behind designing and validating questionnaires is well described, but few practical examples of how to approach validation are available in the literature. OBJECTIVE: We aimed to validate data collected in an ongoing Internet-based longitudinal health study through direct visits to participants and recall of their health records. We demonstrate that despite extensive pre-planning, social desirability can still affect data in unexpected ways and that anticipation of poor quality data may be confounded by positive validation. METHODS: Dogslife is a large-scale, Web-based longitudinal study of canine health, in which owners of Labrador Retrievers were recruited and questioned at regular intervals about the lifestyle and health of their dogs using an Internet-based questionnaire. The Dogslife questionnaire predominantly consists of closed-answer questions. In our work, two separate validation methodologies were used: (1) direct interviews with 43 participants during visits to their households and (2) comparison of owner-entered health reports with 139 historical health records. RESULTS: Our results indicate that user-derived measures should not be regarded as a single category; instead, each measurement should be considered separately as each presents its own challenge to participants. We recommend trying to ascertain the extent of recall decay within a study and, if necessary, using this to guide data collection timepoints and analyses. Finally, we recommend that multiple methods of communication facilitate validation studies and aid cohort engagement. CONCLUSIONS: Our study highlighted how the theory underpinning online questionnaire design and validation translates into practical data issues when applied to Internet-based studies. Validation should be regarded as an extension of questionnaire design, and that validation work should commence as soon as sufficient data are available. We believe that validation is a crucial step and hope our suggested guidelines will help facilitate validation of other Internet-based cohort studies.

What can cohort studies in the dog tell us?

This paper addresses the use of cohort studies in canine medicine to date and highlights the benefits of wider use of such studies in the future. Uniquely amongst observational studies, cohort studies offer the investigator an opportunity to assess the temporal relationship between hypothesised risk factors and diseases. In human medicine cohort studies were initially used to investigate specific exposures but there has been a movement in recent years to more broadly assess the impact of complex lifestyles on morbidity and mortality. Such studies do not focus on narrow prior hypotheses but rather generate new theories about the impact of environmental and genetic risk factors on disease. Unfortunately cohort studies are expensive both in terms of initial investment and on-going costs. There is inevitably a delay between set up and the reporting of meaningful results. Expense and time constraints are likely why this study design has been used sparingly in the field of canine health studies. Despite their rather limited numbers, canine cohort studies have made a valuable contribution to the understanding of dog health, in areas such as the dynamics of infectious disease. Individual exposures such as neutering and dietary restriction have also been directly investigated. More recently, following the trend in human health, large cohort studies have been set up to assess the wider impact of dog lifestyle on their health. Such studies have the potential to develop and test hypotheses and stimulate new theories regarding the maintenance of life-long health in canine populations.

Dogslife: a web-based longitudinal study of Labrador Retriever health in the UK.

BACKGROUND: Dogslife is the first large-scale internet-based longitudinal study of canine health. The study has been designed to examine how environmental and genetic factors influence the health and development of a birth cohort of UK-based pedigree Labrador Retrievers. RESULTS: In the first 12 months of the study 1,407 Kennel Club (KC) registered eligible dogs were recruited, at a mean age of 119 days of age (SD 69 days, range 3 days - 504 days). Recruitment rates varied depending upon the study team's ability to contact owners. Where owners authorised the provision of contact details 8.4% of dogs were recruited compared to 1.3% where no direct contact was possible. The proportion of dogs recruited was higher for owners who transferred the registration of their puppy from the breeder to themselves with the KC, and for owners who were sent an e-mail or postcard requesting participation in the project. Compliance with monthly updates was highly variable. For the 280 dogs that were aged 400 days or more on the 30th June 2011, we estimated between 39% and 45% of owners were still actively involved in the project. Initial evaluation suggests that the cohort is representative of the general population of the KC registered Labrador Retrievers eligible to enrol with the project. Clinical signs of illnesses were reported in 44.3% of Labrador Retrievers registered with Dogslife (median age of first illness 138 days), although only 44.1% of these resulted in a veterinary presentation (median age 316 days). CONCLUSIONS: The web-based platform has enabled the recruitment of a representative population of KC registered Labrador Retrievers, providing the first large-scale longitudinal population-based study of dog health. The use of multiple different methods (e-mail, post and telephone) of contact with dog owners was essential to maximise recruitment and retention of the cohort.