International Perspectives of Extended Genetic Sequencing When Used as Part of Newborn Screening to Identify Cystic Fibrosis.

There is increasing interest in using extended genetic sequencing (EGS) in newborn screening (NBS) for cystic fibrosis (CF). How this is implemented will change the number of children being given an uncertain outcome of CRMS/CFSPID (cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/CF Screen Positive Inconclusive Diagnosis), probable carrier results, and the number of missed CF diagnoses. An international survey of CF health professionals was used to gather views on two approaches to EGS-specific (may reduce detection of CRMS/CFSID but miss some CF cases) versus sensitive (may increase detection of CRMS/CFSPID but avoid missing more CF cases). Health professionals acknowledged the anxiety caused to parents (and health professionals) from the uncertainty surrounding the prognosis and management of CRMS/CFSPID. However, most preferred the sensitive approach, as overall, identifying more cases of CRMS/CFSPID was viewed as less physically and psychologically damaging than a missed case of CF. The importance of early diagnosis and treatment for CF to ensure better health outcomes and reducing diagnostic odysseys for parents were highlighted. A potential benefit to identifying more children with CRMS/CFSPID included increasing knowledge to obtain a better understanding of how these children should best be managed in the future.

Stakeholder Views of the Proposed Introduction of Next Generation Sequencing into the Cystic Fibrosis Screening Protocol in England.

The project aimed to gather, analyse, and compare the views of stakeholders about the proposed UK cystic fibrosis (CF) screening protocol incorporating next generation sequencing (NGS). The study design was based on principles of Q-methodology with a willingness-to-pay exercise. Participants were recruited from 12 CF centres in the UK. The study contained twenty-eight adults who have experience with CF (parents of children with CF (n = 21), including parents of children with CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS)/CF screen positive-inconclusive diagnosis (CFSPID), an uncertain outcome (n = 3), and adults with CF (n = 4)), and nine health professionals involved in caring for children with CF. Parents and health professionals expressed a preference for a sensitive approach to NGS. This was influenced by the importance participants placed on not missing any children with CF via screening and the balance of harm between missing a case of CF compared to picking up more children with an uncertain outcome (CRMS/CFSPID). Given the preference for a sensitive approach, the need for adequate explanations about potential outcomes including uncertainty (CFSPID) at the time of screening was emphasized. More research is needed to inform definitive guidelines for managing children with an uncertain outcome following CF screening.

'We're kind of like genetic nomads': Parents' experiences of biographical disruption and uncertainty following in/conclusive results from newborn cystic fibrosis screening.

As whole genome sequencing is being considered as a tool to deliver expanded newborn screening (NBS) globally, the range of equivocal results it could produce are gaining increased attention. For cystic fibrosis (CF) screening, the use of next generation sequencing within existing UK NBS programmes would increase the number of uncertain designations returned within results, including that of Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CFSPID). However, the experiences of families already living with this designation have been under-explored. This study uses in-depth interviews to explore the perspectives of sixteen parents who received positive results from CF NBS, with varying degrees of prognostic un/certainty; parents with a child diagnosed with CF (n = 6), CF carrier status (n = 3) and those with the CFSPID designation (n = 7). The biographically disruptive nature of positive NBS results-regardless of immediate relevance to the child-dominated early experiences of positive results across all groups. For those with CF, biographical reparation involved becoming 'a CF family', underscoring biological kinship bonds and reinforcing familial identity. For those with uncertain results, biographical re-calibration was more complex. Diagnostic and prognostic uncertainty posed a barrier to entry for both the 'CF world' and the 'healthy kid' world, leading parents to attempt to minimise its role, either through rejection, or re-interpretation of their child's result. Other parents, however, experienced biographical reparation more dynamically. The concept of 'genetic nomadism' captures accounts of oscillation between the two worlds; movements that were responsive to evolving health experiences, as well as social, environmental and temporal factors. Through the concept of genetic nomadism, this paper delineates both the productive, as well as divisive, nature of uncertainty for biographical reparation in the aftermath of NBS, as well as the strategies parents use to harness it, in order to successfully navigate the world with a child with an ambiguous genetic future.

What is a 'serious' genetic condition? The perceptions of people living with genetic conditions.

Despite no consensus on the definition of 'seriousness', the concept is regularly used in policy and practice contexts to categorise conditions, determine access to genetic technologies and uses of selective pregnancy termination. Whilst attempts have been made to create taxonomies of genetic condition seriousness to inform clinical and policy decision-making, these have often relied on condition appraisals made by health and genetics professionals. The views of people with genetic conditions have been largely under-represented. This study explores the concept of seriousness through the perspectives of people with a range of 'clinically serious' conditions (fragile X conditions, spinal muscular atrophy, cystic fibrosis, haemophilia, thalassaemia). Attitudes towards suffering, quality of life (QoL) and selective pregnancy termination were elucidated from 45 in-depth qualitative interviews and 469 postal/online surveys. The majority of participants reported good health/wellbeing, and the capacity for good QoL, despite experiencing suffering with their condition. Notably, participants with later-onset conditions held more negative views of their health and QoL, and were more likely to view their condition as an illness, than those with early-onset conditions. These participants were more likely to see their condition as part of their identity. Whilst most participants supported prenatal screening, there was little support for selective termination. Moreover, social environment emerged as a critical mediator of the experience of the condition. The complex and rich insights of people living with genetic conditions might usefully be incorporated into future genetic taxonomies of 'seriousness' to ensure they more accurately reflect the lived reality of those with genetic conditions.

Development of a Performance Monitoring Instrument for Rating Explosives Search Dog Performance.

The growing body of working dog literature includes many examples of scales robustly developed to measure aspects of dog behavior. However, when comparing behavior to working dog ability, most studies rely on training organizations' own long-established ratings of performance, or simply pass/fail at selection or certification as measures of success. Working ability is multifaceted, and it is likely that different aspects of ability are differentially affected by external factors. In order to understand how specific aspects of selection, training, and operations influence a dog's working ability, numerous facets of performance should be considered. An accurate and validated method for quantifying multiple aspects of performance is therefore required. Here, we describe the first stages of formulating a meaningful performance measurement tool for two types of working search dogs. The systematic methodology used was: (1) interviews and workshops with a representative cross-section of stakeholders to produce a shortlist of behaviors integral to current operational performance of vehicle (VS) and high assurance (HAS) search dogs; (2) assessing the reliability and construct validity of the shortlisted behavioral measures (at the behavior and the individual rater level) using ratings of diverse videoed searches by experienced personnel; and (3) selecting the most essential and meaningful behaviors based on their reliability/validity and importance. The resulting performance measurement tool was composed of 12 shortlisted behaviors, most of which proved reliable and valid when assessed by a group of raters. At the individual rater level, however, there was variability between raters in the ability to use and interpret behavioral measures, in particular, more abstract behaviors such as Independence. This illustrates the importance of examining individual rater scores rather than extrapolating from group consensus (as is often done), especially when designing a tool that will ultimately be used by single raters. For ratings to be practically valuable, individual rater reliability needs to be improved, especially for behaviors deemed as essential (e.g., control and confidence). We suggest that the next steps are to investigate why individuals vary in their ratings and to undertake efforts to increase the likelihood that they reach a common conceptualization of each behavioral construct. Plausible approaches are improving the format in which behaviors are presented, e.g., by adding benchmarks and utilizing rater training.

Does Benchmarking of Rating Scales Improve Ratings of Search Performance Given by Specialist Search Dog Handlers?

Rating scales are widely used to rate working dog behavior and performance. Whilst behaviour scales have been extensively validated, instruments used to rate ability have usually been designed by training and practitioner organizations, and often little consideration has been given to how seemingly insignificant aspects of the scale design might alter the validity of the results obtained. Here we illustrate how manipulating one aspect of rating scale design, the provision of verbal benchmarks or labels (as opposed to just a numerical scale), can affect the ability of observers to distinguish between differing levels of search dog performance in an operational environment. Previous studies have found evidence for range restriction (using only part of the scale) in raters' use of the scales and variability between raters in their understanding of the traits used to measures performance. As provision of verbal benchmarks has been shown to help raters in a variety of disciplines to select appropriate scale categories (or scores), it may be predicted that inclusion of verbal benchmarks will bring raters' conceptualization of the traits closer together, increasing agreement between raters, as well as improving the ability of observers to distinguish between differing levels of search dog performance and reduce range restriction. To test the value of verbal benchmarking we compared inter-rater reliability, raters' ability to discriminate between different levels of search dog performance, and their use of the whole scale before and after being presented with benchmarked scales for the same traits. Raters scored the performance of two separate types of explosives search dog (High Assurance Search (HAS) and Vehicle Search (VS) dogs), from short (~30 s) video clips, using 11 previously validated traits. Taking each trait in turn, for the first five clips raters were asked to give a score from 1, representing the lowest amount of the trait evident to 5, representing the highest. Raters were given a list of adjective-based benchmarks (e.g., very low, low, intermediate, high, very high) and scored a further five clips for each trait. For certain traits, the reliability of scoring improved when benchmarks were provided (e.g., Motivation and Independence), indicating that their inclusion may potentially reduce ambivalence in scoring, ambiguity of meanings, and cognitive difficulty for raters. However, this effect was not universal, with the ratings of some traits remaining unchanged (e.g., Control), or even reducing in reliability (e.g., Distraction). There were also some differences between VS and HAS (e.g., Confidence reliability increased for VS raters and decreased for HAS raters). There were few improvements in the spread of scores across the range, but some indication of more favorable scoring. This was a small study of operational handlers and trainers utilizing training video footage from realistic operational environments, and there are potential cofounding effects. We discuss possible causal factors, including issues specific to raters and possible deficiencies in the chosen benchmarks, and suggest ways to further improve the effectiveness of rating scales. This study illustrates why it is vitally important to validate all aspects of rating scale design, even if they may seem inconsequential, as relatively small changes to the amount and type of information provided to raters can have both positive and negative impacts on the data obtained.

Search Dog Handlers Show Positive Bias When Scoring Their Own Dog's Performance.

Self-assessments of performance are commonly used in the human workplace, although compared to peer or supervisor ratings, they may be subject to positive biases or leniency. The use of subjective ratings scales in animal sciences is also common, although little consideration is usually given to possible rater bias. Dog handlers, work very closely and form strong relationships with their dogs and are also best placed to monitor dog performance since they often work in isolation. Previous work found ratings of search dog performance correlated well between experienced dog trainers, instructors, and scientists; but until now, there has been no investigation into ratings made by a dog's own handler. We compared handlers' subjective assessment of their own dog's search performance to scores given by other handlers and in a second study, to scores made by impartial raters. We found that handlers generally showed leniency; for example scoring their own dogs more favorably for Control (responsiveness to commands) and Strength of Indication. But the degree of bias varied with the trait being scored and between raters. Such differences may be attributable to greater desirability or importance of favorable scores for certain traits, or a lack of clarity of their precise meaning. Handlers may vary in susceptibility to bias due to differing levels of experience and the extent to which they view their dog's ability as dependent on their own. The exact causes require further investigation. We suggest working dog agencies provide rater-training to overcome leniency, improve reliability and validity, and to increase handler's motivation to provide accurate assessments. This study represents one of a series of steps to formulate robust, validated and evidence-based performance rating systems and has relevance to any situation where raters assess their own performance or others (particularly where they may have a vested interest in, or loyalty toward, the ratee).

Social and cultural influences on genetic screening programme acceptability: A mixed-methods study of the views of adults, carriers, and family members living with thalassemia in the UK.

As population-level carrier screening panels for reprogenetic information emerge globally, conditions to be included, and the timing of implementation is widely debated. Thalassemia is the only condition for which population-based prenatal carrier screening is offered in the UK. However, little is known about the views and experiences of the UK thalassemia-affected community toward this screening or other forms of genetic screening for thalassemia (newborn, preconception), despite the range of direct consequences of screening programmes for this group. Using a mixed-methods integrative analysis (qualitative interviews n = 20 and quantitative survey n = 80), this study outlines the experiences and attitudes of adults with thalassemia, their family members, and screen-identified thalassemia carriers toward preconception, prenatal, and newborn screening for thalassemia. The majority of participants described thalassemia as a burdensome condition with a range of negative impacts, which contributed to their strong support for screening in all its potential formats. However, the data also highlight the challenges of each screening mode for this group, reflected in the high level of value conflict in participants' accounts and decisions. Cultural, social, and (to a lesser extent) religious factors were found to mitigate against the advantages of early screens, particularly within faith communities. Social stigma emerged as key to this process, informing the way that thalassemia severity was not only perceived, but also experienced by affected adults, which ultimately influenced screening uptake and outcomes. These findings suggest that cultural and social sensitivity is as important as the mode of screening delivery itself, if the iatrogenic and unintended harms of screening-particularly the social/psychological burden of value conflict-are to be adequately addressed and minimized.

Factors associated with the presence and prevalence of contagious ovine digital dermatitis: A 2013 study of 1136 random English sheep flocks.

In 2013, a questionnaire was used to gather data on risks for introduction, and factors associated with prevalence, of contagious ovine digital dermatitis (CODD). There were 1136 (28.4%) usable responses from 4000 randomly selected sheep farmers in England. CODD was present in 58% (662) of flocks, with a reported prevalence of CODD lesions of 2.3%. The geometric mean period prevalence of all lameness was 4.2% and 2.8% in CODD positive and negative flocks respectively. Factors associated with a greater risk of presence of CODD were purchasing replacement ewes, not always checking the feet of sheep before purchase, not isolating purchased sheep, foot bathing returning ewes, foot trimming the flock more than twice in the year all compared with not doing these activities and increasing log10 flock size. Farmers who vaccinated sheep with Footvax™ were less likely to report presence of CODD. Factors associated with increasing prevalence of CODD lesions were not always checking the feet of purchased sheep, flocks that mixed with other flocks and sheep that left the farm for summer grazing and later returned. In addition, flocks where farmers followed the current recommended managements for control of footrot, had a lower prevalence of CODD whilst those who used foot bathing and where feet bled during routine foot trimming had a higher prevalence of CODD. The prevalence of CODD decreased with each log10 increase in flock size. We conclude that CODD is an infectious cause of lameness in sheep of increasing importance in GB. Introduction is linked to poor biosecurity with one likely source of the pathogen being introduction of or mixing with infected sheep. As with footrot, prevalence of CODD was lower in flocks where farmers focused on individual treatment to manage lameness and avoided foot bathing and trimming feet. We conclude that most of the currently recommended biosecurity and treatment approaches to control footrot in GB are also effective for control of CODD.

Long-term and trans-generational effects of neonatal experience on sheep behaviour.

Early life experiences can have profound long-term, and sometimes transgenerational, effects on individual phenotypes. However, there is a relative paucity of knowledge about effects on pain sensitivity, even though these may impact on an individual's health and welfare, particularly in farm animals exposed to painful husbandry procedures. Here, we tested in sheep whether neonatal painful and non-painful challenges can alter pain sensitivity in adult life, and also in the next generation. Ewes exposed to tail-docking or a simulated mild infection (lipopolysaccharide (LPS)) on days 3­4 of life showed higher levels of pain-related behaviour when giving birth as adults compared with control animals. LPS-treated ewes also gave birth to lambs who showed decreased pain sensitivity in standardized tests during days 2­3 of life. Our results demonstrate long-term and trans-generational effects of neonatal experience on pain responses in a commercially important species and suggest that variations in early life management can have important implications for animal health and welfare.

Do psychological and physiological stressors alter the acute pain response to castration and tail docking in lambs?

OBJECTIVE: To investigate whether events that may be stressful to young lambs, including simulated infection or social isolation, modulate pain experienced by lambs following castration and tail docking (C/D). STUDY DESIGN: Randomised, controlled, prospective study. ANIMALS: Fifty male lambs born to 46 second-parity Mule ewes. METHODS: Lambs were allocated randomly to one of four groups, experiencing either a potential stressor or handling on day 2 after birth, followed by C/D or handling only on day 3. Quantitative sensory testing (QST) data [mechanical nociceptive thresholds (MNT), Semmes Weinstein filaments (SW), response to cold] and serum cortisol concentration were measured at time points after application of treatments to lambs on days 2 and 3 after birth. The treatment groups were LPS, injection of bacterial lipopolysaccharide IV on day 2, C/D on day 3; ISOL, isolation from the dam for 10 minutes on day 2, C/D on day 3; CAST, handling only on day 2, C/D on day 3; CONT, handled only on days 2 and 3. RESULTS: Castration and tail docking caused transient hypoalgesia as measured by MNT and SW. Simulated infection and isolation caused hyperalgesia 3 hours after application, indicated by a reduction in MNT, however they did not alter the pain response to C/D compared to lambs in the CAST group. Injection of LPS and C/D caused increased serum cortisol concentration. The magnitude of the cortisol response to C/D was not altered by prior exposure to either LPS or isolation. CONCLUSIONS AND CLINICAL RELEVANCE: LPS and isolation did not modulate the response to C/D but did cause hyperalgesia. This highlights the importance of flock health management and husbandry techniques to reduce the incidence of either systemic infection or psychological stressors in young lambs.