Development of Novel, Value-Based, Digital Endpoints for Clinical Trials: A Structured Approach Toward Fit-for-Purpose Validation.

Novel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding the validation process of these new measurements. In this paper, we propose a pragmatic approach toward selection and fit-for-purpose validation of digital endpoints. Measurements should be value-based, meaning the measurements should directly measure or be associated with meaningful outcomes for patients. Devices should be assessed regarding technological validity. Most importantly, a rigorous clinical validation process should appraise the tolerability, difference between patients and controls, repeatability, detection of clinical events, and correlation with traditional endpoints. When technically and clinically fit-for-purpose, case building in interventional clinical trials starts to generate evidence regarding the response to new or existing health-care interventions. This process may lead to the digital endpoint replacing traditional endpoints, such as clinical rating scales or questionnaires in clinical trials. We recommend initiating more data-sharing collaborations to prevent unnecessary duplication of research and integration of value-based measurements in clinical care to enhance acceptance by health-care professionals. Finally, we invite researchers and regulators to adopt this approach to ensure a timely implementation of digital measurements and value-based thinking in clinical trial design and health care. SIGNIFICANCE STATEMENT: Novel digital endpoints are often cited as promising for the clinical trial of the future. However, clear validation guidelines are lacking in the literature. This paper contains pragmatic criteria for the selection, technical validation, and clinical validation of novel digital endpoints and provides recommendations for future work and collaboration.

Individualised automated lameness detection in dairy cows and the impact of historical window length on algorithm performance.

Lameness is an important economic problem in the dairy sector, resulting in production loss and reduced welfare of dairy cows. Given the modern-day expansion of dairy herds, a tool to automatically detect lameness in real-time can therefore create added value for the farmer. The challenge in developing camera-based tools is that one system has to work for all the animals on the farm despite each animal having its own individual lameness response. Individualising these systems based on animal-level historical data is a way to achieve accurate monitoring on farm scale. The goal of this study is to optimise a lameness monitoring algorithm based on back posture values derived from a camera for individual cows by tuning the deviation thresholds and the quantity of the historical data being used. Back posture values from a sample of 209 Holstein Friesian cows in a large herd of over 2000 cows were collected during 15 months on a commercial dairy farm in Sweden. A historical data set of back posture values was generated for each cow to calculate an individual healthy reference per cow. For a gold standard reference, manual scoring of lameness based on the Sprecher scale was carried out weekly by a single skilled observer during the final 6 weeks of data collection. Using an individual threshold, deviations from the healthy reference were identified with a specificity of 82.3%, a sensitivity of 79%, an accuracy of 82%, and a precision of 36.1% when the length of the healthy reference window was not limited. When the length of the healthy reference window was varied between 30 and 250 days, it was observed that algorithm performance was maximised with a reference window of 200 days. This paper presents a high-performing lameness detection system and demonstrates the importance of the historical window length for healthy reference calculation in order to ensure the use of meaningful historical data in deviation detection algorithms.

Effect of a photoperiodic green light programme during incubation on embryo development and hatch process.

This study was conducted to evaluate the effect of a 12-h light, 12-h dark (12L : 12D) photoperiod of green light during day 1 to day 18 of incubation time, on embryo growth, hormone concentration and the hatch process. In the test group, monochromatic light was provided by a total of 204 green light-emitting diodes (522 nm) mounted in a frame which was placed above the top tray of eggs to give even spread of illumination. No light-dark cycle was used in the control group. Four batches of eggs (n=300/group per batch) from fertile Ross 308 broiler breeders were used in this experiment. The beak length and crown-rump length of embryos incubated under green light were significantly longer than that of control embryos at day 10 and day 12, respectively (P<0.01). Furthermore, green light-exposed embryos had a longer third toe length compared with control embryos at day 10, day 14 and day 17 (P=0.02). At group level (n=4 batches), light stimulation had no effect on chick weight and quality at take-off, the initiation of hatch and hatch window. However, the individual hatching time of the light exposure focal chicks (n=33) was 3.4 h earlier (P=0.49) than the control focal chicks (n=36) probably due to the change in melatonin rhythm of the light group. The results of this study indicate that green light accelerates embryo development and alters hatch-related hormones (thyroid and corticosterone), which may result in earlier hatching.

Higher levels of CO2 during late incubation alter the hatch time of chicken embryos.

1. It has been reported that the increasing CO2 tension triggers the embryo to pip the air cell and emerge from the egg. However, the mechanism by which higher CO2 concentrations during the last few days of incubation affect chick physiology and the hatching process is unclear. This study investigated the effect of CO2 concentrations up to 1% during pipping, on the onset and length of the hatch window (HW) and chick quality. 2. Four batches of Ross 308 broiler eggs (600 eggs per batch) were incubated in two small-scale custom-built incubators (Petersime NV). During the final 3 d of incubation, control eggs were exposed to a lower CO2 concentration (0.3%), while the test eggs experienced a higher CO2 concentration programme (peak of 1%). 3. There were no significant differences in blood values, organ weight and body weight. There was also no difference in hatchability between control and test groups. However, a small increase in the chick weight and the percentage of first class chicks was found in the test groups. Furthermore, plasma corticosterone profiles during hatching were altered in embryos exposed to higher CO2; however, they dropped to normal levels at d 21 of incubation. Importantly, the hatching process was delayed and synchronised in the test group, resulting in a narrowed HW which was 2.7 h shorter and 5.3 h later than the control group. 4. These results showed that exposing chicks to 1% CO2 concentration during pipping did not have negative impacts on physiological status of newly hatched chicks. In addition, it may have a significant impact on the physiological mechanisms controlling hatching and have benefits for the health and welfare of chickens by reducing the waiting time after hatching.

An insight into the heat and mass transfer mechanisms of eggshells hatching broiler chicks and its effects to the hatcher environment.

Thermodynamic study of incubated eggs is an important component in the optimisation of incubation processes. However, research on the interaction of heat and moisture transfer mechanisms in eggs is rather limited and does not focus on the hatching stage of incubation. During hatch, both the recently hatched chick and the broken eggshell add extra heat and moisture contents to the hatcher environment. In this study, we have proposed a novel way to estimate thermodynamically the amount of water evaporated from a broken eggshell during hatch. The hypothesis of this study considers that previously reported drops in eggshell temperature during hatching of chicks is the result remaining water content evaporating from the eggshell, released on the inner membrane by the recently hatched wet chick, just before hatch. To reproduce this process, water was sprayed on eggshells to mimic the water-fluid from the wet body of a chick. For each sample of eggshell, the shell geometry and weight, surface area and eggshell temperature were measured. Water evaporation losses and convection coefficient were calculated using a novel model approach considering the simultaneous heat and mass transfer profiles in an eggshell. The calculated average convective coefficient was 23.9 ± 7.5 W/m(2) °C, similar to previously reported coefficients in literature as a function of 0.5-1m/s air speed range. Comparison between measured and calculated values for the water evaporation showed 68% probability accuracy, associated to the use of an experimentally derived single heat transfer coefficient. The results support our proposed modelling approach of heat and mass transfer mechanisms. Furthermore, by estimating the amount of evaporated water in an eggshell post-hatch, air humidity levels inside the hatcher can be optimised to ensure wet chicks dry properly while not dehydrating early hatching chicks.

Physiological status of broiler chicks at pulling time and the relationship to duration of holding period.

Newly hatched chicks may be held longer than 48 h and experience long periods of fasting in commercial hatcheries. Limited information is known about the physiological status of chicks in such situations, due to the difficulty of precisely recording time of hatch. This study investigated the effect of the time from hatch to pulling (holding period) on physiological measures/parameters in 109 broiler chicks. Fertile Ross 308 eggs were incubated in a custom built small-scale incubator. The individual hatching time of each focal chick was determined using eggshell temperature monitoring. At 'pulling' (512 h of incubation time), the quality of focal chicks was assessed using the chick scoring method and physiological parameters were measured including BW, organ (heart, liver and stomach) weights, blood values and plasma corticosterone level. The time from hatch to pulling varied from 7.58 to 44.97 h. Egg weight at setting was significantly correlated with chick BW and weight of organs at pulling, but had no effect on chick quality, blood values and plasma corticosterone. Relative BW at pulling was negatively associated with the duration of holding period (P=0.002). However, there was a positive correlation between relative stomach weight and the duration of the holding period (P<0.001). As the holding period duration increased, there was a trend that blood partial pressure of oxygen, haematocrit and haemoglobin also increased, and blood partial pressure of carbon dioxide, total carbon dioxide and bicarbonate decreased (P<0.05). A wide range of plasma corticosterone was observed from chicks that had experienced different durations of holding period. We conclude that shortening the hatch window and minimising the number of chicks that experience a long holding period before pulling may improve chick quality and physiological status, which may be due to unfavourable environmental conditions that include feed and water deprivation.

Effect of species-specific sound stimulation on the development and hatching of broiler chicks.

1. Previous research has reported that chicken embryos develop a functionary auditory system during incubation and that prenatal sound may play an important role in embryo development and alter the hatch time. In this study the effects of prenatal auditory stimulation on hatch process, hatch performance, the development of embryo and blood parameters were investigated. 2. Four batches of Ross 308 broiler breeder eggs were incubated either in control or in sound-stimulated groups. The sound-stimulated embryos were exposed to a discontinuous sound of species-specific calls by means of a speaker at 72 dB for 16 h a day: maternal calls from d 10 to d 19 of incubation time and embryo/chick calls from d 19 until hatching. The species-specific sound was excluded from the control group. 3. The onset of hatch was delayed in the sound-stimulated group compared to the controls. This was also supported by comparison of the exact hatching time of individual focal chicks within the two groups. However, the sound-stimulated embryos had a lower hatchability than the control group, mainly due to significantly increased numbers of late deaths. 4. The embryos exhibited a similar growth pattern between the sound-stimulated group and the control group. Although sound exposure decreased body weight at d 16, no consistent effect of sound on body weight at incubation stage was observed. Species-specific sound stimulation also had no impact on chick quality, blood values and plasma corticosterone concentrations during hatch.

An evaluation of cardiorespiratory and movement features with respect to sleep-stage classification.

Polysomnography (PSG) is considered the gold standard to assess sleep accurately, but it can be expensive, time-consuming, and uncomfortable, specifically in long-term sleep studies. Actigraphy, on the other hand, is both cheap and userfriendly, but depending on the application lacks detail and accuracy. Our aim was to evaluate cardiorespiratory and movement signals in discriminating between wake, rapid-eye-movement (REM), light (N1N2), and deep (N3) sleep. The dataset comprised 85 nights of PSG from a healthy population. Starting from a total of 750 characteristic variables (features), problem-specific subsets of 40 features were forwardly selected using the combination of a wrapper method (Cohen's kappa statistic on radial basis function (RBF)-kernel support vector machine (SVM) classifier) and filter method (minimum redundancy maximum relevance criterion on mutual information). Final classification was performed using an RBF-kernel SVM. Non-subject-specific wake versus sleep classification resulted in a Cohen's kappa value of 0.695, while REM versus NREM resulted in 0.558 and N3 versus N1N2 in 0.553. The broad pool of initial features gave insight in which features discriminated best between the different classes. The classification results demonstrate the possibility of making long-term sleep monitoring more widely available.

Sleep misperception, EEG characteristics and autonomic nervous system activity in primary insomnia: a retrospective study on polysomnographic data.

Misperception of Sleep Onset Latency, often found in Primary Insomnia, has been cited to be influenced by hyperarousal, reflected in EEG- and ECG-related indices. The aim of this retrospective study was to examine the association between Central Nervous System (i.e. EEG) and Autonomic Nervous System activity in the Sleep Onset Period and the first NREM sleep cycle in Primary Insomnia (n=17) and healthy controls (n=11). Furthermore, the study examined the influence of elevated EEG and Autonomic Nervous System activity on Stage2 sleep-protective mechanisms (K-complexes and sleep spindles). Confirming previous findings, the Primary Insomnia-group overestimated Sleep Onset Latency and this overestimation was correlated with elevated EEG activity. A higher amount of beta EEG activity during the Sleep Onset Period was correlated with the appearance of K-complexes immediately followed by a sleep spindle in the Primary Insomnia-group. This can be interpreted as an extra attempt to protect sleep continuity or as a failure of the sleep-protective role of the K-complex by fast EEG frequencies following within one second. The strong association found between K-alpha (K-complex within one second followed by 8-12 Hz EEG activity) in Stage2 sleep and a lower parasympathetic Autonomic Nervous System dominance (less high frequency HR) in Slow-wave sleep, further assumes a state of hyperarousal continuing through sleep in Primary Insomnia.

Effect of transportation duration of 1-day-old chicks on postplacement production performances and pododermatitis of broilers up to slaughter age.

This experiment studied the effect of transportation duration of 1-d-old chicks on dehydration, mortality, production performance, and pododermatitis during the growout period. Eggs from the same breeder flock (Ross PM3) were collected at 35, 45, and 56 wk of age, for 3 successive identical experiments. In each experiment, newly hatched chicks received 1 of 3 transportation duration treatments from the hatchery before placement in the on-site rearing facility: no transportation corresponding to direct placement in less than 5 min (T00), or 4 (T04) or 10 h (T10) of transportation. The chicks were housed in 35-m(2) pens (650 birds each) and reared until 35 d old. Hematocrit and chick BW were measured on sample chicks before and after transportation. During the growout period, bird weight, feed uptake, and feed conversion ratio were measured weekly until slaughter. Transportation duration affected BW; T00 groups had a significantly higher BW than T04 and T10 transported birds but this effect lasted only until d 21. No clear effect on hematocrit, feed uptake, feed conversion ratio, or mortality was observed for birds transported up to 10 h. The decrease in weight in T10 birds was associated with less severe pododermatitis. Increasing age of the breeder flock was correlated with reduced egg fertility and hatchability, and also with higher quality and BW of hatched chicks. Chicks from older breeders also exhibited reduced mortality during the growout period.

Embryonic development and the physiological factors that coordinate hatching in domestic chickens.

Embryonic growth and development is influenced by both endogenous and exogenous factors. The purpose of this review is to discuss the critical stages of chick embryonic development in relation to functional maturation of numerous organ systems, the acquisition of thermoregulation, and the hatching process. In addition, the mechanism of hatching, including sound synchronization and hormonal and environmental stimulation, will be discussed. Finally, the importance of effective hatching synchronization mechanisms will also be highlighted.

Monitoring the hatch time of individual chicken embryos.

This study investigated variations in eggshell temperature (T(egg)) during the hatching process of broiler eggs. Temperature sensors monitored embryo temperature by registering T(egg) every minute. Measurements carried out on a sample of 40 focal eggs revealed temperature drops between 2 to 6°C during the last 3 d of incubation. Video cameras recorded the hatching process and served as the gold standard reference for manually labeling the hatch times of chicks. Comparison between T(egg) drops and the hatch time of individuals revealed a time synchronization with 99% correlation coefficient and an absolute average time difference up to 25 min. Our findings suggest that attaching temperature sensors to eggshells is a precise tool for monitoring the hatch time of individual chicks. Individual hatch monitoring registers the biological age of chicks and facilitates an accurate and reliable means to count hatching results and manage the hatch window.

Biomechanics-based active control of bedding support properties and its influence on sleep.

Proper body support plays an import role in the recuperation of our body during sleep. Therefore, this study uses an automatically adapting bedding system that optimises spinal alignment throughout the night by altering the stiffness of eight comfort zones. The aim is to investigate the influence of such a dynamic sleep environment on objective and subjective sleep parameters. The bedding system contains 165 sensors that measure mattress indentation. It also includes eight actuators that control the comfort zones. Based on the measured mattress indentation, body movements and posture changes are detected. Control of spinal alignment is established by fitting personalized human models in the measured indentation. A total of 11 normal sleepers participated in this study. Sleep experiments were performed in a sleep laboratory where subjects slept three nights: a first night for adaptation, a reference night and an active support night (in counterbalanced order). Polysomnographic measurements were recorded during the nights, combined with questionnaires aiming at assessing subjective information. Subjective information on sleep quality, daytime quality and perceived number of awakenings shows significant improvements during the active support (ACS) night. Objective results showed a trend towards increased slow wave sleep. On the other hand, it was noticed that % N1-sleep was significantly increased during ACS night, while % N2-sleep was significantly decreased. No prolonged N1 periods were found during or immediately after steering.

The role of presleep negative emotion in sleep physiology.

Although daytime emotional stressful events are often presumed to cause sleep disturbances, the few studies of stressful life events on sleep physiology have resulted in various and contradictory findings. As research has focused in particular on stress in itself, the present study is the first to investigate the effect using polysomnography (PSG). Results indicate a significant increase in sleep fragmentation, as expressed by decreased sleep efficiency, total sleep time, percentage of rapid eye movement (REM) sleep, and an increased wake after sleep onset latency, total time awake, latency to SWS, number of awakenings and number of awakenings from REM sleep. The results demonstrate that negative emotion correlates with enhanced sleep fragmentation helping us to understand why sleep patterns change and how sleep disturbances may develop.

Cough sound description in relation to respiratory diseases in dairy calves.

Cough can be a biomarker in case of respiratory diseases. By monitoring and analyzing cough sounds through automatic devices, the farmer can obtain an early warning about a developing outbreak of respiratory infections. Cough sounds can be characterized by particular acoustic features (amplitude, frequency and duration) that are obtained by sound recording, labeling and analytic procedures. Based on these features, it might be possible to develop an automated cough recognition system. The aim of the study described in this paper is to investigate whether it is possible to discriminate cough sounds from other frequently occurring sounds in youngstock stables. Nasal swabs and blood were taken to identify the microbiological agents responsible for the respiratory problems. The collected cough sounds were compared to metal rack sounds, which are very common sounds in cattle farming, to identify acoustic differences between them. Results show that the length of cough sounds was significantly different from metal rack sounds (0.34 versus 0.37 s, P<0.05). Also, the analysis of amplitude and fundamental frequency showed significant differences between both types of sounds (resp. 0.21 and 0.18; 1326 and 3868 HZ). This indicates that it is possible discriminate cough sounds from other sounds and that cough sound can be used as a non-invasively diagnostic tool for respiratory diseases in youngstock groups.