Integrating decision modeling and machine learning to inform treatment stratification.

There is increasing interest in moving away from "one size fits all (OSFA)" approaches toward stratifying treatment decisions. Understanding how expected effectiveness and cost-effectiveness varies with patient covariates is a key aspect of stratified decision making. Recently proposed machine learning (ML) methods can learn heterogeneity in outcomes without pre-specifying subgroups or functional forms, enabling the construction of decision rules ('policies') that map individual covariates into a treatment decision. However, these methods do not yet integrate ML estimates into a decision modeling framework in order to reflect long-term policy-relevant outcomes and synthesize information from multiple sources. In this paper, we propose a method to integrate ML and decision modeling, when individual patient data is available to estimate treatment-specific survival time. We also propose a novel implementation of policy tree algorithms to define subgroups using decision model output. We demonstrate these methods using the SPRINT (Systolic Blood Pressure Intervention Trial), comparing outcomes for "standard" and "intensive" blood pressure targets. We find that including ML into a decision model can impact the estimate of incremental net health benefit (INHB) for OSFA policies. We also find evidence that stratifying treatment using subgroups defined by a tree-based algorithm can increase the estimates of the INHB.

Cost-effectiveness of 5 fraction and partial breast radiotherapy for early breast cancer in the UK: model-based multi-trial analysis.

PURPOSE: We estimated the cost-effectiveness of 4 radiotherapy modalities to treat early breast cancer in the UK. In a subgroup of patients eligible for all modalities, we compared whole-breast (WB) and partial breast (PB) radiotherapy delivered in either 15 (WB15F, PB15F) or 5 fractions (WB5F, PB5F). In a subgroup ineligible for PB radiotherapy, we compared WB15F to WB5F. METHODS: We developed a Markov cohort model to simulate lifetime healthcare costs and quality-adjusted life years (QALYs) for each modality. This was informed by the clinical analysis of two non-inferiority trials (FAST Forward and IMPORT LOW) and supplemented with external literature. The primary analysis assumed that radiotherapy modality influences health only through its impact on locoregional recurrence and radiotherapy-related adverse events. RESULTS: In the primary analysis, PB5F had the least cost and greatest expected QALYs. WB5F had the least cost and the greatest expected QALYs in those only eligible for WB radiotherapy. Applying a cost-effectiveness threshold of £15,000/QALY, there was a 62% chance that PB5F was the cost-effective alternative in the PB eligible group, and there was a 100% chance that WB5F was cost-effective in the subgroup ineligible for PB radiotherapy. CONCLUSIONS: Hypofractionation to 5 fractions and partial breast radiotherapy modalities offer potentially important benefits to the UK health system.

How Uncertainty Matters Under Risk Neutrality.

It is typical in cost-effectiveness analysis to invoke a normative decision-making framework that assumes, as a starting point, that "a quality-adjusted life-year (QALY) is a QALY is a QALY." The implication of this assumption is that the decision maker is risk neutral and that expected values could be considered sufficiently informative for a given "approve or reject" decision. Nevertheless, it seems intuitive that less uncertainty should be desirable and this has led some to incorporate "real" risk aversion (RA) into cost-effectiveness analysis. We illustrate in this article that RA is not always necessary to justify choosing more over less certain options. We show that for a risk neutral decision maker, greater uncertainty can make the approval of technology less likely in the presence of (1) model nonlinearities, (2) nonlinear opportunity costs, and (3) irreversible costs. We call these cases of "apparent" RA. Incorporating explicit risk preferences into decision making can be challenging; nevertheless, as we show here, it is not necessary to justify caring about uncertainty in approval decisions.

Cyber-Security Threats and Side-Channel Attacks for Digital Agriculture.

The invention of smart low-power devices and ubiquitous Internet connectivity have facilitated the shift of many labour-intensive jobs into the digital domain. The shortage of skilled workforce and the growing food demand have led the agriculture sector to adapt to the digital transformation. Smart sensors and systems are used to monitor crops, plants, the environment, water, soil moisture, and diseases. The transformation to digital agriculture would improve the quality and quantity of food for the ever-increasing human population. This paper discusses the security threats and vulnerabilities to digital agriculture, which are overlooked in other published articles. It also provides a comprehensive review of the side-channel attacks (SCA) specific to digital agriculture, which have not been explored previously. The paper also discusses the open research challenges and future directions.

Best Practices: Imaging Strategies for Reduced-Dose Chest CT in the Management of Cystic Fibrosis-Related Lung Disease.

OBJECTIVE. Cystic fibrosis (CF) is a multisystemic life-limiting disorder. The leading cause of morbidity in CF is chronic pulmonary disease. Chest CT is the reference standard for detection of bronchiectasis. Cumulative ionizing radiation limits the use of CT, particularly as treatments improve and life expectancy increases. The purpose of this article is to summarize the evidence on low-dose chest CT and its effect on image quality to determine best practices for imaging in CF. CONCLUSION. Low-dose chest CT is technically feasible, reduces dose, and renders satisfactory image quality. There are few comparison studies of low-dose chest CT and standard chest CT in CF; however, evidence suggests equivalent diagnostic capability. Low-dose chest CT with iterative reconstructive algorithms appears superior to chest radiography and equivalent to standard CT and has potential for early detection of bronchiectasis and infective exacerbations, because clinically significant abnormalities can develop in patients who do not have symptoms. Infection and inflammation remain the primary causes of morbidity requiring early intervention. Research gaps include the benefits of replacing chest radiography with low-dose chest CT in terms of improved diagnostic yield, clinical decision making, and patient outcomes. Longitudinal clinical studies comparing CT with MRI for the monitoring of CF lung disease may better establish the complementary strengths of these imaging modalities.

Computing the Expected Value of Sample Information Efficiently: Practical Guidance and Recommendations for Four Model-Based Methods.

Value of information (VOI) analyses can help policy makers make informed decisions about whether to conduct and how to design future studies. Historically a computationally expensive method to compute the expected value of sample information (EVSI) restricted the use of VOI to simple decision models and study designs. Recently, 4 EVSI approximation methods have made such analyses more feasible and accessible. Members of the Collaborative Network for Value of Information (ConVOI) compared the inputs, the analyst's expertise and skills, and the software required for the 4 recently developed EVSI approximation methods. Our report provides practical guidance and recommendations to help inform the choice between the 4 efficient EVSI estimation methods. More specifically, this report provides: (1) a step-by-step guide to the methods' use, (2) the expertise and skills required to implement the methods, and (3) method recommendations based on the features of decision-analytic problems.

Rapid Assessment of the Need for Evidence: Applying the Principles of Value of Information to Research Prioritisation.

We propose a short-cut heuristic approach to rapidly estimate value of information (VOI) using information commonly reported in a research funding application to make a case for the need for further evaluative research. We develop a "Rapid VOI" approach, which focuses on uncertainty in the primary outcome of clinical effectiveness and uses this to explore the health consequences of decision uncertainty. We develop a freely accessible online tool, Rapid Assessment of the Need for Evidence (RANE), to allow for the efficient computation of the value of research. As a case study, the method was applied to a proposal for research on shoulder pain rehabilitation. The analysis was included as part of a successful application for research funding to the UK National Institute for Health and Care Research. Our approach enables research funders and applicants to rapidly estimate the value of proposed research. Rapid VOI relies on information that is readily available and reported in research funding applications. Rapid VOI supports research prioritisation and commissioning decisions where there is insufficient time and resources available to develop and validate complex decision-analytic models. The method provides a practical means for implementing VOI in practice, thus providing a starting point for deliberation and contributing to the transparency and accountability of research prioritisation decisions.

Constructing Relative Effect Priors for Research Prioritization and Trial Design: A Meta-epidemiological Analysis.

BACKGROUND: Bayesian methods have potential for efficient design of randomized clinical trials (RCTs) by incorporating existing evidence. Furthermore, value of information (VOI) methods estimate the value of reducing decision uncertainty, aiding transparent research prioritization. These methods require a prior distribution describing current uncertainty in key parameters, such as relative treatment effect (RTE). However, at the time of designing and commissioning research, there may be no data to base the prior on. The aim of this article is to present methods to construct priors for RTEs based on a collection of previous RCTs. METHODS: We developed 2 Bayesian hierarchical models that captured variability in RTE between studies within disease area accounting for study characteristics. We illustrate the methods using a data set of 743 published RCTs across 9 disease areas to obtain predictive distributions for RTEs for a range of disease areas. We illustrate how the priors from such an analysis can be used in a VOI analysis for an RCT in bladder cancer and compare the results with those using an uninformative prior. RESULTS: For most disease areas, the predicted RTE favored new interventions over comparators. The predicted effects and uncertainty differed across the 9 disease areas. VOI analysis showed that the expected value of research is much lower with our empirically derived prior compared with an uninformative prior. CONCLUSIONS: This study demonstrates a novel approach to generating informative priors that can be used to aid research prioritization and trial design. The methods can also be used to combine RCT evidence with expert opinion. Further work is needed to create a rich database of RCT evidence that can be used to form off-the-shelf priors. HIGHLIGHTS: Bayesian methods have potential to aid the efficient design of randomized clinical trials (RCTs) by incorporating existing evidence. Value-of-information (VOI) methods can be used to aid research prioritization by calculating the value of current decision uncertainty.These methods require a distribution describing current uncertainty in key parameters, that is, "prior distributions."This article demonstrates a methodology to estimate prior distributions for relative treatment effects (odds and hazard ratios) estimated from a collection of previous RCTs.These results may be combined with expert elicitation to facilitate 1) value-of-information methods to prioritize research or 2) Bayesian methods for research design.

Electric scooter-related triple cervical artery dissection.

A 34-year-old female presented to the emergency department with neck pain, dysphonia and dysphagia ten days after a fall from an electric scooter. Subsequent computed tomography of the neck revealed bilateral vertebral artery and unilateral internal carotid artery non-occlusive dissections, which were managed with antiplatelet therapy. This case describes mechanisms of injury, clinical presentation, imaging appearances, and subsequent management of cervical artery dissection.

Imaging of groin pain in athletes: patterns of injury at MRI and gender differences therein.

AIM: The purpose of our study was to review a large cohort of athletes of all levels presenting with groin pain who underwent investigation with MRI and to determine what the commonest patterns of injury were. We aimed to explore whether particular findings were commonly found in association and whether measurable gender differences exist in the incidence of specific injuries. MATERIALS AND METHODS: Imaging records were reviewed to identify MRI studies of the pelvis performed for the investigation of groin pain in patients who were active in sports/athletic pursuits. Findings were classified and recorded as follows: injury to the common rectus abdominis/adductor longus origin, injury to the short adductor muscles, pubic bone oedema, pubic symphysis degenerative changes, hip joint injury and 'other'. The prevalence of specific injuries in female athletes compared to males was analysed using relative risk ratios. RESULTS: A total of 470 athletes underwent MRI for the investigation of groin pain during the study period. Forty-six were female, and 424 were male. Female athletes were significantly less likely to have rectus abdominis-adductor longus (RR = 0.31, p = .017), short adductor (RR = 0.14, p = .005) or hip (RR = 0.41, p = .003) injuries. Pubic bone degenerative changes were much more common in female athletes (RR = 7.37, p = .002). CONCLUSION: Significant gender differences exist in the frequency with which specific injuries are observed. Female athletes are also significantly underrepresented; this is likely a multifactorial phenomenon; however, the possibility of unconscious referrer bias must be considered.

One versus three weeks hypofractionated whole breast radiotherapy for early breast cancer treatment: the FAST-Forward phase III RCT.

Background: FAST-Forward aimed to identify a 5-fraction schedule of adjuvant radiotherapy delivered in 1 week that was non-inferior in terms of local cancer control and as safe as the standard 15-fraction regimen after primary surgery for early breast cancer. Published acute toxicity and 5-year results are presented here with other aspects of the trial. Design: Multicentre phase III non-inferiority trial. Patients with invasive carcinoma of the breast (pT1-3pN0-1M0) after breast conservation surgery or mastectomy randomised (1 : 1 : 1) to 40 Gy in 15 fractions (3 weeks), 27 Gy or 26 Gy in 5 fractions (1 week) whole breast/chest wall (Main Trial). Primary endpoint was ipsilateral breast tumour relapse; assuming 2% 5-year incidence for 40 Gy, non-inferiority pre-defined as < 1.6% excess for 5-fraction schedules (critical hazard ratio = 1.81). Normal tissue effects were assessed independently by clinicians, patients and photographs. Sub-studies: Two acute skin toxicity sub-studies were undertaken to confirm safety of the test schedules. Primary endpoint was proportion of patients with grade ≥ 3 acute breast skin toxicity at any time from the start of radiotherapy to 4 weeks after completion. Nodal Sub-Study patients had breast/chest wall plus axillary radiotherapy testing the same three schedules, reduced to the 40 and 26 Gy groups on amendment, with the primary endpoint of 5-year patient-reported arm/hand swelling. Limitations: A sequential hypofractionated or simultaneous integrated boost has not been studied. Participants: Ninety-seven UK centres recruited 4096 patients (1361:40 Gy, 1367:27 Gy, 1368:26 Gy) into the Main Trial from November 2011 to June 2014. The Nodal Sub-Study recruited an additional 469 patients from 50 UK centres. One hundred and ninety and 162 Main Trial patients were included in the acute toxicity sub-studies. Results: Acute toxicity sub-studies evaluable patients: (1) acute grade 3 Radiation Therapy Oncology Group toxicity reported in 40 Gy/15 fractions 6/44 (13.6%); 27 Gy/5 fractions 5/51 (9.8%); 26 Gy/5 fractions 3/52 (5.8%). (2) Grade 3 common toxicity criteria for adverse effects toxicity reported for one patient. At 71-month median follow-up in the Main Trial, 79 ipsilateral breast tumour relapse events (40 Gy: 31, 27 Gy: 27, 26 Gy: 21); hazard ratios (95% confidence interval) versus 40 Gy were 27 Gy: 0.86 (0.51 to 1.44), 26 Gy: 0.67 (0.38 to 1.16). With 2.1% (1.4 to 3.1) 5-year incidence ipsilateral breast tumour relapse after 40 Gy, estimated absolute differences versus 40 Gy (non-inferiority test) were -0.3% (-1.0-0.9) for 27 Gy (p = 0.0022) and -0.7% (-1.3-0.3) for 26 Gy (p = 0.00019). Five-year prevalence of any clinician-assessed moderate/marked breast normal tissue effects was 40 Gy: 98/986 (9.9%), 27 Gy: 155/1005 (15.4%), 26 Gy: 121/1020 (11.9%). Across all clinician assessments from 1 to 5 years, odds ratios versus 40 Gy were 1.55 (1.32 to 1.83; p < 0.0001) for 27 Gy and 1.12 (0.94-1.34; p = 0.20) for 26 Gy. Patient and photographic assessments showed higher normal tissue effects risk for 27 Gy versus 40 Gy but not for 26 Gy. Nodal Sub-Study reported no arm/hand swelling in 80% and 77% in 40 Gy and 26 Gy at baseline, and 73% and 76% at 24 months. The prevalence of moderate/marked arm/hand swelling at 24 months was 10% versus 7% for 40 Gy compared with 26 Gy. Interpretation: Five-year local tumour incidence and normal tissue effects prevalence show 26 Gy in 5 fractions in 1 week is a safe and effective alternative to 40 Gy in 15 fractions for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. Future work: Ten-year Main Trial follow-up is essential. Inclusion in hypofractionation meta-analysis ongoing. A future hypofractionated boost trial is strongly supported. Trial registration: FAST-Forward was sponsored by The Institute of Cancer Research and was registered as ISRCTN19906132. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information.

Patients diagnosed with early breast cancer are often recommended to have radiotherapy after surgery because research has shown that it lowers the risk of the cancer returning. However, it may cause some short- and long-term side effects. Previous clinical trials showed that the same, or even better, outcomes with a lower total dose of radiotherapy given in fewer, larger daily doses compared with older historical treatment schedules. The National Institute for Health and Care Research Health Technology Assessment Programme-funded FAST-Forward Trial aimed to see whether the number of doses could be reduced further without reducing the beneficial effects of radiotherapy. Between November 2011 and June 2014, 4096 patients agreed to take part in the FAST-Forward Main Trial testing three schedules of radiotherapy to the breast. Standard treatment given on 15 days over 3 weeks (Control Group) was compared with two different lower dose schedules where treatment was given on 5 days over 1 week (lower dose Test Groups). An additional 469 patients entered a sub-study where the gland area under the arm also received radiotherapy (Nodal Sub-Study). Main Trial 5-year results reported in April 2020 showed that the number of patients whose cancer had returned in the treated breast was low in all groups: around 2 in 100 (2.1%) for the Control Group, and 1.7% in the higher dose and 1.4% in the lower dose Test Groups. The majority of reported side effects assessed by patients and doctors up to 5 years after radiotherapy were mild for all treatment groups. Patients in the Control Group and in the lower dose Test Group experienced similar levels of side effects. More side effects were reported in the higher dose Test Group, although differences were small. Overall, the FAST-Forward findings suggest that the lower dose 1-week schedule gave similar results in terms of the cancer returning and side effects to the standard 3-week treatment and this schedule can now be used to help treat future patients.

Denervation pseudo hypertrophy of the calf: An important cause of lower limb swelling.

Denervation pseudohypertrophy is an uncommon cause of limb swelling, which may be overlooked. It is an important diagnosis to arrive at, as it instructs the search for an underlying cause which may itself require intervention. We present the case of a 32-year-old male rugby player with a 2-year history of left calf swelling and intermittent pain and tightness. He described a previous history of 2 left sided lumbar micro-discectomy surgeries. There was no tenderness or sensory deficit on examination. MRI of the left calf revealed muscular enlargement, with fat interspersed between the muscle fibers, in keeping with pseudohypertrophy. This has a number of causes, in this cause attributed to lumbar radiculopathy. This case highlights a rare but important cause of limb swelling which should be considered in the workup of a unilateral swollen limb.

Glomangiomatosis of the lower leg.

This paper demonstrates a case of multiple glomangiomas, or glomangiomatosis, including clinical presentation, imaging appearances, and subsequent management. Differentiating features from typical glomus tumors are described. To the best of our knowledge, this is the first reported case of a glomangioma involving the distal tibiofibular syndesmosis.

Simulating Study Data to Support Expected Value of Sample Information Calculations: A Tutorial.

The expected value of sample information (EVSI) can be used to prioritize avenues for future research and design studies that support medical decision making and offer value for money spent. EVSI is calculated based on 3 key elements. Two of these, a probabilistic model-based economic evaluation and updating model uncertainty based on simulated data, have been frequently discussed in the literature. By contrast, the third element, simulating data from the proposed studies, has received little attention. This tutorial contributes to bridging this gap by providing a step-by-step guide to simulating study data for EVSI calculations. We discuss a general-purpose algorithm for simulating data and demonstrate its use to simulate 3 different outcome types. We then discuss how to induce correlations in the generated data, how to adjust for common issues in study implementation such as missingness and censoring, and how individual patient data from previous studies can be leveraged to undertake EVSI calculations. For all examples, we provide comprehensive code written in the R language and, where possible, Excel spreadsheets in the supplementary materials. This tutorial facilitates practical EVSI calculations and allows EVSI to be used to prioritize research and design studies.

Exploring Heterogeneity in Histology-Independent Technologies and the Implications for Cost-Effectiveness.

BACKGROUND: The National Institute for Health and Care Excellence and a number of international health technology assessment agencies have recently undertaken appraisals of histology-independent technologies (HITs). A strong and untested assumption inherent in the submissions included identical clinical response across all tumour histologies, including new histologies unrepresented in the trial. Challenging this assumption and exploring the potential for heterogeneity has the potential to impact upon cost-effectiveness. METHOD: Using published response data for a HIT, a Bayesian hierarchical model (BHM) was used to identify heterogeneity in response and to estimate the probability of response for each histology included in single-arm studies, which informed the submission for the HIT, larotrectinib. The probability of response for a new histology was estimated. Results were inputted into a simplified response-based economic model using hypothetical parameters. Histology-independent and histology-specific incremental cost-effectiveness ratios accounting for heterogeneity were generated. RESULTS: The results of the BHM show considerable heterogeneity in response rates across histologies. The predicted probability of response estimated by the BHM is 60.9% (95% credible interval 16.0; 91.8%), lower than the naively pooled probability of 74.5%. A mean response probability of 56.9% (0.2; 99.9%) is predicted for an unrepresented histology. Based on the economic analysis, the probability of the hypothetical HIT being cost-effective under the assumption of identical response is 78%. Allowing for heterogeneity, the probability of various approval decisions being cost-effective ranges from 93% to 11%. CONCLUSIONS: Central to the challenge of reimbursement of HITs is the potential for heterogeneity. This study illustrates how heterogeneity in clinical effectiveness can result in highly variable and uncertain estimates of cost-effectiveness. This analysis can help improve understanding of the consequences of histology-independent versus histology-specific decisions.

Hospital-Acquired Blood Stream Infection in an Adult Intensive Care Unit.

BACKGROUND: Hospital-acquired blood stream infections are a common and serious complication in critically ill patients. METHODS: A retrospective case series was undertaken investigating the incidence and causes of bacteraemia in an adult intensive care unit with a high proportion of postoperative cardiothoracic surgical and oncology patients. RESULTS: 405 eligible patients were admitted to the intensive care unit over the course of nine months. 12 of these patients developed a unit-acquired blood stream infection. The average Acute Physiology And Chronic Health Evaluation II (APACHE II) score of patients who developed bacteraemia was greater than that of those who did not (19.8 versus 16.8, respectively). The risk of developing bacteraemia was associated with intubation and higher rates of invasive procedures. The mortality rate amongst the group of patients that developed bacteraemia was 33%; this is in contrast to the mortality rate in our unit as 27.2%. There was a higher proportion of Gram-negative bacteria isolated on blood cultures (9 out of 13 isolates) than in intensive care units reported in other studies. CONCLUSION: Critical-care patients are at risk of secondary bloodstream infection. This study highlights the importance of measures to reduce the risk of infection in the intensive-care setting, particularly in patients who have undergone invasive procedures.

Modelling approaches for histology-independent cancer drugs to inform NICE appraisals: a systematic review and decision-framework.

BACKGROUND: The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. METHODS: Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. RESULTS: We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. CONCLUSIONS: Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. FURTHER RESEARCH: Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.

In May 2017, the US Food and Drug Administration granted the first approval for a cancer treatment based on a common biomarker rather than the location in the body at which the tumour originated (the tumour site); that is, a site-agnostic or 'histology-independent' indication was granted. Research from the National Institute for Health and Care Excellence suggests that there are approximately 20 technologies currently in development for histology-independent indications. The first marketing authorisation was granted in Europe in 2019. Histology-independent treatments have the potential to have important effects in patient populations for whom there are currently limited or no available treatment options. However, it is also important to ensure that the use of these treatments in the NHS is supported by systematic and robust assessments of clinical evidence (i.e. how well the medicine or treatment works) and economic evidence (i.e. the medicine's value for money). These assessments are undertaken by the National Institute for Health and Care Excellence, usually for treatments targeting specific tumours sites. However, a histology-independent marketing authorisation would probably include many tumour sites and it is not possible for the National Institute for Health and Care Excellence to conduct a separate assessment for each tumour site for which the treatment could be beneficial. As a result, the National Institute for Health and Care Excellence needs to consider how these products can be appropriately assessed without creating unnecessary delays in patient access. This research explores the extent to which the National Institute for Health and Care Excellence's existing approaches for assessing clinical and economic value can be applied to histology-independent indications, and any changes that might be required. We explore the nature and amount of evidence that is typically available at the point of initial marketing authorisation and develop recommendations to establish the evidence and analyses required to help inform the National Institute for Health and Care Excellence's decisions. We use case studies to highlight possible challenges and to explore ways that these challenges might be addressed. This research will help to inform future National Institute for Health and Care Excellence policy on how to appraise cancer drugs with histology-independent indications. It will also inform the development of guidance for those developing these treatments to help their understanding of the clinical effectiveness and cost-effectiveness assessments that will be required to inform the National Institute for Health and Care Excellence's appraisals.

Can free-ranging rhesus monkeys (Macaca mulatta) extract artificially created rules comprised of natural vocalizations?

Though nonhuman animals lack anything like a set of grammatical structures in their natural vocalizations, studies now suggest that at least some animals can extract patterns from a structured input that appear abstract and rule-like. The authors continue this line of research by adding three new methodological contributions, specifically, tests of (1) a free-ranging animal population (as opposed to captive laboratory subjects), (2) a new taxonomic group (i.e., Old World monkeys: rhesus macaques, Macaca mulatta), and (3), the presentation of artificially sequenced strings of species-specific vocalizations (as opposed to artificial symbols or speech stimuli). Specifically, the authors created artificial strings of rhesus vocalizations in the pattern notated as AAB (i.e., two identical calls [AA] followed by a different one [B]) or ABB. Following habituation to AAB strings, rhesus monkeys showed significantly more orienting responses to novel ABB strings than to novel AAB strings. Further, following habituation to an ABB pattern, rhesus responded more in test trials to AAB than ABB. These results, combined with other parallel studies, suggest that animals can extract an identity relationship from an artificial sequence of sounds, and can do so even though the tokens are species-specific vocalizations that are never produced in this sequence.

Free-ranging rhesus monkeys spontaneously individuate and enumerate small numbers of non-solid portions.

Fundamental questions in cognitive science concern the origins and nature of the units that compose visual experience. Here, we investigate the capacity to individuate and store information about non-solid portions, asking in particular whether free-ranging rhesus monkeys (Macaca mulatta) quantify portions of a non-solid substance presented in discrete pouring actions. When presented with portions of carrot pieces poured from a cup into opaque boxes, rhesus picked the box with the greatest number of portions for comparisons of 1 vs. 2, 2 vs. 3, and 3 vs. 4, but not for comparisons of 4 vs. 5 and 3 vs. 6. Additional experiments indicate that rhesus based their decisions on both the number of portions and the total amount of food. These results show that the capacity to individuate non-solid portions is not unique to humans, and does not depend on structures of natural language. Further, the fact that rhesus' ability to represent non-solid portions is constrained by the same 4-item limit typically ascribed to the system of parallel individuation that operates over solid objects suggests that the visual system recruits common working memory processes for retaining information about solid objects and non-solid portions. We discuss our results with respect to theories of visual processing, as well as to the role that the human language faculty may have played in both the evolution and development of quantification.