Eliciting judgements about dependent quantities of interest: The SHeffield ELicitation Framework extension and copula methods illustrated using an asthma case study.

Pharmaceutical companies regularly need to make decisions about drug development programs based on the limited knowledge from early stage clinical trials. In this situation, eliciting the judgements of experts is an attractive approach for synthesising evidence on the unknown quantities of interest. When calculating the probability of success for a drug development program, multiple quantities of interest-such as the effect of a drug on different endpoints-should not be treated as unrelated. We discuss two approaches for establishing a multivariate distribution for several related quantities within the SHeffield ELicitation Framework (SHELF). The first approach elicits experts' judgements about a quantity of interest conditional on knowledge about another one. For the second approach, we first elicit marginal distributions for each quantity of interest. Then, for each pair of quantities, we elicit the concordance probability that both lie on the same side of their respective elicited medians. This allows us to specify a copula to obtain the joint distribution of the quantities of interest. We show how these approaches were used in an elicitation workshop that was performed to assess the probability of success of the registrational program of an asthma drug. The judgements of the experts, which were obtained prior to completion of the pivotal studies, were well aligned with the final trial results.

Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis.

BACKGROUND: Ofatumumab, a fully human anti-CD20 monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (RMS), binds to a unique conformational epitope, thereby depleting B cells very efficiently and allowing subcutaneous administration at lower doses. OBJECTIVES: The aims were to characterize the relationship between ofatumumab concentration and B cell levels, including the effect of covariates such as body weight, age, or baseline B cell count, and use simulations to confirm the chosen therapeutic dose. METHODS: Graphical and regression analyses previously performed based on data from a dose-range finding study provided the B cell depletion target used in the present work. All available adult phase 2/3 data for ofatumumab in RMS patients were pooled to develop a population pharmacokinetics (PK)-B cell count model, using nonlinear mixed-effects modeling. The population PK-B cell model was used to simulate B cell depletion and repletion times and the effect of covariates on PK and B cell metrics, as well as the dose response across a range of subcutaneous ofatumumab monthly doses. RESULTS: The final PK-B cell model was developed using data from 1486 patients. The predetermined B cell target was best achieved and sustained with the 20-mg dose regimen, with median B cell count reaching 8 cells/µL in 11 days and negligible repletion between doses. Only weight had a significant effect on PK, which did not translate into any clinically relevant effect on B cell levels. CONCLUSION: The PK-B cell modeling confirms the dose chosen for the licensed ofatumumab regimen and demonstrates no requirement for dose adjustment based on adult patient characteristics.

A New Comprehensive Approach to Assess the Probability of Success of Development Programs Before Pivotal Trials.

The point at which clinical development programs transition from early phase to pivotal trials is a critical milestone. Substantial uncertainty about the outcome of pivotal trials may remain even after seeing positive early phase data, and companies may need to make difficult prioritization decisions for their portfolio. The probability of success (PoS) of a program, a single number expressed as a percentage reflecting the multitude of risks that may influence the final program outcome, is a key decision-making tool. Despite its importance, companies often rely on crude industry benchmarks that may be "adjusted" by experts based on undocumented criteria and which are typically misaligned with the definition of success used to drive commercial forecasts, leading to overly optimistic expected net present value calculations. We developed a new framework to assess the PoS of a program before pivotal trials begin. Our definition of success encompasses the successful outcome of pivotal trials, regulatory approval and meeting the requirements for market access as outlined in the target product profile. The proposed approach is organized in four steps and uses an innovative Bayesian approach to synthesize all relevant evidence. The new PoS framework is systematic and transparent. It will help organizations to make more informed decisions. In this paper, we outline the rationale and elaborate on the structure of the proposed framework, provide examples, and discuss the benefits and challenges associated with its adoption.

Improving the assessment of the probability of success in late stage drug development.

There are several steps to confirming the safety and efficacy of a new medicine. A sequence of trials, each with its own objectives, is usually required. Quantitative risk metrics can be useful for informing decisions about whether a medicine should transition from one stage of development to the next. To obtain an estimate of the probability of regulatory approval, pharmaceutical companies may start with industry-wide success rates and then apply to these subjective adjustments to reflect program-specific information. However, this approach lacks transparency and fails to make full use of data from previous clinical trials. We describe a quantitative Bayesian approach for calculating the probability of success (PoS) at the end of phase II which incorporates internal clinical data from one or more phase IIb studies, industry-wide success rates, and expert opinion or external data if needed. Using an example, we illustrate how PoS can be calculated accounting for differences between the phase II data and future phase III trials, and discuss how the methods can be extended to accommodate accelerated drug development pathways.

Confidentiality and Capacity.

This article focuses on confidentiality and capacity issues affecting patients receiving care in the emergency department. The patient-physician relationship begins with presumed confidentiality. The article also clarifies instances where a physician may be required to break confidentiality for the safety of patients or others. This article then discusses risk management issues relevant to determining a patient's capacity to accept or decline medical care in the emergency department setting. Situations pertaining to refusal of care and discharges against medical advice are examined in detail, and best practices for mitigating risk in informed consent and barriers to consent are reviewed.

Broadband electro-optic frequency comb generation in a lithium niobate microring resonator.

Optical frequency combs consist of equally spaced discrete optical frequency components and are essential tools for optical communication, precision metrology, timing and spectroscopy1-9. At present, combs with wide spectra are usually generated by mode-locked lasers10 or dispersion-engineered resonators with third-order Kerr nonlinearity11. An alternative method of comb production uses electro-optic (EO) phase modulation in a resonator with strong second-order nonlinearity, resulting in combs with excellent stability and controllability12-14. Previous EO combs, however, have been limited to narrow widths by a weak EO interaction strength and a lack of dispersion engineering in free-space systems. Here we overcome these limitations by realizing an integrated EO comb generator in a thin-film lithium niobate photonic platform that features a large EO response, ultralow optical loss and highly co-localized microwave and optical fields15, while enabling dispersion engineering. Our measured EO comb spans more frequencies than the entire telecommunications L-band (over 900 comb lines spaced about 10 gigahertz apart), and we show that future dispersion engineering can enable octave-spanning combs. Furthermore, we demonstrate the high tolerance of our comb generator to modulation frequency detuning, with frequency spacing finely controllable over seven orders of magnitude (10 hertz to 100 megahertz), and we use this feature to generate dual-frequency combs in a single resonator. Our results show that integrated EO comb generators are capable of generating wide and stable comb spectra. Their excellent reconfigurability is a powerful complement to integrated Kerr combs, enabling applications ranging from spectroscopy16 to optical communications8.

Early onset of efficacy with erenumab in patients with episodic and chronic migraine.

BACKGROUND: Subcutaneous erenumab reduced monthly migraine days and increased the likelihood of achieving a ≥ 50% reduction at all monthly assessment points tested in 2 pivotal trials in episodic migraine (EM) and chronic migraine (CM). Early efficacy of migraine preventive medications is an important treatment characteristic to patients. Delays in achievement of efficacy can result in failed adherence. The objective of these post-hoc analyses were to evaluate efficacy in the first 4 weeks after initial subcutaneous administration of erenumab 70 mg, erenumab 140 mg, or placebo. METHODS: There is no generally accepted methodology to measure onset of action for migraine preventive medications. We used a comprehensive approach with data from both studies to evaluate change from baseline in weekly migraine days (WMD), achievement of ≥ 50% reduction in WMD, and proportion of patients experiencing migraine measured on a daily basis. The 7-day moving averages were overlaid with observed data. RESULTS: In both studies (EM: N = 955; CM: N = 667), there was evidence of onset of efficacy of erenumab vs. placebo during the first week of treatment, which in some cases reached nominal significance. For EM the changes in WMD were (least squares mean [LSM] [95% CI]): placebo, - 0.1 (- 0.3, 0.0); erenumab 70 mg, - 0.3 (- 0.5, - 0.2) p = 0.130; erenumab 140 mg, - 0.6 (- 0.7, - 0.4) p < 0.001. For CM the changes were: placebo, - 0.5 (- 0.8, - 0.3); erenumab 70 mg, - 0.9 (- 1.2, - 0.7) p = 0.047; erenumab 140 mg, - 0.8 (- 1.1, - 0.5) p = 0.18. Achievement of ≥ 50% reduction in WMD was observed as early as Week 1 (adjusted OR [95% CI] erenumab vs placebo) in EM: erenumab 70 mg, 1.3 (1.0, 1.9) p = 0.097; erenumab 140 mg, 2.0 (1.4, 2.7) p < 0.001. A similar outcome was observed for CM: erenumab 70 mg, 1.8 (1.1, 2.8) p = 0.011; erenumab 140 mg, 1.9 (1.2, 2.9) p = 0.009. Seven-day moving averages of observed data showed each treatment arm differed from placebo by Week 1 (OR [95% CI]): in EM Day 3 for erenumab 140 mg, 0.7 (0.5, 1.0) p = 0.031 and at Day 7 for 70 mg, 0.6 (0.4, 0.8) p = 0.002; in CM: Day 6 for erenumab 70 mg, 0.6 (0.4, 0.9) p = 0.022 and at Day 7 for 140 mg, 0.7 (0.4, 1.0); p = 0.038. CONCLUSION: Erenumab showed early onset of efficacy with separation from placebo within the first week of treatment in both chronic and episodic migraine patients.

Are Geriatric Patients Placed in an Emergency Department Observation Unit on a Chest Pain Pathway More Likely Than Non-Geriatric Patients to Re-Present to the Hospital within 30 Days?

BACKGROUND: Emergency department observation units (EDOUs) are used frequently for low-risk chest pain evaluations. OBJECTIVE: The purpose of this study was to determine whether geriatric compared to non-geriatric patients evaluated in an EDOU for chest pain have differences in unscheduled 30-day re-presentation, length of stay (LOS), and use of stress testing. METHODS: We conducted an exploratory, retrospective, cohort study at a single academic, urban ED of all adult patients placed in an EDOU chest pain protocol from June 1, 2014 to May 31, 2015. Our primary outcome was any unscheduled return visits within 30 days of discharge from the EDOU. Secondary outcomes included EDOU LOS and stress testing. We used Wilcoxon non-parametric and χ2 tests to compare geriatric to non-geriatric patients. RESULTS: There were 959 unique EDOU placements of geriatric (n = 219) and non-geriatric (n = 740) patients. Geriatric compared to non-geriatric patients had: no significant difference in unscheduled 30-day return visits after discharge from the EDOU (15.5% vs. 18.5%; p = 0.31); significantly longer median EDOU LOS (22.1 vs. 20.6 h; p < 0.01) with a greater percentage staying longer than 24 h (42% vs. 29.1%; p < 0.01). Geriatric patients had significantly fewer stress tests (39.7% vs. 51.4%; p < 0.01), more of which were nuclear stress tests (78.2% vs. 39.5%; p < 0.01). CONCLUSIONS: In this exploratory retrospective study, geriatric EDOU chest pain patients did not have an increased rate of re-presentation to the hospital within 30 days compared to non-geriatric patients. Geriatric patients had a longer EDOU LOS than non-geriatric patients. Geriatric patients in the EDOU had fewer stress tests, but more of those were nuclear stress tests.

A nonparametric method to detect increased frequencies of adverse drug reactions over time.

Signal detection is routinely applied to spontaneous report safety databases in the pharmaceutical industry and by regulators. As an example, methods that search for increases in the frequencies of known adverse drug reactions for a given drug are routinely applied, and the results are reported to the health authorities on a regular basis. Such methods need to be sensitive to detect true signals even when some of the adverse drug reactions are rare. The methods need to be specific and account for multiplicity to avoid false positive signals when the list of known adverse drug reactions is long. To apply them as part of a routine process, the methods also have to cope with very diverse drugs (increasing or decreasing number of cases over time, seasonal patterns, very safe drugs versus drugs for life-threatening diseases). In this paper, we develop new nonparametric signal detection methods, directed at detecting differences between a reporting and a reference period, or trends within a reporting period. These methods are based on bootstrap and permutation distributions, and they combine statistical significance with clinical relevance. We conducted a large simulation study to understand the operating characteristics of the methods. Our simulations show that the new methods have good power and control the family-wise error rate at the specified level. Overall, in all scenarios that we explored, the method performs much better than our current standard in terms of power, and it generates considerably less false positive signals as compared to the current standard.

Effect of atmospheric anisoplanatism on earth-to-satellite time transfer over laser communication links.

The need for an accurate time reference on orbiting platforms motivates study of time transfer via free-space optical communication links. The impact of atmospheric turbulence on earth-to-satellite optical time transfer has not been fully characterized, however. We analyze limits to two-way laser time transfer accuracy posed by anisoplanatic non-reciprocity between uplink and downlink. We show that despite limited reciprocity, two-way time transfer can still achieve sub-picosecond accuracy in realistic propagation scenarios over a single satellite visibility period.

Direct-detection mode-division multiplexing in modal basis using phase retrieval.

Mode-division multiplexing (MDM) can increase the capacity of direct-detection short-reach systems in proportion to the number of modes employed. MDM requires compensation of modal crosstalk at a transmitter or receiver by the multi-input multi-output (MIMO) signal processing. We show that the channel estimation required for the MIMO processing in a basis of modes can be expressed as a phase retrieval problem. We propose three techniques for the estimation: sparse training sequences, convex optimization (CO) and alternating minimization. We demonstrate the superior performance of the CO technique.

Current Trends in Geriatric Emergency Medicine.

The number of geriatric visits to United States emergency departments continues to rise. This article reviews demographics, statistics, and future projections in geriatric emergency medicine. Included are discussions of US health care spending, geriatric emergency departments, prehospital care, frailty of geriatric patients, delirium, geriatric trauma, geriatric screening and prediction tools, medication safety, long-term care, and palliative care.

Design of flexible multi-mode fiber endoscope.

Multi-mode fiber (MMF) endoscopes are extremely thin and have higher spatial resolution than conventional endoscopes; however, all current MMF endoscope designs require either that the MMF remain rigid during insertion and imaging or that the orientation of the MMF be known. This limits their possible medical applications. We describe an MMF endoscope design that allows the MMF to be arbitrarily bent as it is maneuvered to the target site prior to imaging. This is achieved by the addition of a partial reflector to the distal end of the MMF, which allows measurement of the mode coupling in the MMF using the reflected light arriving at the proximal end of the MMF. This measurement can be performed while the distal end of the endoscope is not directly accessible, as when the endoscope is being maneuvered. We simulate imaging through such a flexible MMF endoscope, where the MMF is step-index with 1588 spatial modes, and obtain an image even after the mode coupling matrix of the MMF is altered randomly, corresponding to an unknown bending of the MMF.

Noise-reduction algorithms for optimization-based imaging through multi-mode fiber.

Three modifications are shown to improve resolution and reduce noise amplification in endoscopic imaging through multi-mode fiber using optimization-based reconstruction (OBR). First, random sampling patterns are replaced by sampling patterns designed to have more nearly equal singular values. Second, the OBR algorithm uses a point-spread function based on the estimated spatial frequency spectrum of the object. Third, the OBR algorithm gives less weight to modes having smaller singular values. In simulations for a step-index fiber supporting 522 spatial modes, the modifications yield a 20% reduction in image error (l(2) norm) in the noiseless case, and a further 33% reduction in image error at a 22-dB shot noise-limited SNR as compared to the original method using random sampling patterns and OBR.

Diversity-multiplexing tradeoff in mode-division multiplexing.

The capacity of mode-division multiplexing (MDM) systems is limited, for a given outage probability, by mode-dependent loss (MDL) and gain. Modal degrees of freedom may be exploited to increase transmission rate (multiplexing gain) or lower outage probability (diversity gain), but there is a fundamental tradeoff between the achievable multiplexing and diversity gains. In this Letter, we present the diversity-multiplexing tradeoff in MDM systems for the first time, studying the impact of signal-to-noise ratio, MDL, and frequency diversity order on the tradeoff in the strong-mode-coupling regime.

Optical network scaling: roles of spectral and spatial aggregation.

As the bit rates of routed data streams exceed the throughput of single wavelength-division multiplexing channels, spectral and spatial traffic aggregation become essential for optical network scaling. These aggregation techniques reduce network routing complexity by increasing spectral efficiency to decrease the number of fibers, and by increasing switching granularity to decrease the number of switching components. Spectral aggregation yields a modest decrease in the number of fibers but a substantial decrease in the number of switching components. Spatial aggregation yields a substantial decrease in both the number of fibers and the number of switching components. To quantify routing complexity reduction, we analyze the number of multi-cast and wavelength-selective switches required in a colorless, directionless and contentionless reconfigurable optical add-drop multiplexer architecture. Traffic aggregation has two potential drawbacks: reduced routing power and increased switching component size.

Resolution limits for imaging through multi-mode fiber.

We experimentally demonstrate endoscopic imaging through a multi-mode fiber (MMF) in which the number of resolvable image features approaches four times the number of spatial modes per polarization propagating in the fiber. In our method, a sequence of random field patterns is input to the fiber, generating a sequence of random intensity patterns at the output, which are used to sample an object. Reflected power values are returned through the fiber and linear optimization is used to reconstruct an image. The factor-of-four resolution enhancement is due to mixing of modes by the squaring inherent in field-to-intensity conversion. The incoherent point-spread function (PSF) at the center of the fiber output plane is an Airy disk equivalent to the coherent PSF of a conventional diffraction-limited imaging system having a numerical aperture twice that of the fiber. All previous methods for imaging through MMF can only resolve a number of features equal to the number of modes. Most of these methods use localized intensity patterns for sampling the object and use local image reconstruction.

Basic neuroanatomy and stroke syndromes.

Stroke should not solely be considered a disease of the elderly, and racial disparities are most evident among young adults. Acute stroke can present at any age and it is important to be familiar with the evaluation and treatment of stroke to provide timely care. The National Institute of Health Stroke Scale helps physicians objectively evaluate stroke patients. This article presents an overview of basic information on neuroanatomy, pathophysiology, and stroke syndromes.