We propose a new performance attribution framework that decomposes a constrained portfolio’s holdings, expected returns, variance, expected utility, and realized returns into components at- attributable to: (1) the unconstrained mean-variance optimal portfolio; (2) individual static constraints; and (3) information, if any, arising from those constraints. A key contribution of our framework is the recognition that constraints may contain information that is correlated with returns, in which case imposing such constraints can affect performance. We extend our framework to accommodate estimation risk in portfolio construction using Bayesian portfolio analysis, which allows one to select constraints that improve—or are least detrimental to—future performance. We provide simulations and empirical examples involving constraints on ESG portfolios. Under certain scenarios, constraints may improve portfolio performance relative to a passive benchmark that does not account for the information contained in these constraints.

Within the contemporary context of environmental, social, and governance (ESG) investing principles, the authors explore the risk–reward characteristics of portfolios in the United States, Europe, and Japan constructed using the foundational tenets of Markowitz’s modern portfolio theory with data from six major ESG rating agencies. They document statistically significant excess returns in ESG portfolios from 2014 to 2020 in the United States and Japan. They propose several statistical and voting-based methods to aggregate individual ESG ratings, the latter based on the theory of social choice. They find that aggregating individual ESG ratings improves portfolio performance. In addition, the authors find that a portfolio based on Treynor–Black weights further improves the performance of ESG portfolios. Overall, these results suggest that significant signals in ESG rating scores can enhance portfolio construction despite their noisy nature.

We identify some of the most pressing issues facing the adoption of large language models (LLMs) in practical settings, and propose a research agenda to reach the next technological inflection point in generative AI. We focus on three challenges facing most LLM applications: domain-specific expertise and the ability to tailor that expertise to a user’s unique situation, trustworthiness and adherence to the user’s moral and ethical standards, and conformity to regulatory guidelines and oversight. These challenges apply to virtually all industries and endeavors in which LLMs can be applied, such as medicine, law, accounting, education, psychotherapy, marketing, and corporate strategy. For concreteness, we focus on the narrow context of financial advice, which serves as an ideal test bed both for determining the possible shortcomings of current LLMs and for exploring ways to overcome them. Our goal is not to provide solutions to these challenges—which will likely take years to develop—but to propose a framework and road map for solving them as part of a larger research agenda for improving generative AI in any application.

The National Center for Advancing Translational Sciences' virtual 2021 conference on gene-targeted therapies (GTTs) encouraged multidisciplinary dialogue on a wide range of GTT topic areas. Each of three parallel working groups included social scientists and clinical scientists, and the three major sessions included a presentation on economic issues related to their focus area. These experts also coordinated their efforts across the three groups. The economics-related presentations covered three areas with some overlap: (1) value assessment, uncertainty, and dynamic efficiency; (2) affordability, pricing, and financing; and (3) evidence generation, coverage, and access. This article provides a synopsis of three presentations, some of their key recommendations, and an update on related developments in the past year. The key high-level findings are that GTTs present unique data and policy challenges, and that existing regulatory, health technology assessment, as well as payment and financing systems will need to adapt. But these adjustments can build on our existing foundation of regulatory and incentive systems for innovation, and much can be done to accelerate progress in GTTs. Given the substantial unmet medical need that exists for these oft-neglected patients suffering from rare diseases, it would be a tragedy to not leverage these exciting scientific advances in GTTs.

BACKGROUND: We consider two key challenges that early-stage biotechnology firms face in developing a sustainable financing strategy and a sustainable business model: developing a valuation model for drug compounds, and choosing an appropriate operating model and corporate structure. We use the specific example of Unravel Biosciences—a therapeutics platform company that identifies novel drug targets through off-target mechanisms of existing drugs and then develops optimized new molecules—throughout the paper and explore a specific scenario of drug repurposing for rare genetic diseases.

RESULTS: The first challenge consists of producing a realistic financial valuation of a potential rare disease repurposed drug compound, in this case targeting Rett syndrome. More generally, we develop a framework to value a portfolio of pairwise correlated rare disease compounds in early-stage development and quantify its risk profile. We estimate the probability of a negative return to be for a single compound and for a portfolio of 8 drugs. The probability of selling the project at a loss decreases from (phase 3) for a single compound to (phase 3) for the 8-drug portfolio. For the second challenge, we find that the choice of operating model and corporate structure is crucial for early-stage biotech startups and illustrate this point with three concrete examples.

CONCLUSIONS: Repurposing existing compounds offers important advantages that could help early-stage biotech startups better align their business and financing issues with their scientific and medical objectives, enter a space that is not occupied by large pharmaceutical companies, and accelerate the validation of their drug development platform.

A fixed one-sided significance level of 5% is commonly used to interpret the statistical significance of randomized clinical trial (RCT) outcomes. While it is necessary to reduce the false positive rate, the threshold used could be chosen quantitatively and transparently to specifically reflect patient preferences regarding benefit–risk tradeoffs as well as other considerations. How can patient preferences be explicitly incorporated into RCTs in Parkinson’s disease (PD), and what is the impact on statistical thresholds for device approval? In this analysis, we apply Bayesian decision analysis (BDA) to PD patient preference scores elicited from survey data. BDA allows us to choose a sample size (n) and significance level (α) that maximizes the overall expected value to patients of a balanced two-arm fixed-sample RCT, where the expected value is computed under both null and alternative hypotheses. For PD patients who had previously received deep brain stimulation (DBS) treatment, the BDA-optimal significance levels fell between 4.0% and 10.0%, similar to or greater than the traditional value of 5%. Conversely, for patients who had never received DBS, the optimal significance level ranged from 0.2% to 4.4%. In both of these populations, the optimal significance level increased with the severity of the patients’ cognitive and motor function symptoms. By explicitly incorporating patient preferences into clinical trial designs and the regulatory decision-making process, BDA provides a quantitative and transparent approach to combine clinical and statistical significance. For PD patients who have never received DBS treatment, a 5% significance threshold may not be conservative enough to reflect their risk-aversion level. However, this study shows that patients who previously received DBS treatment present a higher tolerance to accept therapeutic risks in exchange for improved efficacy which is reflected in a higher statistical threshold.

BACKGROUND: The statistical significance of clinical trial outcomes is generally interpreted quantitatively according to the same threshold of 2.5% (in one-sided tests) to control the false-positive rate or type I error, regardless of the burden of disease or patient preferences. The clinical significance of trial outcomes—including patient preferences—are also considered, but through qualitative means that may be challenging to reconcile with the statistical evidence.

OBJECTIVE: We aimed to apply Bayesian decision analysis to heart failure device studies to choose an optimal significance threshold that maximizes the expected utility to patients across both the null and alternative hypotheses, thereby allowing clinical significance to be incorporated into statistical decisions either in the trial design stage or in the post-trial interpretation stage. In this context, utility is a measure of how much well-being the approval decision for the treatment provides to the patient.

METHODS: We use the results from a discrete-choice experiment study focusing on heart failure patients’ preferences, questioning respondents about their willingness to accept therapeutic risks in exchange for quantifiable benefits with alternative hypothetical medical device performance characteristics. These benefit–risk trade-off data allow us to estimate the loss in utility—from the patient perspective—of a false-positive or false-negative pivotal trial result. We compute the Bayesian decision analysis-optimal statistical significance threshold that maximizes the expected utility to heart failure patients for a hypothetical two-arm, fixed-sample, randomized controlled trial. An interactive Excel-based tool is provided that illustrates how the optimal statistical significance threshold changes as a function of patients’ preferences for varying rates of false positives and false negatives, and as a function of assumed key parameters.

RESULTS: In our baseline analysis, the Bayesian decision analysis-optimal significance threshold for a hypothetical two-arm randomized controlled trial with a fixed sample size of 600 patients per arm was 3.2%, with a statistical power of 83.2%. This result reflects the willingness of heart failure patients to bear additional risks of the investigational device in exchange for its probable benefits. However, for increased device-associated risks and for risk-averse subclasses of heart failure patients, Bayesian decision analysis-optimal significance thresholds may be smaller than 2.5%.

CONCLUSIONS: A Bayesian decision analysis is a systematic, transparent, and repeatable process for combining clinical and statistical significance, explicitly incorporating burden of disease and patient preferences into the regulatory decision-making process.

The COVID-19 pandemic has raised awareness about the global imperative to develop and stockpile vaccines against future outbreaks of emerging infectious diseases (EIDs). Prior to the pandemic, vaccine development for EIDs was stagnant, largely due to the lack of financial incentives for pharmaceutical firms to invest in vaccine research and development (R&D). This R&D requires significant capital investment, most notably in conducting clinical trials, but vaccines generate much less profit for pharmaceutical firms compared with other therapeutics in disease areas such as oncology. The portfolio approach of financing drug development has been proposed as a financial innovation to improve the risk/return trade-off of investment in drug development projects through the use of diversification and securitization. By investing in a sizable and well-diversified portfolio of novel drug candidates, and issuing equity and securitized debt based on this portfolio, the financial performance of such a biomedical “megafund” can attract a wider group of private-sector investors. To analyze the viability of the portfolio approach in expediting vaccine development against EIDs, we simulate the financial performance of a hypothetical vaccine megafund consisting of 120 messenger RNA (mRNA) vaccine candidates in the preclinical stage, which target 11 EIDs, including a hypothetical “disease X” that may be responsible for the next pandemic. We calibrate the simulation parameters with input from domain experts in mRNA technology and an extensive literature review and find that this vaccine portfolio will generate an average annualized return on investment of −6.0% per annum and a negative net present value of −$9.5 billion, despite the scientific advantages of mRNA technology and the financial benefits of diversification. We also show that clinical trial costs account for 94% of the total investment; vaccine manufacturing costs account for only 6%. The most important factor of the megafund’s financial performance is the price per vaccine dose. Other factors, such as the increased probability of success due to mRNA technology, the size of the megafund portfolio, and the possibility of conducting human challenge trials, do not significantly improve its financial performance. Our analysis indicates that continued collaboration between government agencies and the private sector will be necessary if the goal is to create a sustainable business model and robust vaccine ecosystem for addressing future pandemics.

Natural language processing (NLP) has revolutionized the financial industry, providing advanced techniques for the processing, analyzing, and understanding of unstructured financial text. The authors provide a comprehensive overview of the historical development of NLP, starting from early rules-based approaches to recent advances in deep learning–based NLP models. They also discuss applications of NLP in finance along with its challenges, including data scarcity and adversarial examples, and speculate about the future of NLP in the financial industry. To illustrate the capability of current NLP models, a state-of-the-art chatbot is employed as a co-author of this article.

We identify some of the most pressing issues facing the adoption of large language models (LLMs) in practical settings and propose a research agenda to reach the next technological inflection point in generative AI. We focus on three challenges facing most LLM applications: domain-specific expertise and the ability to tailor that expertise to a user’s unique situation, trustworthiness and adherence to the user’s moral and ethical standards, and conformity to regulatory guidelines and oversight. These challenges apply to virtually all industries and endeavors in which LLMs can be applied, such as medicine, law, accounting, education, psychotherapy, marketing, and corporate strategy. For concreteness, we focus on the narrow context of financial advice, which serves as an ideal test bed both for determining the possible shortcomings of current LLMs and for exploring ways to overcome them. Our goal is not to provide solutions to these challenges—which will likely take years to develop—but rather to propose a framework and road map for solving them as part of a larger research agenda for improving generative AI in any application.