Multidimensional Thresholding for Individual-Level Preference Elicitation.

OBJECTIVES: Multiple methods are available for collecting health preference information. However, information on the design and analysis of novel methods is limited. This article aims to provide the first introduction into the design and analysis of multidimensional thresholding (MDT). METHODS: We introduce MDT as a 2-step approach: First, participants rank the largest possible improvements in all considered attributes by their importance. Second, participants complete a series of systematically combined trade-off questions. Hit-and-Run sampling is used for obtaining preference weights. We also use a computational experiment to compare different MDT designs. RESULTS: The outlined MDT can generate preference information suitable for specifying a multiattribute utility function at the individual level. The computational experiment demonstrates the method's ability to recover preference weights at a high level of precision. While all designs in the computation experiment perform comparably well on average, the design outlined in the paper stands out with a high level of precision even if differences in relative attribute importance are large. CONCLUSION: MDT is suitable for preference elicitation, in particular if sample sizes are small. Future research should help improve the methods (e.g., remove the need for an initial ranking) to increase the potential reach of MDT.

Two Methods, One Story? Comparing Results of a Choice Experiment and Multidimensional Thresholding From a Clinician Preference Study in Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: An increasing number of methods are used to elicit health preference information. It is unclear whether different elicitation methods produce similar results and policy advice. Here, we compared the results from a discrete choice experiment (DCE) and multidimensional thresholding (MDT) that were conducted in the same sample. METHODS: Clinicians (N = 350) completed a DCE and MDT to elicit their preferences for 4 attributes related to the medical management of subarachnoid hemorrhage after aneurysm repair. Preference weights were compared between the DCE and MDT using a complete combinatorial convolution test. Additionally, data from the DCE and MDT were used to compute preference-based net treatment values for 16 hypothetical treatment profiles versus 1000 simulated comparators. The implied treatment recommendations were compared between the DCE and MDT. RESULTS: Preference weight distributions and median weights did not differ significantly between the DCE and MDT for any attribute: likelihood of delayed cerebral ischemia (medians 0.48 vs 0.40; P = .41), risk of lung complications (medians 0.27 vs 0.30; P = .52), risk of hypotension (medians 0.10 vs 0.11; P = .55), and risk of anemia (medians 0.07 vs 0.07; P = .50). The DCE and MDT produced similar treatment net value distributions (P > .05) and implied the same treatment recommendations in 82.3% of cases. CONCLUSIONS: The DCE and MDT elicited similar preference distributions and produced the same treatment recommendations for most tested cases. However, the share of people supporting the average treatment recommendation differed. More research is needed to determine how these findings would compare with those in other populations (in particular, patients) and applications.

A Roadmap for Increasing the Usefulness and Impact of Patient-Preference Studies in Decision Making in Health: A Good Practices Report of an ISPOR Task Force.

Many qualitative and quantitative methods are readily available to study patient preferences in health. These methods are now being used to inform a wide variety of decisions, and there is a growing body of evidence showing studies of patient preferences can be used for decision making in a wide variety of contexts. This ISPOR Task Force report synthesizes current good practices for increasing the usefulness and impact of patient-preference studies in decision making. We provide the ISPOR Roadmap for Patient Preferences in Decision Making that invites patient-preference researchers to work with decision makers, patients and patient groups, and other stakeholders to ensure that studies are useful and impactful. The ISPOR Roadmap consists of 5 key elements: (1) context, (2) purpose, (3) population, (4) method, and (5) impact. In this report, we define these 5 elements and provide good practices on how patient-preference researchers and others can actively contribute to increasing the usefulness and impact of patient-preference studies in decision making. We also present a set of key questions that can support researchers and other stakeholders (eg, funders, reviewers, readers) to assess efforts that promote the ongoing impact (both intended and unintended) of a particular preference study and additional studies in the future.

Patient preferences for the treatment of systemic sclerosis-associated interstitial lung disease: a discrete choice experiment.

OBJECTIVES: Treatments for SSc-associated interstitial lung disease (SSc-ILD) differ in attributes, i.e. mode of administration, adverse events (AEs) and efficacy. As physicians and patients may perceive treatments differently, shared decision-making can be essential for optimal treatment provision. We therefore aimed to quantify patient preferences for different treatment attributes. METHODS: Seven SSc-ILD attributes were identified from mixed-methods research and clinician input: mode of administration, shortness of breath, skin tightness, cough, tiredness, risk of gastrointestinal AEs (GI-AEs) and risk of serious and non-serious infections. Patients with SSc-ILD completed an online discrete choice experiment (DCE) in which they were asked to repeatedly choose between two alternatives characterized by varying severity levels of the included attributes. The data were analysed using a multinomial logit model; relative attribute importance and maximum acceptable risk measures were calculated. RESULTS: Overall, 231 patients with SSc-ILD completed the DCE. Patients preferred twice-daily oral treatments and 6-12 monthly infusions. Patients' choices were mostly influenced by the risk of GI-AEs or infections. Improvement was more important in respiratory symptoms than in skin tightness. Concerning trade-offs, patients accepted different levels of increase in GI-AE risk: +21% if it reduced the infusions' frequency; +15% if changing to an oral treatment; up to +37% if it improved breathlessness; and up to +36% if it reduced the risk of infections. CONCLUSIONS: This is the first study to quantitatively elicit patients' preferences for treatment attributes in SSc-ILD. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in clinical practice.

Ising-like Critical Behavior of Vortex Lattices in an Active Fluid.

Turbulent vortex structures emerging in bacterial active fluids can be organized into regular vortex lattices by weak geometrical constraints such as obstacles. Here we show, using a continuum-theoretical approach, that the formation and destruction of these patterns exhibit features of a continuous second-order equilibrium phase transition, including long-range correlations, divergent susceptibility, and critical slowing down. The emerging vorticity field can be mapped onto a two-dimensional (2D) Ising model with antiferromagnetic nearest-neighbor interactions by coarse graining. The resulting effective temperature is found to be proportional to the strength of the nonlinear advection in the continuum model.

Accounting for Preference Heterogeneity in Discrete-Choice Experiments: An ISPOR Special Interest Group Report.

OBJECTIVES: Discrete choice experiments (DCEs) are increasingly used to elicit preferences for health and healthcare. Although many applications assume preferences are homogenous, there is a growing portfolio of methods to understand both explained (because of observed factors) and unexplained (latent) heterogeneity. Nevertheless, the selection of analytical methods can be challenging and little guidance is available. This study aimed to determine the state of practice in accounting for preference heterogeneity in the analysis of health-related DCEs, including the views and experiences of health preference researchers and an overview of the tools that are commonly used to elicit preferences. METHODS: An online survey was developed and distributed among health preference researchers and nonhealth method experts, and a systematic review of the DCE literature in health was undertaken to explore the analytical methods used and summarize trends. RESULTS: Most respondents (n = 59 of 70, 84%) agreed that accounting for preference heterogeneity provides a richer understanding of the data. Nevertheless, there was disagreement on how to account for heterogeneity; most (n = 60, 85%) stated that more guidance was needed. Notably, the majority (n = 41, 58%) raised concern about the increasing complexity of analytical methods. Of the 342 studies included in the review, half (n = 175, 51%) used a mixed logit with continuous distributions for the parameters, and a third (n = 110, 32%) used a latent class model. CONCLUSIONS: Although there is agreement about the importance of accounting for preference heterogeneity, there are noticeable disagreements and concerns about best practices, resulting in a clear need for further analytical guidance.

Turbulence-induced clustering in compressible active fluids.

We study a novel phase of active polar fluids, which is characterized by the continuous creation and destruction of dense clusters due to self-sustained turbulence. This state arises due to the interplay between self-advection of the aligned swimmers and their defect topology. The typical cluster size is determined by the characteristic vortex size. Our results are obtained by investigating a continuum model of compressible polar active fluids, which incorporates typical experimental observations in bacterial suspensions, in particular a non-monotone dependence of speed on density.

Is relational continuity of care as important to people as policy makers think? Preferences for continuity of care in primary care.

BACKGROUND: In 2005, the Portuguese government launched a Primary Care reform that aimed to reinforce continuity of care. After a promising start, the reform is still incomplete and continuity has been compromised by the lack of General Practice doctors. OBJECTIVE: This study evaluates public preferences for relational continuity of care alongside other attributes of Primary Care services in Portugal. METHODS: We use a discrete choice experiment (DCE) to evaluate preferences and estimate the population's willingness to pay (WTP) for Primary Care attributes. We use a sequential, mixed-methods approach to develop a D-efficient fractional factorial design for the DCE. Five attributes were included in the DCE and there were 32 DCE choice sets. The data collection was conducted in 2014 and the final sample had 517 respondents. A random parameters multinomial logit was used to analyse the data. RESULTS: We find that respondents value relational continuity of care, but that the current focus of the Portuguese NHS on relational continuity at the expense of other attributes is too simplistic. CONCLUSIONS: Relational continuity should be part of a broader policy that emphasizes person-centred care and considers the preferences of patients for Primary Care attributes.

Maintenance inhaler therapy preferences of patients with asthma or chronic obstructive pulmonary disease: a discrete choice experiment.

BACKGROUND: A variety of maintenance inhaler therapies are available to treat asthma and COPD. Patient-centric treatment choices require understanding patient preferences for the alternative therapies. METHODS: A self-completed web-based discrete choice experiment was conducted to elicit patient preferences for inhaler device and medication attributes. Selection of attributes was informed by patient focus groups and literature review. RESULTS: The discrete choice experiment was completed by 810 patients with asthma and 1147 patients with COPD. Patients with asthma most valued decreasing the onset of action from 30 to 5 min, followed by reducing yearly exacerbations from 3 to 1. Patients with COPD most and equally valued decreasing the onset of action from 30 to 5 min and reducing yearly exacerbations from 3 to 1. Both patients with asthma and patients with COPD were willing to accept an additional exacerbation in exchange for a 15 min decrease in onset of action and a longer onset of action in exchange for a lower risk of adverse effects from inhaled corticosteroids. Patients with asthma and COPD valued once-daily over twice-daily dosing, pressurised inhalers over dry powder inhalers and non-capsule priming over single-use capsules, although these attributes were not valued as highly as faster onset of action or reduced exacerbations. CONCLUSIONS: The most important maintenance inhaler attributes for patients with asthma and COPD were fast onset of symptom relief and a lower rate of exacerbations. Concerns about safety of inhaled corticosteroids and device convenience also affected patient preferences but were less important.

Correction: The value of diagnostic testing for parents of children with rare genetic diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The value of diagnostic testing for parents of children with rare genetic diseases.

PURPOSE: Exome sequencing (ES) can rapidly identify disease-causing variants responsible for rare, single-gene diseases, and potentially reduce the duration of the diagnostic odyssey. Our study examines how parents and families value ES. METHODS: We developed a discrete choice experiment (DCE) survey that was administered to parents of children with rare diseases. The DCE included 14 choice tasks with 6 attributes and 3 alternatives. A valuation-space model was used to estimate willingness to pay, willingness to wait for test results, and minimum acceptable chance of a diagnosis for changes in each attribute. RESULTS: There were n = 319 respondents of whom 89% reported their child had genetic testing, and 66% reported their child had a diagnosis. Twenty-six percent reported that their child had been offered ES. Parents were willing to pay CAD$6590 (US$4943), wait 5.2 years to obtain diagnostic test results, and accept a reduction of 3.1% in the chance of a diagnosis for ES compared with operative procedures. CONCLUSION: Timely access to ES could reduce the diagnostic odyssey and associated costs. Before ES is incorporated routinely into care for patients with rare diseases in Canada and more broadly, there must be a clear understanding of its value to patients and families.

Decision heuristic or preference? Attribute non-attendance in discrete choice problems.

This paper investigates if respondents' choice to not consider all characteristics of a multiattribute health service may represent preferences. Over the last decade, an increasing number of studies account for attribute non-attendance (ANA) when using discrete choice experiments to elicit individuals' preferences. Most studies assume such behaviour is a heuristic and therefore uninformative. This assumption may result in misleading welfare estimates if ANA reflects preferences. This is the first paper to assess if ANA is a heuristic or genuine preference without relying on respondents' self-stated motivation and the first study to explore this question within a health context. Based on findings from cognitive psychology, we expect that familiar respondents are less likely to use a decision heuristic to simplify choices than unfamiliar respondents. We employ a latent class model of discrete choice experiment data concerned with National Health Service managers' preferences for support services that assist with performance concerns. We present quantitative and qualitative evidence that in our study ANA mostly represents preferences. We also show that wrong assumptions about ANA result in inadequate welfare measures that can result in suboptimal policy advice. Future research should proceed with caution when assuming that ANA is a heuristic.

Generalized Swift-Hohenberg models for dense active suspensions.

In describing the physics of living organisms, a mathematical theory that captures the generic ordering principles of intracellular and multicellular dynamics is essential for distinguishing between universal and system-specific features. Here, we compare two recently proposed nonlinear high-order continuum models for active polar and nematic suspensions, which aim to describe collective migration in dense cell assemblies and the ordering processes in ATP-driven microtubule-kinesin networks, respectively. We discuss the phase diagrams of the two models and relate their predictions to recent experiments. The satisfactory agreement with existing experimental data lends support to the hypothesis that non-equilibrium pattern formation phenomena in a wide range of active systems can be described within the same class of higher-order partial differential equations.

Meso-scale turbulence in living fluids.

Turbulence is ubiquitous, from oceanic currents to small-scale biological and quantum systems. Self-sustained turbulent motion in microbial suspensions presents an intriguing example of collective dynamical behavior among the simplest forms of life and is important for fluid mixing and molecular transport on the microscale. The mathematical characterization of turbulence phenomena in active nonequilibrium fluids proves even more difficult than for conventional liquids or gases. It is not known which features of turbulent phases in living matter are universal or system-specific or which generalizations of the Navier-Stokes equations are able to describe them adequately. Here, we combine experiments, particle simulations, and continuum theory to identify the statistical properties of self-sustained meso-scale turbulence in active systems. To study how dimensionality and boundary conditions affect collective bacterial dynamics, we measured energy spectra and structure functions in dense Bacillus subtilis suspensions in quasi-2D and 3D geometries. Our experimental results for the bacterial flow statistics agree well with predictions from a minimal model for self-propelled rods, suggesting that at high concentrations the collective motion of the bacteria is dominated by short-range interactions. To provide a basis for future theoretical studies, we propose a minimal continuum model for incompressible bacterial flow. A detailed numerical analysis of the 2D case shows that this theory can reproduce many of the experimentally observed features of self-sustained active turbulence.

Preferences of Patients with Amyotrophic Lateral Sclerosis for Intrathecal Drug Delivery: Choosing between an Implanted Drug-Delivery Device and Therapeutic Lumbar Puncture.

BACKGROUND: Novel intrathecal treatments for amyotrophic lateral sclerosis (ALS) may require delivery using lumbar puncture (LP). Implanted drug-delivery devices (IDDDs) could be an alternative but little is known about patients' preferences for intrathecal drug-delivery methods. OBJECTIVE: We aimed to elicit preferences of patients with ALS for routine LP and IDDD use. METHODS: A discrete choice experiment (DCE) and a threshold technique (TT) exercise were conducted online among patients with ALS in the US and Europe. In the DCE, patients made trade-offs between administration attributes. Attributes were identified from qualitative interviews. The TT elicited maximum acceptable risks (MARs) of complications from device implantation surgery. DCE data were analyzed using mixed logit to quantify relative attribute importance (RAI) as the maximum contribution of each attribute to a preference, and to estimate MARs of device failure. TT data were analyzed using interval regression. Four scenarios of LP and IDDD were compared. RESULTS: Participants (N = 295) had a mean age of 57.7 years; most (74.2%) were diagnosed < 3 years ago. Preferences were affected by device failure risk (RAI 28.6%), administration frequency (26.4%), administration risk (19.7%), overall duration (17.8%), and appointment location (7.5%). Patients accepted a 5.6% device failure risk to reduce overall duration from 2 h to 30 min and a 3.6% risk for administration in a local clinic instead of a hospital. The average MAR of complications from implantation surgery was 29%. Patients preferred IDDD over LP in three of four scenarios. CONCLUSION: Patients considered an IDDD as a valuable alternative to LP in multiple clinical settings.

From Qualitative Research to Quantitative Preference Elicitation: An Example in Invasive Meningococcal Disease.

BACKGROUND: Qualitative research is fundamental for designing discrete choice experiments (DCEs) but is often underreported in the preference literature. We developed a DCE to elicit preferences for vaccination against invasive meningococcal disease (IMD) among adolescents and young people (AYP) and parents and legal guardians (PLG) in the United States. This article reports the targeted literature review and qualitative interviews that informed the DCE design and demonstrates how to apply the recent reporting guidelines for qualitative developmental work in preference studies. METHODS: This study included two parts: a targeted literature review and qualitative interviews. The Medline and Embase databases were searched for quantitative and qualitative studies on IMD and immunization. The results of the targeted literature review informed a qualitative interview guide. Sixty-minute, online, semi-structured interviews with AYP and PLG were used to identify themes related to willingness to be vaccinated against IMD. Participants were recruited through a third-party recruiter's database and commercial online panels. Interviews included vignettes about IMD and vaccinations and three thresholding exercises examining the effect of incidence rate, disability rate, and fatality rate on vaccination preferences. Participant responses related to the themes were counted. RESULTS: The targeted literature review identified 31 concepts that were synthesized into six topics for the qualitative interviews. Twenty AYP aged 16-23 years and 20 PLG of adolescents aged 11-17 years were interviewed. Four themes related to willingness to be vaccinated emerged: attitudes towards vaccination, knowledge and information, perception of IMD, and vaccine attributes. Most participants were concerned about IMD (AYP 60%; PLG 85%) and had positive views of vaccination (AYP 80%; PLG 60%). Ninety percent of AYP and 75% of PLG always chose vaccination over no vaccination, independent of IMD incidence rate, disability rate, or fatality rate. CONCLUSION: Willingness to be vaccinated against IMD was affected by vaccine attributes but largely insensitive to IMD incidence and severity. This article provides an example of how to apply the recent reporting guidelines for qualitative developmental work in preference studies, with 21 out of 22 items in the guidelines being considered.

What benefit-risk trade-offs are acceptable to rheumatoid arthritis patients during treatment selection? Evidence from a multicountry choice experiment.

OBJECTIVE: Understanding preferences of patients with rheumatoid arthritis (RA) can facilitate tailored patient-centric care. This study elicited trade-offs that patients with RA were willing to make during treatment selection. METHODS: Patients with RA completed an online discrete choice experiment, consisting of a series of choices between hypothetical treatments. Treatment attributes were selected based on literature review and qualitative patient interviews. Eligible patients were ≥18 years old, diagnosed with RA, receiving systemic disease-modifying antirheumatic drug therapy, and residents of Europe or USA. Male patients were oversampled for subgroup analyses. Data were analysed using a correlated mixed logit model. RESULTS: Of 2090 participants, 42% were female; mean age was 45.2 years (range 18-83). Estimated effects were significant for all attributes (p<0.001) but varied between patients. Average relative attribute importance scores revealed different priorities (p<0.001) between males and females. While reducing pain and negative effect on semen parameters was most important to males, females were most concerned by risk of blood clots and serious infections. No single attribute explained treatment preferences by more than 30%. Preferences were also affected by patients' age: patients aged 18-44 years placed less importance on frequency and mode of treatment administration (p<0.05) than older age groups. Patients were willing to accept higher risk of serious infections and blood clots in exchange for improvements in pain, daily activities or administration convenience. However, acceptable trade-offs varied between patients (p<0.05). CONCLUSION: Treatment preferences of patients with RA were individual-specific, but driven by benefits and risks, with no single attribute dominating the decision-making.

Fluid dynamics of bacterial turbulence.

Self-sustained turbulent structures have been observed in a wide range of living fluids, yet no quantitative theory exists to explain their properties. We report experiments on active turbulence in highly concentrated 3D suspensions of Bacillus subtilis and compare them with a minimal fourth-order vector-field theory for incompressible bacterial dynamics. Velocimetry of bacteria and surrounding fluid, determined by imaging cells and tracking colloidal tracers, yields consistent results for velocity statistics and correlations over 2 orders of magnitude in kinetic energy, revealing a decrease of fluid memory with increasing swimming activity and linear scaling between kinetic energy and enstrophy. The best-fit model allows for quantitative agreement with experimental data.

Clinicians' preferences for managing aneurysmal subarachnoid hemorrhage using endothelin receptor antagonists.

Background: The endothelin receptor antagonist (ERA) clazosentan is being investigated for the medical prevention of cerebral vasospasm and associated complications, such as delayed cerebral ischemia (DCI), after aneurysmal subarachnoid hemorrhage (aSAH). This study quantified how clinicians weigh the benefits and risks of ERAs for DCI prevention to better understand their treatment needs and expectations. Methods: An online choice experiment was conducted to elicit preferences of neurologists, intensivists, and neurosurgeons treating aSAH in the US and UK for the use of ERAs. The design of the choice experiment was informed by a feasibility assessment (N = 100), one-on-one interviews with clinicians (N = 10), a qualitative pilot (N = 13), and a quantitative pilot (N = 50). Selected treatment attributes included in the choice experiment were: one benefit (likelihood of DCI); and three risks (lung complications, hypotension, and anemia). In the choice experiment, clinicians repeatedly chose best and worst treatment options based on a scenario of a patient being treated in the ICU after aneurism repair. A correlated mixed logit model determined the relative attribute importance (RAI) and associated highest density interval (HDI) as well as acceptable benefit-risk trade-offs. Results: The final choice experiment was completed by 350 clinicians (116 neurologists, 129 intensivists/intensive care clinicians, and 105 neurosurgeons; mean age, 47.4 years). Reducing the likelihood of DCI (RAI = 56.5% [HDI, 53.6-59.5%]) had the largest impact on clinicians' treatment choices, followed by avoiding the risks of lung complications (RAI = 29.6% [HDI, 27.1-32.3%]), hypotension (RAI = 9.2% [HDI, 7.5-10.8%]), and anemia (RAI = 4.7% [HDI, 3.7-5.8%]). Clinicians expected the likelihood of DCI to decrease by ≥8.1% for a 20% increase in the risk of lung complications, ≥2.4% for a 20% increase in the risk of hypotension, and ≥1.2% for a 20% increase in the risk of anemia. Conclusions: Clinicians were willing to accept certain increased risks of adverse events for a reduced risk of DCI after aSAH. The likelihood of DCI occurring after aSAH can therefore be considered a clinically relevant endpoint in aSAH treatment development. Thus, evaluations of ERAs might focus on whether improvements (i.e., reductions) in the likelihood of DCI justify the risks of adverse events.

Patient Preferences for Treatment of Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer: A Cross-country Choice Experiment.

Background: Patients with non-muscle-invasive bladder cancer (NMIBC) that is unresponsive to bacillus Calmette-Guérin (BCG) immunotherapy face a difficult choice. Immediate radical cystectomy (RC) is effective but might represent overtreatment. Continuing bladder preservation with medical therapy is an alternative, but it risks progression to muscle-invasive bladder cancer (MIBC) and a reduction in survival. Objective: To understand the trade-offs patients are willing to make in selecting treatments for BCG-unresponsive NMIBC. Design setting and participants: Adults with NMIBC from the UK, France, Germany, and Canada who reported current receipt of BCG, disease unresponsive to BCG, or receipt of RC in the previous 12 mo after failure of BCG were recruited to participate in an online choice experiment. Patients were asked to make repeated choices between two hypothetical medical treatments and the option to undergo immediate RC. The medical treatments required trade-offs between the time to RC, the mode and frequency of administration, the risk of experiencing serious side effects, and the risk of disease progression. Outcome measurements and statistical analysis: Error component logit models were used to calculate relative attribute importance (RAI) scores as the maximum percentage contribution to a preference and acceptable benefit-risk trade-offs. Results and limitations: Most of the 107 participants (average age 63 yr) never selected RC (89%) as their preferred option in the choice experiment. Preferences were most affected by time to RC (RAI 55%), followed by risk of progressing to MIBC (RAI 25%), medication administration (RAI 12%), and the risk of serious side effects (RAI 8%). To increase the time to RC from 1 yr to 6 yr, patients accepted a 43.8% increase in the risk of progression and a 66.1% increase in the risk of serious side effects. Conclusions: Patients with BCG-treated NMIBC valued bladder-sparing treatments and were willing to make substantial benefit-risk trade-offs to delay RC. Patient summary: Adults with bladder cancer not invading the bladder muscle completed an online experiment in which they chose between hypothetical medications and bladder removal. The results show that patients would be willing to accept different risks associated with medications to delay bladder removal. Patients considered disease progression the most important risk of medicinal treatment.