Eliciting Exploratory Patient Preference Data: A Case Study in a Rare Disease.

INTRODUCTION: Qualitative and quantitative methods provide different and complementary insights into patients' preferences for treatment. OBJECTIVE: The aim of this study was to use a novel, mixed-methods approach employing qualitative and quantitative approaches to generate preliminary insights into patient preferences for the treatment of a rare disease-generalized myasthenia gravis (gMG). METHODS: We conducted a mixed-methods study to collect exploratory qualitative and quantitative patient preference information and generate informative results within a condensed timeline (about 4 months). Recruitment was facilitated by an international health research firm. Study participants first reviewed a brief document describing six treatment attributes (to facilitate more efficient review of the material during the focus groups) and were then provided a link to complete an online quantitative survey with a single risk threshold task. They then participated in online focus groups, during which they discussed qualitative questions about their experience with gMG treatment and completed up to three quantitative threshold tasks, the first of which repeated the threshold task from the online survey. RESULTS: The study elicited both quantitative data on 18 participants' risk tolerance and qualitative data on their treatment experience, additional treatment attributes of importance, the reasoning behind their preferences, and the trade-offs they were willing to make. Most participants (n = 15) chose the same hypothetical treatment in the first threshold task in the online survey and the focus groups. Focus group discussions provided insights into participants' choices in the threshold tasks, confirmed that all the attributes were relevant, and helped clarify what was important about the attributes. CONCLUSIONS: Patient preference information can be collected using a variety of approaches, both qualitative and quantitative, tailored to fit the research needs of a study. The novel mixed-methods approach employed in this study efficiently captured patient preference data that were informative for exploratory research, internal decision making, and future research.

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.

Assessing Patient Preferences in Rare Diseases: Direct Preference Elicitation in the Rare Chronic Kidney Disease, Immunoglobulin A Nephropathy.

BACKGROUND: Patient preference information is increasingly being used to inform decision making; however, further work is required to support the collection of preference information in rare diseases. This study illustrates the use of direct preference elicitation methods to collect preference data from small samples in the context of early decision making to inform the development of a product for the treatment of immunoglobulin A nephropathy. METHOD: An interview-based swing weighting approach was used to elicit preferences from 40 patients in the US and China. Attributes were identified through a background review, expert engagement and patient focus groups. Participants completed a series of tasks that involved ranking, rating and scoring improvements in the attributes to obtain attribute swing weights and partial value functions. The preference results were then incorporated into a benefit-risk assessment simulation tool. RESULTS: Participants placed the greatest value on avoiding end-stage renal/kidney disease. Similar weight was given to short-term quality-of-life improvements and avoiding infections. Treatment burden (number of vaccinations) received the least weight. Heterogeneity in preferences was also observed. Consistency tests did not identify statistically significant variation in preferences, and qualitative data suggested that the elicitation exercise was sensitive to participants' interpretation of attributes and that participants were able to express their preferences. CONCLUSION: Direct preference elicitation methods can be used to collect preference data from small samples. Further work should continue to test the validity of the estimate generated by such methods.

Alignment of preferences in the treatment of multiple myeloma - a discrete choice experiment of patient, carer, physician, and nurse preferences.

BACKGROUND: Multiple Myeloma (MM) is a cancer characterised by the proliferation of malignant plasma cells in the bone marrow. This study examined the treatment preferences of people living with MM compared to the treatment preferences of other groups involved in treatment decision making, including carers, as well as physicians and nurses who treat people living with MM in Australia. METHODS: Data were collected using discrete choice experiments (DCEs) through an online survey. The DCEs presented participants with a traditional treatment generic choice experiment (e.g., treatment A vs treatment B), focusing on the clinical benefits of treatments and the associated risks. The attributes and levels of the attributes were selected based on previous research, literature review, qualitative research and expert opinion. The DCE data were modelled using a Latent Class Model (LCM). RESULTS: The model revealed significant heterogeneity in preferences for treatment attributes. In particular, overall survival, remission period and annual out of pocket cost were the attributes with the most variation. In comparison to people living with MM, carers were less cost-sensitive and more concerned with quality of life (remission period). Physicians and nurses were generally more concerned with overall survival and more cost sensitive than people living with MM. CONCLUSIONS: This study demonstrated that not all people living with MM valued the same treatment attributes equally. Further, not all groups involved in MM treatment decision making had preference alignment on all treatment attributes. This has important implications for healthcare policy decisions and shared decision making. Results from this study could be used to guide decisions around the value of new MM medicines or the medical plan surrounding the needs of those living with MM, as well as those caring for them.

Patient and physician preferences for atopic dermatitis injection treatments in Japan.

Background: Recently, biologic agents administered as a subcutaneous injection have been introduced as treatment options for atopic dermatitis (AD). Biologic treatments differ considerably from traditional topical and systemic anti-inflammatory treatments, and it is unclear how this may impact patient and physician preferences for treatments.Objective: To examine the treatment preferences for new injection treatments of patients and physicians.Methods: Discrete choice experiment methodology was used to quantify preferences for treatments via an online survey. Participants were presented with a series of choice scenarios; treatment options were described using the following attributes: add-on or replacement treatment, efficacy of improving rashes and itching, time until response, place of administration, injection site reaction, risk of mild-to-moderate and severe side effects, frequency of administration and cost.Results: 76.67% of physicians and 46.24% of patients opted-in to the new treatment in the scenarios presented. Of those who opted-in to treatment, physicians were more likely to value the efficacy of treating rashes and were more concerned about cost than patients. Patients preferred add-on treatments and were against self-administering the treatment at home.Conclusion: Overall patients and physicians differ in their preferences for AD treatments. These findings have implications for shared decision making and clinical practice.

What do Australian patients with inflammatory arthritis value in treatment? A discrete choice experiment.

BACKGROUND AND OBJECTIVES: The purpose of this study was to develop an understanding of treatment preferences in patients with inflammatory arthritis (IA) [rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA)] focussing on treatment attributes that patients' value, their relative importance, and the risk-benefit trade-offs that characterise patients' choices around treatment. METHODS: A discrete choice experiment (DCE) approach was used. Attributes of interest were clinical efficacy; slowing of disease progression; risk of mild-moderate side effects; risk of severe side effects; frequency of administration; real-world product evidence; management of related conditions; and availability of a patient support programme. Using data from the DCE component, a restricted latent class model (LCM) was estimated to determine discrete 'classes' of treatment preferences. RESULTS: In this analysis, 206 participants were included (AS n = 59; PsA n = 62; RA n = 85). Two classes were identified. For 'class 1' (59.9%), the most important attributes (across all treatment modalities) were preventing disease progression, clinical efficacy and risk of mild-to-moderate side effects. For 'class 2' (40.1%), clinical and non-clinical attributes were important, and attribute importance depended on treatment modality. Patient demographic and treatment characteristics did not predict class membership. CONCLUSION: For most patients with IA, clinical efficacy, stopping disease progression and risks of mild-to-moderate side effects are important treatment attributes. Patients with prior biologic DMARD experience had greater preference for injection treatments. For a subset of patients, patient support programmes and the frequency of administration were important. Clinicians should be mindful of preferences when prescribing treatment to patients with IA.Key Points• Most patients consider clinical efficacy, stopping disease progression and the risk of mild-to-moderate side effects as important treatment attributes• Patients with prior biologic DMARD experience have greater preference for injection treatments.• For a subset of patients, patient support programmes, and the frequency of administration were important.• Clinicians should be mindful of preferences when prescribing treatment to patients with IA.

Increase in PAS-induced neuroplasticity after a treatment course of intranasal ketamine for depression. Report of three cases from a placebo-controlled trial.

BACKGROUND: Animal studies suggest that neural plasticity may play a role in the antidepressant effects of a single ketamine dose. However, the potential effects of repeated ketamine treatments on human neuroplasticity are unknown. METHODS: This pilot RCT study measured plasticity-induced changes before and after a ketamine course, in three treatment-resistant depressed subjects, who were randomized to receive 8 intranasal treatments of 100mg ketamine or 4.5mg midazolam. Mood ratings were performed by a trained blinded rater at baseline and 24h-48h after the ketamine course, using the Montgomery Asberg Depression Rating Scale (MADRS). Neuroplasticity was assessed in the motor cortex using a paired associative stimulation (PAS) paradigm at baseline and 24h-48h after the treatment course. No changes in current psychotropic medication or dosage were permitted for 4weeks prior to trial entry and throughout the trial. RESULTS: The subject receiving ketamine, but not those receiving midazolam, presented a marked increase in neural plasticity after the treatment course. However, mood changes were not associated with changes in neural plasticity. LIMITATIONS: Pilot study with small sample size. Concomitant antidepressant medications taken. Plasticity was tested in the motor cortex only, thus the generalizability of these findings to other brain areas cannot be assumed. CONCLUSIONS: These results suggest that a course of intranasal ketamine may enhance synaptic plasticity in subjects with depression, but this was not associated with antidepressant effects. Further research on this topic is warranted.

The Effect of Transcranial Direct Current Stimulation (tDCS) Electrode Size and Current Intensity on Motor Cortical Excitability: Evidence From Single and Repeated Sessions.

BACKGROUND: Current density is considered an important factor in determining the outcomes of tDCS, and is determined by the current intensity and electrode size. Previous studies examining the effect of these parameters on motor cortical excitability with small sample sizes reported mixed results. OBJECTIVE/HYPOTHESIS: This study examined the effect of current intensity (1 mA, 2 mA) and electrode size (16 cm(2), 35 cm(2)) on motor cortical excitability over single and repeated tDCS sessions. METHODS: Data from seven studies in 89 healthy participants were pooled for analysis. Single-session data were analyzed using mixed effects models and repeated-session data were analyzed using mixed design analyses of variance. Computational modeling was used to examine the electric field generated. RESULTS: The magnitude of increases in excitability after anodal tDCS was modest. For single-session tDCS, the 35 cm(2) electrodes produced greater increases in cortical excitability compared to the 16 cm(2) electrodes. There were no differences in the magnitude of cortical excitation produced by 1 mA and 2 mA tDCS. The repeated-sessions data also showed that there were greater increases in excitability with the 35 cm(2) electrodes. Further, repeated sessions of tDCS with the 35 cm(2) electrodes resulted in a cumulative increase in cortical excitability. Computational modeling predicted higher electric field at the motor hotspot for the 35 cm(2) electrodes. CONCLUSIONS: 2 mA tDCS does not necessarily produce larger effects than 1 mA tDCS in healthy participants. Careful consideration should be given to the exact positioning, size and orientation of tDCS electrodes relative to cortical regions.

Inter- and Intra-individual Variability in Response to Transcranial Direct Current Stimulation (tDCS) at Varying Current Intensities.

BACKGROUND: Translation of transcranial direct current stimulation (tDCS) from research to clinical practice is hindered by a lack of consensus on optimal stimulation parameters, significant inter-individual variability in response, and in sufficient intra-individual reliability data. OBJECTIVES: Inter-individual differences in response to anodal tDCS at a range of current intensities were explored. Intra-individual reliability in response to anodal tDCS across two identical sessions was also investigated. METHODS: Twenty-nine subjects participated in a crossover study. Anodal-tDCS using four different current intensities (0.2, 0.5, 1 and 2 mA), with an anode size of 16 cm2, was tested. The 0.5 mA condition was repeated to assess intra-individual variability. TMS was used to elicit 40 motor-evoked potentials (MEPs) before 10 min of tDCS, and 20 MEPs at four time-points over 30 min following tDCS. RESULTS: ANOVA revealed no main effect of TIME for all conditions except the first 0.5 mA condition, and no differences in response between the four current intensities. Cluster analysis identified two clusters for the 0.2 and 2 mA conditions only. Frequency distributions based on individual subject responses (excitatory, inhibitory or no response) to each condition indicate possible differential responses between individuals to different current intensities. Test-retest reliability was negligible (ICC(2,1) = -0.50). CONCLUSIONS: Significant inter-individual variability in response to tDCS across a range of current intensities was found. 2 mA and 0.2 mA tDCS were most effective at inducing a distinct response. Significant intra-individual variability in response to tDCS was also found. This has implications for interpreting results of single-session tDCS experiments.

Neuromodulation therapies for geriatric depression.

Depression is frequent in old age and its prognosis is poorer than in younger populations. The use of pharmacological treatments in geriatric depression is limited by specific pharmacodynamic age-related factors that can diminish tolerability and increase the risk of drug interactions. The possibility of modulating cerebral activity using brain stimulation techniques could result in treating geriatric depression more effectively while reducing systemic side effects and medication interactions. This may subsequently improve treatment adherence and overall prognosis in the older patient. Among clinically available neuromodulatory techniques, electroconvulsive therapy (ECT) remains the gold standard for the treatment of severe depression in the elderly. Studies have proven that ECT is more effective and has a faster onset of action than antidepressants in the treatment of severe, unipolar, geriatric depression and that older age is a predictor of rapid ECT response and remission. The application of novel and more tolerable forms of ECT for geriatric depression is currently being examined. Preliminary results suggest that right unilateral ultrabrief ECT (RUL-UB ECT) is a promising intervention, with similar efficacy to brief-pulse ECT and fewer adverse cognitive effects. Overall findings in repetitive transcranial magnetic stimulation (rTMS) suggest that it is a safe intervention in geriatric depression. Higher rTMS stimulation intensity and more treatments may need to be given in the elderly to achieve optimal results. There is no specific data on vagus nerve stimulation in the elderly. Transcranial direct current stimulation, magnetic seizure therapy and deep brain stimulation are currently experimental, and more data from geriatric samples is needed.

Clinical Pilot Study and Computational Modeling of Bitemporal Transcranial Direct Current Stimulation, and Safety of Repeated Courses of Treatment, in Major Depression.

OBJECTIVES: This study aimed to examine a bitemporal (BT) transcranial direct current stimulation (tDCS) electrode montage for the treatment of depression through a clinical pilot study and computational modeling. The safety of repeated courses of stimulation was also examined. METHODS: Four participants with depression who had previously received multiple courses of tDCS received a 4-week course of BT tDCS. Mood and neuropsychological function were assessed. The results were compared with previous courses of tDCS given to the same participants using different electrode montages. Computational modeling examined the electric field maps produced by the different montages. RESULTS: Three participants showed clinical improvement with BT tDCS (mean [SD] improvement, 49.6% [33.7%]). There were no adverse neuropsychological effects. Computational modeling showed that the BT montage activates the anterior cingulate cortices and brainstem, which are deep brain regions that are important for depression. However, a fronto-extracephalic montage stimulated these areas more effectively. No adverse effects were found in participants receiving up to 6 courses of tDCS. CONCLUSIONS: Bitemporal tDCS was safe and led to clinically meaningful efficacy in 3 of 4 participants. However, computational modeling suggests that the BT montage may not activate key brain regions in depression more effectively than another novel montage--fronto-extracephalic tDCS. There is also preliminary evidence to support the safety of up to 6 repeated courses of tDCS.

Comparison of the effects of transcranial random noise stimulation and transcranial direct current stimulation on motor cortical excitability.

OBJECTIVE: The objective of this study was to examine the effect of transcranial random noise stimulation (tRNS) with and without a direct current (DC) offset on motor cortical excitability and compare results to transcranial DC stimulation (tDCS). METHODS: Fifteen healthy participants were tested in a within-subjects design. Motor-evoked potentials were measured before and up to 90 minutes after stimulation using transcranial magnetic stimulation. Five stimulation conditions were examined: sham, 1-mA tDCS, 2-mA tDCS, 2-mA tRNS (with no DC offset), and 2-mA tRNS + 1-mA DC offset. RESULTS: There were no significant differences between the stimulation conditions. An analysis of individual stimulation conditions found that there was a significant increase in motor-evoked potential amplitudes after 1-mA tDCS, 2-mA tDCS, and 2-mA tRNS + DC offset when compared with baseline. Sham and 2-mA tRNS did not result in changes in cortical excitability. CONCLUSIONS: Although differences between the stimulation conditions did not reach a statistical significance, the findings suggest that stimulation involving a DC (tDCS and tRNS + DC offset) but not solely tRNS is more likely to lead to increases in cortical excitability.

A pilot study of alternative transcranial direct current stimulation electrode montages for the treatment of major depression.

BACKGROUND: Typically, transcranial direct current stimulation (tDCS) treatments for depression have used bifrontal montages with anodal (excitatory) stimulation targeting the left dorsolateral prefrontal cortex (DLPFC). There is limited research examining the effects of alternative electrode montages. OBJECTIVE/HYPOTHESIS: This pilot study aimed to examine the feasibility, tolerability and safety of two alternative electrode montages and provide preliminary data on efficacy. The montages, Fronto-Occipital (F-O) and Fronto-Cerebellar (F-C), were designed respectively to target midline brain structures and the cerebellum. METHODS: The anode was placed over the left supraorbital region and the cathode over the occipital and cerebellar region for the F-O and F-C montages respectively. Computational modelling was used to determine the electric fields produced in the brain regions of interest compared to a standard bifrontal montage. The two montages were evaluated in an open label study of depressed participants (N=14). Mood and neuropsychological functioning were assessed at baseline and after four weeks of tDCS. RESULTS: Computational modelling revealed that the novel montages resulted in greater activation in the anterior cingulate cortices and cerebellum than the bifrontal montage, while activation of the DLPFCs was higher for the bifrontal montage. After four weeks of tDCS, overall mood improvement rates of 43.8% and 15.9% were observed under the F-O and F-C conditions, respectively. No significant neuropsychological changes were found. LIMITATIONS: The clinical pilot was open-label, without a control condition and computational modelling was based on one healthy participant. CONCLUSIONS: Results found both montages safe and feasible. The F-O montage showed promising antidepressant potential.

When size matters: large electrodes induce greater stimulation-related cutaneous discomfort than smaller electrodes at equivalent current density.

BACKGROUND: Cutaneous discomfort is typically reported during transcranial direct current stimulation (tDCS), restricting the current intensity and duration at which tDCS can be applied. It is commonly thought that current density is associated with the intensity of perceived cutaneous perception such that larger electrodes with a lower current density results in milder cutaneous sensations. OBJECTIVE: The present study examined the relationship between current density, current intensity and cutaneous sensations perceived during tDCS. METHODS: Two experiments were performed. In the first control experiment, the cutaneous sensations induced by varying current intensities (0.025, 0.5, 1.0 and 1.5 mA) were examined up to 10 min. These data were used for optimizing inter-stimulation intervals in the second main experiment, where participants rated the intensity, spatial size and location of the cutaneous sensations experienced during tDCS using two electrodes sizes (16 cm2 and 35 cm2). In the equivalent current density condition, the current density was kept constant under both electrodes (0.014, 0.029 and 0.043 mA/cm2), whereas in the equal current intensity condition (0.5, 1.0 and 1.5 mA) the same intensities were used for the two electrode sizes. RESULTS: Large electrodes were associated with greater cutaneous discomfort when compared to smaller electrodes at a given current density. Further, levels of cutaneous perception were similar for small and large electrodes when current intensity was kept constant. CONCLUSION: Cutaneous sensations during stimulation can be minimized by reducing the electrode size from 35 cm2 to 16 cm2.

A computational modelling study of transcranial direct current stimulation montages used in depression.

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique which involves passing a mild electric current to the brain through electrodes placed on the scalp. Several clinical studies suggest that tDCS may have clinically meaningful efficacy in the treatment of depression. The objective of this study was to simulate and compare the effects of several tDCS montages either used in clinical trials or proposed, for the treatment of depression, in different high-resolution anatomically-accurate head models. Detailed segmented finite element head models of two subjects were presented, and a total of eleven tDCS electrode montages were simulated. Sensitivity analysis on the effects of changing the size of the anode, rotating both electrodes and displacing the anode was also conducted on selected montages. The F3-F8 and F3-F4 montages have been used in clinical trials reporting significant antidepressant effects and both result in relatively high electric fields in dorsolateral prefrontal cortices. Other montages using a fronto-extracephalic or fronto-occipital approach result in greater stimulation of central structures (e.g. anterior cingulate cortex) which may be advantageous in treating depression, but their efficacy has yet to be tested in randomised controlled trials. Results from sensitivity analysis suggest that electrode position and size may be adjusted slightly to accommodate other priorities, such as skin discomfort and damage.

Continuation transcranial direct current stimulation for the prevention of relapse in major depression.

BACKGROUND: Transcranial direct current stimulation (tDCS) is gaining attention as an effective new treatment for major depression. Little is known, however, of the duration of antidepressant effects following acute treatment. In this study, we describe the use of continuation tDCS treatment for up to 6 months following clinical response to an acute treatment course. METHODS: Twenty-six participants pooled from two different studies involving different tDCS protocols received continuation tDCS treatment on a weekly basis for 3 months and then once per fortnight for the final 3 months. Mood ratings were completed at 3 and 6 months. Analyses examined clinical predictors of relapse during continuation tDCS treatment. RESULTS: The cumulative probability of surviving without relapse was 83.7% at 3 months and 51.1% at 6 months. Medication resistance was found to be a predictor of relapse during continuation tDCS. LIMITATIONS: This was an open label prospective study with no control group. Two different forms of tDCS were used. CONCLUSION: Similar to other antidepressant treatments, continuation tDCS appears to be a useful strategy to prevent relapse following clinical response. These preliminary data suggest that the majority of patients maintained antidepressant benefit with a continuation schedule of at least weekly treatment. Future controlled studies are required to confirm these findings.