Clinician's attitudes & perspective on chemical adherence testing in hypertension (CATCH): A qualitative interview study

Abstract

Aims

Chemical Adherence Testing (CAT) is gaining prominence as a reliable and valid clinical method to detect whether antihypertensive agents are being taken as prescribed. This study aimed to explore clinicians' attitudes and perspectives on the clinical use of CAT.

Methods

Clinicians involved in hypertension care were recruited through purposive and snowball sampling (N = 9). Participants represented general practice, cardiology, geriatric medicine, clinical pharmacology, nephrology and internal medicine. Semi‐structured interviews were carried out, and transcripts were analysed using reflexive thematic analysis with an inductive, constructivist approach. Theme development was peer‐reviewed by a health psychologist and clinical pharmacologist to enhance reflexivity.

Results

Three themes were developed: (1) The impactful weight of new evidence‐ CAT was perceived as a valuable, more objective tool for checking for non‐adherence and informing treatment, especially in cases of suspected treatment‐resistant hypertension; (2) CAT meets clinical reality‐ participants highlighted practical barriers such as test availability, workflow disruption, staffing needs and costs that could impact implementation in an overburdened healthcare system; (3) The human side of CAT‐ while CAT supported discussions around adherence, clinicians highlighted the need for trust, consent and sensitive communication to avoid perceptions of policing or blame.

Conclusion

Clinicians viewed CAT as a promising tool for improving diagnostic clarity and prompting adherence discussions. However, concerns about logistical feasibility, ethical use and potential strain on patient relationships were evident. Successful implementation requires clinician training, clear communication and system‐level support to ensure CAT is integrated in an ethical, patient‐centred way that preserves trust and supports collaborative care.

What is already known about this subject

• Chemical adherence testing (CAT) is gaining prominence as a useful clinical tool to assess medication adherence as part of hypertension care.

• There is an emerging evidence base about the feasibility and acceptability of CAT for patients, however further qualitative evidence from clinical stakeholders is needed before CAT can be successfully implemented in routine hypertension care.

What this study adds

• Clinicians valued CAT's objectivity in addressing medication non‐adherence, but recognized practical and ethical considerations that could limit widespread implementation of CAT.

• CAT potentially risks being perceived as intrusive, punitive or weakening trust, unless it is framed as a supportive, dialogue‐enhancing tool, rather than a surveillance method to catch patients out.

1. INTRODUCTION

Adherence rates to prescribed medications are particularly low among people with hypertension. ¹ This gives rise to a pernicious clinical problem, which healthcare providers report feeling ill‐equipped to meet. ² A systematic review and meta‐analysis by Durand et al., ³ which included studies from multiple international healthcare contexts, found an average non‐adherence rate of 31% in patients labelled as having apparent treatment‐resistant hypertension (aTRH). Studies relying on self‐report (13%) or pharmacy data (19%) demonstrate significantly lower rates of non‐adherence compared with those using direct measurements such as urine or blood tests (49%) or directly observed therapy (45%). ³ , ⁴

One category of more objective adherence assessment is referred to as Chemical Adherence Testing (CAT). CAT uses blood or urine samples to confirm the ingestion of medications. ⁵ It involves the chemical analysis of patient samples, using methods such as liquid chromatography high resolution mass spectrometry (LC‐HRMS), which is favoured for its high sensitivity and efficiency. ⁶ CAT provides a point‐in‐time estimation of adherence by detecting the presence or absence of prescribed medications and their metabolites in bodily fluids. ⁷ This method represents an important alternative method in detecting non‐adherence compared to more subjective measures, which can potentially overestimate adherence. ⁸ LC‐HRMS is currently only available in specialized central laboratories with a typical turnaround time of at least 2 weeks.

However, CAT is not without limitations. Gupta et al. ⁶ noted that some patients might feel monitored or lose a sense of autonomy. Soldan et al. ⁹ found that some patients receiving unexpected CAT results felt embarrassed or frustrated by their non‐adherence, while others denied the results and felt wrongly accused. There are also concerns that CAT might damage the therapeutic relationship between patients and clinicians. ⁷ , ¹⁰ Despite these worries, evidence from centres carrying CAT out at scale over several years indicates that only a minority of patients refuse CAT and that on the contrary, many patients appreciate open, respectful discussions about CAT results. ⁷ , ¹⁰

Two significant concerns, however, is the potential for CAT to be perceived as ‘policing’ patients, which could potentially lead to feelings of humiliation, disappointment, anger or feeling ‘falsely accused’ among patients ¹ , ⁹ and the generation of new clinical tasks and time pressures for clinicians. Many healthcare providers involved in hypertension care frequently report that they do not have enough time to support this type of new clinical tests. ² , ⁸ , ¹¹ Although CAT is becoming increasingly accepted and recommended by clinical guidelines, ¹² , ¹³ it is not yet widely available ⁵ and more qualitative evidence, in particular, is needed to support effective implementation.

While patient perceptions of the acceptability of CAT have been studied, much less is known about how clinicians perceive this clinical tool. The aim of this study is to examine how clinicians perceive CAT, including its potential benefits, challenges and impact on patient care. Specifically, the research will aim to investigate clinicians' experiences or perspectives with CAT, identify any ethical considerations and explore what additional support may be required to effectively implement CAT in routine clinical practice.

2. METHODS

2.1. Design

A qualitative methodology was employed, as it is appropriate for developing rich, in‐depth data on human experiences and professional perspectives. Semi‐structured interviews were employed for their ability to offer both consistency and flexibility, allowing topics to be developed while also allowing participants to reflect, elaborate and introduce issues of personal or professional significance. This approach facilitated a reflexive engagement with the data, enabling the researcher to explore the nuanced, often complex interaction between clinical judgement, patient relationships and systemic pressures in the implementation of CAT. Ethical approval for the study was granted by the University of Galway School of Psychology Research Ethics Committee (SREC, Feb 2025).

2.2. Participants

In total, nine participants were interviewed. This included participants involved in Clinical Pharmacology and Therapeutics (n = 2), Geriatric Medicine (n = 2), General Practice (n = 2), Cardiology (n = 2) and Nephrology (n = 1). Prior to recruitment, a sample size of 10–12 was anticipated in order to achieve information power. ¹⁴ This was based largely on the relatively narrow aim of the study focusing on a very specific class of test that was specified in advance, in a specific clinical condition and the likely information‐rich participants given their expert level of knowledge of their respective clinical contexts. A tenth participant was initially scheduled to take part in the study; however, due to repeated rescheduling and the need to conclude data collection within the study timeline, the interview did not take place.

2.3. Procedure

A combination of purposive and snowball sampling strategies was employed to recruit participants who were clinically involved in hypertension care. This allowed for the intentional selection of individuals with appropriate clinical backgrounds and expertise, while snowball sampling helped identify additional participants through professional networks and recommendations. Interviews were conducted remotely via Microsoft Teams, Zoom or by telephone, depending on participants' preferences. Each interview lasted approximately 15 to 30 min. The semi‐structured interview topic guide was developed based on the aim of the study, the relevant literature on CAT and consultation with a clinical pharmacologist with experience of CAT, hypertension care and the relevant clinical contexts where the study participants were based. All interviews were audio‐recorded with the participants' consent to ensure accuracy in capturing their responses. Recordings were transcribed verbatim by the researcher, and all transcripts were subsequently anonymized to protect participant confidentiality.

2.4. Data‐analysis

Data were analysed using reflexive thematic analysis (RTA). ¹⁵ , ¹⁶ An inductive approach was used. The analysis was based on a constructivist perspective. ¹⁷ , ¹⁸

The RTA process began with data familiarization, which involved the researcher transcribing each interview, listening to the audio recordings and reading the transcripts multiple times. This immersion enabled a deeper understanding of the content and context of participants' responses. From this foundation, initial codes were generated to identify and capture the main features of the data that were relevant to the research questions.

Once coding was completed, the codes were systematically reviewed, compared and assembled into potential candidate themes. The development of themes followed, where candidate themes were reviewed, refined and in some cases restructured or combined to ensure coherence and clarity. To support the development and refinement of themes, two additional members of the research team, a health psychologist and a clinical pharmacologist, assisted in peer‐reviewing and discussing the thematic structure. The purpose of this stage was not to reach consensus, but rather to enrich interpretation through dialogue and reflexivity. ¹⁶ Following this, final themes were clearly defined, named and described in preparation for the narrative reporting of findings.

3. RESULTS

Three themes were identified, two of which have two subthemes. The first theme is the impactful weight of new evidence, which touches on the perceived objectivity of CAT as a tool that can modify practice. The second theme that was developed from the data is noted as CAT meets clinical reality, which explores how participants navigate the dual challenge of integrating CAT into strained healthcare systems while remaining attentive to patient‐centred care. The two subthemes within this theme were the feasibility of introducing a new tool in an overburdened system. The second subtheme focuses on putting patients first in CAT integration. The third theme constructed focuses on the human side of CAT, which addresses the ethical, relational and communication considerations associated with the test. The two subthemes generated within this theme were trust and policing, and the second being the importance of consent and transparency. The generated themes and subthemes are presented in Table 1.

TABLE 1.

Themes and subthemes generated from the data.

Themes	Subthemes
The impactful weight of new evidence
CAT meets clinical reality	Introducing a new tool in an overburdened system
	Putting patients first in CAT integration
The human side of CAT	Trust and policing
	The importance of consent and transparency

3.1. The impactful weight of new evidence

All participants made note of the more objective nature of CAT compared to some other measures, and how its objectivity can not only address non‐adherence in their patients, but can influence other areas of their practice. The perceived highly accurate nature of CAT was identified as essential for checking for non‐adherence before escalating treatment, particularly in cases of resistant hypertension where blood pressure remained uncontrolled.

I think it could help confirm whether non‐adherence is a factor before escalating treatment, especially in cases where blood pressure isn’t responding

(Participant 1)

I think it's of most value is in people with, what you think are […] looking like treatment resistant conditions

(Participant 6)

Other participants perceived its objectivity as a tool to differentiate between non‐adherence and genuine treatment failure. Participant 5 specifically referred to how in their study, “we found in our so‐called resistant patients, 50% were not taking their drugs […] when we checked their urine” (Participant 5).

This then has a knock‐on effect, as it was mentioned that CAT was recognized to be able to inform and optimize treatment plans, potentially avoiding unnecessary polypharmacy and associated side effects.

Of the patients that we see, usually, they're resistant or partially resistant to treatment […] so naturally enough, adherence can be question mark over whether they are truly adherent or not. It's really important to try and tease that out fully, and that then helps us. The alternative is you keep adding additional treatments, none of which are taken, and many of which will have side effects if they are taken

(Participant 3)

I think it would help inform treatment strategies and rationalizing treatment plans.

So and I guess maybe it's an opportunity to deprescribe things that aren't going to be taken anyway.

(Participant 6)

CAT was can also acknowledged to promote more open and honest discussions with patients, offering an opportunity to explore underlying reasons for non‐adherence, something difficult when patients insist they are adhering. Participant 3 believes it “initiates useful conversations with our patients about their adherence” (Participant 3).

then it gives you the opportunity to discuss their care appropriately with them and you know and explore their concerns and their reasons for not taking the meds, which obviously we can't do if they're telling us they're taking them.

(Participant 4)

But no matter how truthful you think somebody's being, I find they lie. So to have a urine testing, it's just invaluable […] would love to have it here. I really miss it.

(Participant 5)

CAT was seen as particularly useful for newly diagnosed or younger hypertensive patients who are less accustomed to daily medication or required more education. Additionally, it was perceived as beneficial in vulnerable populations where communication barriers exist.

where it might have a lot of value is in populations in whom you don't share the same first language as in terms of educating them around the need[…] but having a definitive result might help adherence in those more vulnerable populations where communication is a barrier in general, or whose literacy may not be that high or you're just struggling to get through the message

(Participant 6)

It was highlighted that by identifying non‐adherence, CAT could ultimately reduce healthcare costs by preventing unnecessary investigations or treatments for resistant hypertension.

the cost to us of running clinics and investigating at costs several €1000 for us to work a patient up properly as it is and. You know, it would take a whole lot of those patients out of the system, you know, so we could actually not be taken away from managing patients with genuine difficult hypertension.

(Participant 4).

3.2. CAT meets clinical reality

Participants' accounts of incorporating CAT into their routine practice highlighted two interrelated fields, system‐level considerations and person‐centred priorities. This theme was developed due to the intersection of these dimensions, capturing the logistical, operational and relational challenges faced when integrating CAT into already pressured clinical environments. It reflects both the structural demands of implementing a new tool within constrained healthcare systems and the ethical imperative to centre patient experience throughout the process.

3.2.1. Introducing a new tool in an overburdened system

This subtheme was identified in the data with the emphasis on the complexity of ordering, processing and incorporating CAT into existing workflows, particularly given the time pressure in already busy clinics.

Logistically, we'd need clarity on how to order and process tests, right now, that's completely unfamiliar.

(Participant 1)

it adds an extra patient contact point, and then an extra result to go through with your patients. So all of that means a longer consultation as well.

(Participant 3)

If you have a result coming a month after all the other results, it just fragments as well, and it's very frustrating to follow up twice.

(Participant 8)

There is a strong preference for rapid test results from CAT to prevent delays in patient follow‐up and documentation.

point‐of‐care test would ideally be the most ideal

(Participant 6)

I like to sign off my letters and close the loop within 24 hours, usually, control the volume. So if I had to waste few days and it was delaying me getting like, letters out to people […] I probably wouldn't find it that helpful

(Participant 7)

Participants highlight the need for additional resources. Cost is once again mentioned; however, in this context, participants concerns over financial cost stemmed from the need for additional staff, particularly nurses with specialist training to collect the sample collection and patient communication.

cost would definitely be a concern

(Participant 1)

can't do hypertension management without a nurse […] It's key and patients will tell nurses stuff they don't tell doctors, and they've the time to spend with them.

(Participant 5)

3.2.2. Putting patients first in CAT integration

CAT's integration depends on more than logistics and protocols, it must align with what clinicians perceive to be in the patient's best interest. This subtheme explores participants' reflections on how CAT fits within patient‐centred care, exploring concerns about the individual needs, preferences and contexts of those they care for.

Concerns also relate to the feasibility of urine collection in certain populations, such as older or frailer patients. Participant 7 remarked that “a urine collection [would be] less easy to do” (Participant 7).

a lot of our population might be quite difficult to capture a urine sample in a timely way […] for somebody who's got mobility issues

(Participant 6)

There was also questions of CATs' appropriateness for all patient groups, especially those with cognitive impairment or complex polypharmacy, where interpretation of results may be confounded.

does it interfere [with] any other medications, interfere with the interpretation of the results? Because we have populations that often have polypharmacy […] Often as well, non‐adherence might be because they've got cognitive impairment

(Participant 6)

There is also recognition that CAT offers only a short‐term snapshot of adherence at a specific point in time, and does not address the underlying reasons for non‐adherence. Participant 6 asked of CAT, “would it fix the root cause in the frailer older population” (Participant 6).

So, you know, it's not a long term answer to the issue. It's, you know, a short term point in time

(Participant 3)

urine testing isn't perfect because they may just have missed their tablets in the last day or two

(Participant 5)

3.3. The human side of CAT

While CAT offers a more objective measure of medication adherence, the participants' perspectives highlighted that its use is deeply embedded in human relationships. This theme captures the ethical, emotional and interpersonal dimensions that arise when and if CAT is introduced to consultations. Participants focused on how issues of trust, perceived surveillance and the need for clear communication shape the acceptability and success of CAT in practice. Rather than viewing adherence purely through a clinical lens, this theme brings light to the nuanced relational work involved in positioning CAT in a way that honours consent, preserves trust and supports collaborative care.

3.3.1. Trust and policing

A prominent concern is that CAT could be perceived as intrusive or a sign of mistrust, potentially making patients feel policed or as though their honesty is being questioned. Participant 2 noted ‘that patients may know there may be an element of mistrust’ (Participant 2). Participant 4 proposed that “patients might think […] you're doing something behind their back”(Participant 4). Participant 8 added, “There's an element of, are you spying on your patients?” (Participant 8).

[Ensuring] making people feel that they're not under the microscope or feel like that they're being penalised.

(Participant 6)

Such perceptions may jeopardise the therapeutic relationship and alienate patients. Participant 1 warned that patients may “feel like they're being tricked and they're not going to come back”(Participant 1). Participant 8 raised the concern that “the relationship in particular, with something like this, it's whether it impacts on the relationship, and the trust that you hope is there in that context” (Participant 8).

3.3.2. Importance of consent and transparency

Clinicians consistently emphasised the need for clear, honest and respectful communication with patients about the purpose and rationale behind CAT.

So think about the rapport, the phrasing of it, and, you know, making sure the patient is priority, and if they don't consent to it, then that's fair enough. That's their choice.

(Participant 1)

I think the conversation around the test and consenting for the test would need to be well worded, as well as honest around the purposes of it […] it can't be accusatory in nature.

(Participant 2)

Some participants noted how being up‐front with their patients avoided any confusion, thus patients were willing to take the test. This reaffirmed the need for clarity with patients about the nature of CAT.

I was very open about it. I would say, “Can I check your urine to see is there drugs in them? The drugs you're taking in them?” […] I never had the patient refuse.

(Participant 5)

it's probably better to be upfront about it, because you're doing something that's potentially challenging a patient you know, […] so it doesn't seem like I'm being sneaky or anything.

(Participant 7)

Participants reaffirmed the importance of informed consent to avoid legal or ethical repercussions from testing without adequate patient understanding.

I think if the patient gives informed consent, I don't think there'll be any problem. I think if you were to do it to try and kind of catch them out, then that might be a problem.

(Participant 9)

4. DISCUSSION

This study explored clinicians' attitudes and perspectives on the implementation of CAT in hypertension care. Three overarching themes were identified, the impactful weight of new evidence, CAT meets clinical reality, and the human side of CAT. Together, these themes reveal both eagerness for the potential of CAT and concerns around its integration into routine care, particularly, regarding feasibility, relational impact and patient‐centredness.

The key implications for clinical practice are that the design and implementation of CAT into hypertension care requires careful consideration of both the potential benefits and harms of CAT. In particular, the integration of CAT into existing workflows in a way that minimizes additional workload and the careful framing of CAT in a patient‐centred way is key. Widespread adoption of CAT will require that these aspects of feasibility and acceptability are addressed.

Both the current clinician‐focused data and the patient‐centred work by Soldan et al. ⁹ recognize CAT as a potentially more objective, reliable method for assessing adherence, with potential to improve diagnostic clarity and optimize treatment. ¹⁹ Clinicians emphasized its role in distinguishing non‐adherence from true treatment resistance, supporting targeted strategies and reducing unnecessary polypharmacy. Similarly, patients described CAT as a ‘wake‐up call’ that increased awareness and encouraged adherence. ⁹

In the present study data clinicians saw CAT as a tool for opening adherence discussions, noting transparency, consent and sensitive introduction. With a focus on this perspective, it can likely facilitate helpful and open clinician‐patient dialogue. However, in Soldan et al., ⁹ patients mentioned the emotional impact of conflicting results shame, frustration, mistrust and, in some cases, scepticism about the test's validity. ⁹ In the present study, clinicians acknowledged these risks but focused on mitigating them through clear communication and relationship building. Clinicians also stressed systemic barriers‐workflow integration, resources, turnaround times and suitability for some populations, which were less evident in patient accounts. ⁹ Finally, while clinicians trusted CAT's objectivity, there were some concerns for patients about reliability, showcasing the need for education to build mutual understanding and acceptance of CAT. ⁹

Within the impactful weight of new evidence, clinicians described CAT as a more objective, evidence‐based tool that could enhance diagnostic certainty and guide therapeutic decisions, particularly in cases of aTRH. This reflects Rogers' ²⁰ ‘relative advantage’ in diffusion of innovation (DOI) theory, where adoption of new innovations is more likely if an innovation is seen as superior to existing options. CAT's potential to detect likely non‐adherence, avoid unnecessary medication escalation and reduced healthcare costs aligns with this principle. ²¹ Clinicians believed CAT could optimize prescribing, improve consultations and strengthen their professional role. These views mirror prior evidence of CAT's accuracy in distinguishing true treatment resistance from non‐adherence. ³ , ²²

CAT meets clinical reality notes that despite recognition of its potential, clinicians voiced concerns about the practicality of integrating CAT into overburdened systems. These challenges, ranging from the complexity of ordering and processing tests to resource limitations and staffing pressures, correspond with the DOI attributes of ‘complexity’ and ‘compatibility’. Clinicians considered whether CAT would introduce additional administrative burdens, longer consultations or a lack of follow‐up, factors that lower the likelihood of acceptance. ²³ Such findings were also found in Burnier et al.’s ³ paper, where barriers frequently mentioned include the difficulty of identifying non‐adherent patients, the short duration of consultations, high workload and inadequate resources.

Putting patients first was another critical subtheme. Participants questioned whether CAT would be suitable for all patient populations, particularly those with mobility challenges, cognitive impairment or complex medication regimens. If CAT does not align with participant's understanding of holistic, patient‐centred care or if it appears to reduce patient autonomy, its normalization and adoption may be hindered. These findings mirror those in broader implementation literature, where clinician uptake of novel technologies often relies not only on evidence but also on feasibility, values alignment and contextual fit. ⁵ , ²⁴ Ultimately, clinicians in both primary and secondary care contexts would need to be able to easily access the relevant human, e.g. laboratory and relevant clinical laboratory staff, and digital resources, e.g. electronic records and referral systems, to implement CAT as part of their hypertension care. Such a system‐level change would be required before CAT could become a mainstream part of hypertension care.

Beyond clinical and logistical issues, the human side of CAT explores the concerns raised by participants about the ethical and interpersonal dimensions of using CAT. Some were concerned that introducing an ‘objective’ test of adherence might compromise trust, make patients feel policed or accused and damage the therapeutic relationship. Participants repeatedly stressed the importance of informed consent and transparent communication when using CAT. When participants could regard CAT as a collaborative tool rather than a tool to catch out patients, they believed it had greater potential to be accepted by both staff and patients. These findings are similar to existing literature emphasizing the balance between ‘objective’ testing and relational care. Research highlights the importance of clear, respectful communication and non‐confrontational feedback when discussing adherence. ⁵ , ⁷ The implications for practice indicate that for CAT to be effectively adopted, it must be accompanied by strategies that address both logistical and interpersonal challenges. This includes training clinicians on how to introduce and discuss CAT results, building it into multidisciplinary care pathways, and ensuring that it complements, rather than compromises, patient‐centred care.

This study had some noteworthy limitations. The sample size was small and may not fully capture the diversity of clinical perspectives. Furthermore, as most participants had limited direct experience with CAT, many responses were hypothetical and speculative in nature. CAT was not available as a routine test for hypertension care in the healthcare settings where this study was carried out. Where participants had direct experience with CAT, this was through funded research studies where CAT was used as part of a research protocol or through experience in other clinical contexts where CAT or similar testing was available. The interview durations in this study may have constrained the depth of insight. Additional or longer interviews might have captured richer accounts of the potential of real‐world CAT use. Nonetheless, the findings offer valuable, in‐depth insights into the complex considerations that clinicians navigate in assessing the feasibility and appropriateness of introducing CAT into hypertension practice. Longitudinal and mixed‐methods studies could help assess its impact on adherence, clinical outcomes, service delivery and patient‐clinician relationships across diverse contexts.

5. CONCLUSION

Clinicians valued CAT's greater objectivity and ability to address medication non‐adherence, but noted practical and ethical considerations, including resource needs, workflow integration and clear implementation pathways. If poorly introduced, CAT risked being perceived as intrusive, punitive or weakening trust. Participants stressed framing CAT as a supportive, dialogue‐enhancing intervention requiring sensitivity, transparency and informed consent, rather than a disciplinary measure, to ensure its acceptance and ethical use.

AUTHOR CONTRIBUTIONS

Roshan Shahab: Conceptualization; formal analysis; investigation; methodology; writing—original draft. Louise Rabbitt: Conceptualization; methodology; secondary supervision; writing—review and editing. Gerard J. Molloy: Conceptualization; methodology; primary supervision; writing—review and editing; finalising.

CONFLICT OF INTEREST STATEMENT

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supporting information

Data S1. Supporting Information.

Shahab R, Rabbitt L, Molloy GJ. Clinician's attitudes & perspective on chemical adherence testing in hypertension (CATCH): A qualitative interview study. Br J Clin Pharmacol. 2026;92(6):1779‐1786. doi: 10.1002/bcp.70462

DATA AVAILABILITY STATEMENT

Study participants did not give consent for their interview data to be shared in a public repository. The participant information they received stated that their data would be anonymized, and any potentially identifying details would be removed from transcripts. This was deemed necessary as the study is reporting on a qualitative interview study with a small number of participants with specific clinical roles, where they may be easily identified. However, additional data supporting the findings of this study is available, via the corresponding author, on reasonable request.