Understanding the impact of non-alcoholic steatohepatitis with metabolic comorbidities on adults: a real-world qualitative study

Abstract

Objective

Limited real-world evidence exists to better understand the patient experience of living with symptoms and impacts of non-alcoholic steatohepatitis (NASH). This study aimed to (1) describe patient-reported perspectives of NASH symptoms and impacts on patients’ daily lives and (2) develop a patient-centered conceptual NASH model.

Methods

A cross-sectional study using semi-structured qualitative interviews was conducted among adults (≥18 years) in the United States living with NASH. Eligible participants were diagnosed with NASH, had mild to advanced fibrosis (F1-F3), and no other causes of liver disease. The interview guide was informed by a targeted literature review (TLR) to identify clinical signs, symptoms, impacts, and unmet treatment needs of NASH. Participants described their experiences and perspectives around NASH and the symptoms, symptom severity/bother, and impact of NASH on their daily activities. Interviews were audio-recorded and transcribed verbatim for coding and thematic analysis.

Results

Twenty participants (age: 42.4 years; female: 50.0%) were interviewed. Participants discussed their experience with NASH symptoms (most frequent: fatigue [75.0%]; weakness/lethargy [70.0%]) and impacts (most frequent: physical and psychological/emotional [70.0% each]; dietary [68.4%]). Participants considered most symptoms to be moderately severe or severe and moderately or highly bothersome. Findings from the TLR and qualitative interviews were incorporated into a conceptual model that describes patient-reported symptoms and impacts of NASH, clinical signs, risk factors, and unmet treatment needs.

Conclusion

Our study provides insights into patients’ perspectives of NASH symptoms and their impact on their daily lives. These findings may guide patient-physician conversations, supporting patient-centered treatment decisions and disease management.

KEY POINTS FOR DECISION MAKERS

• Study findings help to address the gap in current literature about patients’ perspectives on NASH and its symptoms as well as its impact on daily life.

• The study proposes a holistic conceptual model that describes patients’ perspectives of living with NASH, including symptoms and their impact, the clinical signs and risk factors of NASH, and the unmet treatment needs of the disease.

• Healthcare providers can use study findings to inform patient-focused decisions around treatment strategies for NASH.

Keywords:

• Non-alcoholic steatohepatitis
• metabolic comorbidity
• conceptual model
• qualitative study

1. Introduction

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD)¹. NASH is characterized by steatosis (fatty liver) and inflammation with hepatocyte injury (ballooning), with or without fibrosis, and develops in the absence of significant alcohol consumption^1–5. The most common risk factors associated with NASH are obesity, insulin resistance, and features of metabolic syndrome^4,6,7. In advanced stages, adults living with NASH have an increased risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma⁶.

NASH is strongly associated with several metabolic comorbidities such as obesity and diabetes⁸, with a high prevalence of obesity (81.8%), diabetes (43.6%), hyperlipidemia (72.1%), hypertension (68.0%), and metabolic syndrome (70.7%) among people with NASH⁴. Furthermore, the prevalence of NASH is increasing in parallel to the rising prevalence of obesity and type 2 diabetes (T2D), with over 37% of people living with T2D also living with NASH^1,4–6,9,10. An estimated 22.5% of people with T2D in the United States (US) have high-risk NASH (i.e. at risk of progression to cirrhosis)¹¹. Obtaining an accurate estimation of the prevalence of NASH is complicated because the diagnosis requires a liver biopsy, which is not performed routinely for all patients with NAFLD, leading to the underdiagnosis of NASH^5,12. Furthermore, studies evaluating NASH prevalence are often limited to tertiary hospital populations^7,13. To date, no US Food and Drug Administration-approved pharmacological therapies are available for the treatment of NASH, and patients are advised to make lifestyle modifications through diet and exercise to promote weight loss^6,14. Therefore, unmet clinical needs remain in the treatment of NASH^5,15.

The current understanding of the patient experience and perspectives regarding NASH symptoms (i.e. physical manifestations of illness) is limited, likely because most patients with NASH do not develop symptoms in the early stages of the disease or they develop ambiguous/generic symptoms like fatigue and abdominal pain⁵. Furthermore, the generic symptoms and clinical signs of the disease overlap with those of other metabolic comorbidities such as T2D, and hence NASH is often considered to be a clinically “silent” disease¹⁵.

Real-world evidence suggests that people living with NASH perceive a lack of knowledge and clarity about their condition and have limited social support¹⁶. NASH symptoms can have considerable physical and psychological impacts on a patient’s health-related quality of life, affecting their diet, sleep, and work, as well as family life and social activities^16–23. While previous studies have explored different aspects of patients’ experiences with NASH, such as the symptom burden and impact of living with NASH^16,19–23, gaps remain in understanding patients’ perspectives on the overall humanistic burden of NASH and its impact on their daily activities.

The current study aimed to (1) describe patient-reported experiences and perspectives around NASH symptoms and disease impact on patients’ daily lives, and (2) develop a patient-centered conceptual model by conducting a targeted literature review (TLR) and qualitative concept elicitation interviews among adults living with NASH.

2. Methods

2.1. Concept elicitation interviews

2.1.1. Study design and participants

This non-interventional, cross-sectional study gathered insights from participants living with NASH through semi-structured qualitative concept elicitation interviews. Purposive sampling was used to identify and recruit participants from three clinical sites across the US (West, South, and Northeast geographic regions). After potential participants were identified through clinical charts and databases, they were contacted by clinical site staff to undergo screening and determine their eligibility to participate. Adults (aged ≥18 years) with a clinically confirmed or suspected NASH diagnosis were eligible for study participation. Individuals were excluded if they had liver disease from causes other than NASH. Table 1 presents the complete list of study inclusion and exclusion criteria. Participants received compensation for their participation in the study.

Table 1. Study inclusion and exclusion criteria.

Inclusion criteria

Exclusion criteria

Confirmed or suspected diagnosis of fibrosis stage F1, F2, or F3^31 NASH as determined within the past 2 years by either biopsy or transient elastography (FibroScan) or an ultrasound Adults ≥18 years of age BMI ≥27 kg/m^2 and ≤50 kg/m^2 At least one of the following comorbidities: T2D, hypertension, or dyslipidemia Able to read, speak, and understand English Willing and able to provide written informed consent Willing and able to be audio-recorded for a virtual (webcam or telephone) one-on-one interview lasting approximately 60 minutes

Liver disease from causes other than NASH: alcohol consumption (>14 drinks/week for females, >21 drinks/week for males), alcoholic liver disease, viral/mumps hepatitis, HIV/AIDS, Wilson disease, autoimmune/chronic toxic hepatitis, Gaucher disease, lysosomal acid lipase deficiency, or primary biliary cholangitis Liver cirrhosis Prior bariatric surgery Liver transplant Participation in a clinical trial for NASH Visual or hearing problems, mental illness, or cognitive impairments that might have interfered with the ability to participate in the study

BMI body mass index, HIV/AIDS human immunodeficiency virus/acquired immunodeficiency syndrome, NASH non-alcoholic steatohepatitis, T2D type 2 diabetes.

All recruitment procedures complied with US patient confidentiality requirements, including the Health Insurance Portability and Accountability Act of 1996 regulations. The study protocol, informed consent form, and individual clinical sites were each approved by a centralized institutional review board (Ethical and Independent Review Services – E&I 20169-01) before this research was conducted. This study was conducted in accordance with the principles of the Declaration of Helsinki.

2.1.2. Procedures and data collection

Participants were invited to complete a one-on-one concept elicitation interview between December 2020 and August 2021. Participants could choose to be interviewed via telephone or a web-based video conference call. Before the scheduled interview, participants received a study packet by mail that contained an informed consent form and a brief sociodemographic questionnaire. Participants provided their written informed consent before starting the interview.

The interviews were conducted by trained research staff experienced in qualitative interviewing, including the authors of this article (RW: PhD; NT: MPH). Interviewers used a semi-structured interview guide to collect qualitative (open-ended questions) and quantitative (rating and ranking questions) data. The development of the interview guide was informed by findings from a TLR conducted to identify key concepts, including clinical signs, symptoms, impact, and unmet treatment needs among adults living with NASH. The interview guide was designed to capture insights into participants’ experiences and perspectives around living with NASH. Participants were asked to describe their condition, their current NASH symptom experience, and the impact of NASH symptoms on their daily life (including physical, functional, emotional/psychological, social/relationship, dietary, and economic impacts). For each NASH symptom, participants described their experiences, the severity of the symptom, and the level of symptom bother. Participants were asked to rate their symptom severity on a scale of 1 to 10 (1 = not severe; 10 = extremely severe) and symptom bother (1 = not bothered; 10 = extremely bothered). In addition, participants ranked their top three most bothersome symptoms. Next, participants were asked to describe how NASH-related symptoms had impacted their daily lives and to rank their top three most bothersome impacts. When time permitted, participants were queried about their NASH symptoms and associated impacts that they may not have spontaneously described during the interview. At the end of the interview, participants completed the sociodemographic questionnaire. All interviews were audio-recorded with participant’s permission.

2.1.3. Sample size

A saturation analysis was conducted to determine the sample size required for the study. Saturation was the point at which participants did not provide any new or previously unidentified concepts during the interviews²⁴. A saturation grid was used to establish and document concept saturation on the basis of spontaneously mentioned symptoms/impacts²⁴. The saturation grid was used to compare and identify new information, as well as to detect when no new information emerged. Concept saturation was evaluated in an ongoing manner, and interviews were stopped once concept saturation was achieved. To assess concept saturation, participant responses were coded and analyzed to compare the number of new concepts that arose in each subsequent participant interview.

2.1.4. Data analyses

Audio recordings were transcribed verbatim by a professional third-party transcription service, with all personally identifiable information removed from the transcripts. ATLAS.ti (Version 8) was used to code and analyze the transcripts according to an initial coding dictionary. The coding dictionary was developed a priori based on the interview guide. Two experienced coders independently coded one transcript and compared and reconciled the application of codes. Following reconciliation, the coding dictionary was updated as needed to capture emerging themes or streamline the coding process before coding the remaining transcripts. An output consisting of participant quotes organized by thematic code and the number of times each code was applied was produced. A final quality check was performed once coding was completed to ensure accuracy.

Qualitative results were synthesized and summarized descriptively using illustrative quotes, along with participant descriptors: gender (female, male, or non-binary), age, and fibrosis stage (F1, F2, or F3). NASH symptoms were classified as key (i.e. those identified from the TLR) or frequently endorsed (i.e. symptoms reported by five or more participants). Quantitative analysis was conducted on participants’ sociodemographic data and ranking/rating responses. Continuous variables (e.g. age and ranking/rating responses) were described using means, standard deviations (SDs), and ranges. Categorical variables (e.g. gender, ethnicity, and clinical characteristics) were presented using frequencies and percentages.

2.2. NASH conceptual model development

A conceptual model for NASH was developed in a multi-step process. First, a preliminary model was developed based on the findings of the TLR. The preliminary model included more frequently mentioned symptoms and impacts in the literature (i.e. five or more times). Following the analysis of the concept elicitation interviews, the conceptual model was updated to incorporate concepts from both the TLR and the interviews. Finally, concepts identified from analyses of social media conversations using an artificial intelligence-based listening tool were also incorporated into the final conceptual model²⁵.

3. Results

3.1. Concept elicitation interviews

3.1.1. Participant characteristics

A total of 20 participants were recruited and completed a telephone or virtual (web-based) interview. Table 2 summarizes the participants’ sociodemographic and clinical characteristics: mean (SD) age: 42.4 (15.6) years; female: 50.0%; White: 75.0%; non-Hispanic/Latino: 55.0%; mean (SD) body mass index (BMI): 36.4 (6.5) kg/m². Participants were primarily in fibrosis stage F2 (45.0%) or F3 (40.0%) and 55.0% of participants had a NASH diagnosis confirmed by FibroScan. Overall, 55.0% of the participants had T2D and/or hypertension each, while 50.0% had dyslipidemia (Table 2).

Table 2. Participants’ sociodemographic and clinical characteristics.

Variable	Total (N = 20)
Age, years, mean (SD)	42.4 (15.6)
Gender, n (%)
Male	9 (45.0)
Female	10 (50.0)
Non-binary	1 (5.0)
Ethnicity, n (%)
Hispanic or Latino	9 (45.0)
Non-Hispanic or Latino	11 (55.0)
Race, n (%)
White	15 (75.0)
Asian	2 (10.0)
American Indian or Alaska Native	1 (5.0)
Hispanic	2 (10.0)
Level of education, n (%)
High school	4 (20.0)
College or higher and technical/vocational	16 (80.0)
NASH diagnosis, n (%)
FibroScan	11 (55.0)
Liver Biopsy	9 (45.0)
Fibrosis stage, n (%)
F1	3 (15.0)
F2	9 (45.0)
F3	8 (40.0)
Time since diagnosis, days, mean (SD)	127.8 (114.2)
BMI, kg/m^2, mean (SD)	36.4 (6.5)
Comorbidities, n (%)^a^,b
T2D	11 (55.0)
Hypertension	11 (55.0)
Dyslipidemia	10 (50.0)

BMI body mass index, n number of participants, N total number of participants, NASH non-alcoholic steatohepatitis, SD standard deviation, T2D, type 2 diabetes.

^a Comorbidities based on the three conditions for participant eligibility; this did not represent all possible diagnoses or conditions that participants may have experienced.

^b Responses were not mutually exclusive.

3.1.2. NASH symptoms

3.1.2.1. Overall experience of living with NASH and its symptoms

When asked to describe their condition, participants most frequently used the terms “fatty liver disease” and “NASH” (Supplementary Figure 1). When asked about their experience of living with NASH, participants reported disease burden associated with the symptoms including fatigue, pain, sweatiness, nausea/vomiting, headache, and swelling.

Table 3 presents the symptoms endorsed by participants with illustrative quotes. The key NASH symptoms (both spontaneous and probed) were: being fatigued/tired (n = 15/20; 75.0%), experiencing weakness/lethargy/decreased energy level (n = 14/20; 70.0%), and feeling bloated/swollen (n = 13/20; 65.0%; Table 3). The most frequently endorsed signs and symptoms (i.e. reported by five or more participants) were: being overweight (n = 14/19; 73.7%), abdominal discomfort (n = 13/19; 68.4%), and general discomfort (n = 10/18; 55.6%; Table 3).

Table 3. Summary of key and frequently endorsed NASH symptoms with example quotes from study participants.

Symptom concept	Participants endorsing symptom n/N (%)	Example quote
Key symptoms
Fatigued/ tired	15/20 (75.0)	“Yes. I constantly feel fatigued and I just haven’t gotten enough sleep, no matter what I do. I’ll wake up and it feels like all my muscles just wore out. Like I’ve gone and run a mile but I haven’t done anything.” NB_19_F2 “Just without energy. I don’t necessarily have to be functioning, like doing something to feel tired. I can just basically feel tired without doing anything.” F_53_F2
Weakness/ lethargy/ decreased level of energy	14/20 (70.0)	“Yes, lethargic overall. Like, a giant weight is setting on me.” M_54_F2 “For me it just feels like when I wake up for the day, I’ve got a lot less energy to do things in my day before I have to just sit around and do nothing. I don’t know if you’ve ever heard of spoon theory where it’s like each task you do requires a certain number of spoons and you only have so many in a day. It feels like that number went from like 20, and now I’ve got like 10.” NB_19_F2
Bloated/ swollen	13/20 (65.0)	“All the bloated or swollen feeling, it feels like somebody’s put a air hose to my stomach and just let it fill my stomach up. It really is an uncomfortable feeling.” F_47_F3 “It just makes you feel like you’re just extended, like your stomach is extended more. And just uncomfortable. It doesn’t actually hurt, hurt.” F_53_F3
Nauseous/ queasy	8/20 (40.0)	“I wake up early in the morning to go to work…leaving my house to the entrance of where I live I'm already sick to my stomach, so I have to pull over, I’m gagging. Sometimes I throw up…But it’s an intensive gag to where your chest feels like it’s going to explode and your head is exploding.” F_35_F1
Problems focusing/ concentrating	7/20 (35.0)	“During work there will be meetings that are important on a major system update or upgrade we’ll be doing or meeting with a vendor for the first time and it’ll be 20 minutes into the conversation and I’ll realize I’ve been thinking about X, Y and Z and not anything about what I need to focus on.” M_28_F1 “Sometimes I’ll ask my husband the same question like four times because I’ll sit there and think, well I’m not really sure if I asked him that or not…And then sometimes he’ll tell me stuff and it’s like I don’t have a clue that he told me.” F_53_F3
Pruritus/ itching	5/20 (25.0)	“It’s just uncomfortable because you’re already having trouble sleeping, so you get really itchy and you’re like, “Oh my God, I can’t stop scratching. But I have to lay on my hands and just not think about it, and it’s still hard because you’re like, ‘I can’t go to sleep, but I’m tired’.” F_35_F1 “It’s like a bunch of, I would say bugs crawling on you, but it’s not that. I just want to grab something and start scratching because it just itches.” F_63_F2
Frequently endorsed symptoms
Overweight	14/19 (73.7)	“I’ve gained a lot of weight from having NASH because I’m not able to go out and exercise. And it’s hard for me to eat so I’ve gained a lot of weight because my body is kind of in starvation mode. So a lot of my clothes already aren’t fitting.” NB_19_F2 “It’s just that my weight is like, you know, slowly creeping up more.” M_41_F2
Abdominal discomfort	13/19 (68.4)	“Abdominal discomfort, I usually feel that when I come in to see the doctor and she examines my abdomen or she palpates it, then I would feel discomfort.” F_27_F1 “It’s very uncomfortable. It hurts. It’s like you need to let your pants out. It just feels like there’s pressure there.” F_47_F3
Discomfort (general)	10/18 (55.6)	“It’s like a whole-body ache, basically. I think it’s like where you’re so fatigued and tired that you don’t want to do anything, but it just makes your body so sore. So I would say that it is related to NASH.” F_35_F1
Dry mouth	10/19 (52.6)	“It can get a little uncomfortable because you’re in the middle of a conversation, or just walking, and your throat just turns into a cotton ball, so I always have water with me. I think I drink like 12 bottles of water a day or more.” F_35_F1 “Well, I drink a lot of water, so it’s like constantly-but at night I wake up, and I’m very parched.” F_64_F3
Abdominal pain	9/20 (45.0)	“Yeah, it’s on the upper… right below the breast and below the rib. It starts like a dull pain, and then it turns more into almost like a cramp, but it’s not a cramp.” F_35_F1 “I used to get severe abdominal pain and I didn’t know why. Then they later told me I did have the NASH…I want to say it’s almost like a knot in my stomach.” F_53_F2
Pain (general)	9/20 (45.0)	“Pain would extend up from my back, and when I walked, when I tried to lean down to get something on the floor, I had pain…it’s in the back on the liver. I had so much pain that I couldn’t even jump…And walk and exercise. I couldn’t do nothing because of the pain…It limited me a lot.” M_44_F3 “I mean I know it’s not like an organ pain or anything like that. I just know that somehow it is directly related to this because the pain and the suffering that I feel is immediately- it’s felt immediately like I work out.” M_41_F2
Daytime tiredness	8/18 (44.4)	“So daytime tiredness to me is like, you’re going about your day and you’re like, oh I need a nap.” NB_19_F2
Shortness of breath	7/19 (36.8)	“I was feeling shortness of breath and I was – when I had my blood pressure that was high. I thought it was like something psychological or something, but I didn’t know it was about that.” F_46_F3 “…it’s mostly just been being out of, you know, being short of breath. But I think that’s just, hey, you don’t exercise and you’re overweight.” M_28_F1
Sleep problems	6/17 (35.3)	“Yes, I have those [sleep problems]. My doctor actually prescribed something for me to sleep because I would wake up in the middle of the night, my mind’s going wide open. But I never thought of it as being NASH.” F_47_F3 “So it [back pain] could be really painful, especially throughout the day. Sometimes it can hurt to lay down. I definitely don’t get any sleep, so it’s really challenging to go about your day when you’re working.” F_35_F1
Constipation	7/20 (35.0)	“It’s usually just kind of the general pressure and discomfort needing to go and not being able to go and then finally going and then not feeling as if bowel movement is complete.” F_29_F2
Decreased strength	7/20 (35.0)	INTERVIEWER: “Decreased strength?” PARTICIPANT: “It’s like low energy?” INTERVIEWER: “Is that how you think of it?” PARTICIPANT: “Like when you have like low energy?” INTERVIEWER: “Is that what decreased strength means to you?” PARTICIPANT: “Mm-hm.” F_46_F3
Heartburn	6/19 (31.6)	“Yes, I have had quite a bit of heartburn. My gastro doctor actually put me on a higher dose of the generic Prilosec, and of course told me that I needed to watch what I eat…and I was like, But I didn’t eat anything that would have triggered it.” F_47_F3 “I have acid reflux, so could be associated with that, I don’t know.” F_64_F3
Malaise or generally feeling bad	6/19 (31.6)	“Yes. I feel bad more days than I feel good, but I don’t know if that is contributed to the NASH or… like I say, it would make sense.” F_47_F3 “You feel so bad like you don’t want to do anything. You just want to sleep, but you can’t sleep. It’s hard to get motivated to do the things that you know you need to do.” F_35_F1
Muscle cramps	5/19 (26.3)	“I do have some muscle cramps in my legs, usually at nighttime.” F_71_F3 “I do have a lot of leg cramps.” F_64_F3
Other symptoms^a	15/20 (75.0)	“Yeah. I’ll wake up in the middle of the night and my pillow will actually be saturated with sweat and, I mean, I won’t really feel discomfort or anything. I’ll just notice that I’ve gotten to a little period of sweatiness.” M_54_F2 “I’ve always been kind of prone to headaches. I have light sensitivity issues…it’s causing high levels of stress so I’ve been getting stress headaches more frequently because of this condition.” NB_19_F2

n number of participants, N total number of participants, NASH non-alcoholic steatohepatitis.

Note: The participant code is provided next to each quote for easy identification. It includes the gender (female, F; male, M; non-binary, NB), age, and fibrosis stage (F1, F2, or F3): Gender_Age_Fibrosis stage.

Note: Key symptoms refer to those identified from the targeted literature review; frequently endorsed symptoms refer to those reported by five or more participants.

^a Other symptoms endorsed by less than five participants included: headache (n = 4/20; 20.0%); joint pain (n = 4/20; 20.0%); brain fog (n = 3/20; 15.0%); diarrhea (n = 3/20; 15%); dizziness (n = 3/20; 15.0%); memory problems (n = 3/19; 15.7%); frequent urination (n = 2/20; 10.0%); burning feeling in stomach (n = 1/20; 5.0%); chest pain (n = 1/20; 5.0%); feeling bruised under ribs (n = 1/20; 5.0%); sweatiness at night (n = 1/20; 5.0%); skin discoloration/jaundice (n = 1/20; 5.0%); and vomiting (n = 1/20; 5.0%).

Regarding fatigue and lethargy, participants described feeling tired or exhausted without doing anything, even feeling demotivated for activities that they previously enjoyed and having difficulty managing tasks or responsibilities at home or work (Table 3). Participants also reported feeling pain and discomfort due to bloating or swelling. Some of the responses were:

Just without energy. I don’t necessarily have to be functioning, like doing something to feel tired. I can just basically feel tired without doing anything.

For me it just feels like when I wake up for the day, I’ve got a lot less energy to do things in my day before I have to just sit around and do nothing.

All the bloated or swollen feeling, it feels like somebody’s put… air hose to my stomach and just let it fill my stomach up. It really is an uncomfortable feeling.

Signs and symptoms discussed by five or more participants were: being overweight, abdominal discomfort, and general discomfort (Table 3). In this category, some participant responses were as follows:

I’ve gained a lot of weight from having NASH because I’m not able to go out and exercise. And it’s hard for me to eat so I’ve gained a lot of weight because my body is kind of in starvation mode.

Abdominal discomfort, I usually feel that when I come in to see the doctor and she examines my abdomen or she palpates it… then I would feel discomfort.

3.1.2.2. Severity of NASH symptoms

When asked to rank their symptom severity on a scale of 1 to 10 (1 = not severe; 10 = extremely severe), participants rated most symptoms as moderately severe (4 to 6) or severe (7 to 10; Figure 1). Participants noted that severe fatigue or tiredness made them feel like they had not slept or they could not function without laying down first (Supplementary Table 1). Those who experienced severe weakness, lethargy, or decreased energy found it “debilitating”. In general, participants described severe bloating or feeling swollen as uncomfortable and irritating but did not find it debilitating or intense. Similarly, nausea or queasiness was generally manageable. Problems with focusing or concentrating were most severe when they interfered with participants’ focus at work and in social settings. Pruritus or itching was mildly severe or severe to the point of bleeding, while abdominal discomfort and general pain were considered to be moderately severe. Being overweight was perceived as mild or severe, and it impacted participants’ ability to do activities that they could do previously (e.g. running; Supplementary Table 1).

Figure 1. Average severity ratings for key and frequently endorsed NASH symptoms. n number of participants, NASH non-alcoholic steatohepatitis. Note: Key symptoms refer to those identified from the targeted literature review; frequently endorsed symptoms refer to those reported by five or more participants. Participants were asked to rank symptom severity on a scale of 1 to 10 (1 = not severe; 10 = extremely severe).

3.1.2.3. NASH symptom bother

When asked to rate their symptom bother on a scale of 1 to 10 (1 = not bothered; 10 = extremely bothered), participants rated most symptoms between moderately bothersome (4 to 6) and highly bothersome (7 to 10; Figure 2). Participants reported being bothered by fatigue and lethargy when the symptoms interfered with their daily activities (Supplementary Table 1). Perceptions of being bloated or swollen varied, with participants reporting either being bothered by it or getting accustomed to it when it did not impact their daily life. Nausea or queasiness was considered to be severely bothersome, while pruritus/itching was considered to be moderately bothersome. Participants were bothered by being overweight, elaborating that they disliked looking at pictures of themselves (Supplementary Table 1).

Figure 2. Average bother ratings for key and frequently endorsed NASH symptoms. n number of participants, NASH non-alcoholic steatohepatitis. Note: Key symptoms refer to those identified from the targeted literature review; frequently endorsed symptoms refer to those reported by five or more participants. Bother rating categories were low (1-3), moderate (4-6), or high (7-10).

After the interviewers confirmed they had a complete picture of NASH symptoms, they asked the participants to choose their three most bothersome symptoms. Feeling fatigued or tired (n = 11/15; 73.3%), nauseous or queasy (n = 5/8; 62.5%), and abdominal discomfort and feeling bloated/swollen (n = 5/13; 38.5% each) were considered to be the most bothersome NASH symptoms (Table 4).

Table 4. Topmost bothersome NASH symptoms and impacts.

Symptom	Participants endorsing symptom, n/N (%)	Participants selecting symptom among top three most bothersome, n (%)
Most bothersome symptom
Fatigued/ tired	15/20 (75.0)	11/15 (73.3)
Nauseous/ queasy	8/20 (40.0)	5/8 (62.5)
Abdominal discomfort	13/19 (68.4)	5/13 (38.5)
Bloated/ swollen	13/20 (65.0)	5/13 (38.5)
Overweight	14/19 (73.7)	4/14 (28.6)
Weakness/ lethargy/ decreased energy levels	14/20 (70.0)	4/14 (28.6)
Most bothersome impact
Psychological/ emotional	14/20 (70.0)	11/14 (78.6)
Physical	14/20 (70.0)	6/14 (42.9)
Daily activity	13/20 (65.0)	5/13 (38.5)
Diet	13/19 (68.4)	4/13 (30.8)
Relationship/ social interaction	11/19 (57.9)	10/11 (90.9)
Economic burden	11/20 (55.0)	5/11 (45.5)
Work productivity	8/18 (44.4)	3/8 (37.5)
Depression	8/20 (40.0)	3/8 (37.5)

n number of participants, N total number of participants, NASH non-alcoholic steatohepatitis.

3.1.3. Impact of NASH on participants’ daily lives

When asked to describe how NASH had impacted their daily lives, participants most frequently endorsed physical and psychological/emotional (n = 14/20; 70.0% each), dietary (n = 13/19; 68.4%), and daily activity (n = 13/20; 65.0%; Table 5) impacts. Participants discussed the physical impact of NASH in terms of their vitality and not having the energy to do household chores or an inability to exercise. For example:

Table 5. Summary of the impact of NASH with example quotes from study participants.

Impact And Sub-impact	Participants Endorsing Symptom n/N (%)	Example Quote
Physical impact	14/20 (70.0)	“It’s just like I have to…it’s not as easy as it was before. I have to be careful because my back, my knees. I don’t know, I thought it was age, like I cannot do things like I used to do. I just have to be careful when lifting heavy things, bending. I thought it was normal.” F_46_F3
Vitality (i.e. energy level)	5/14 (35.7)	“It’s just most of… I would say most of the day I feel tired. I don’t have the energy to do anything, so I can’t really do house chores after work. Or even on my days off, sometimes I’ll just be in bed the whole day, so I don’t get do a lot.” F_27_F1
Limited/ reduced exercise	4/14 (28.6)	“I cannot do exercise…And walk and exercise, this exercise bicycle, and I couldn’t do that.” M_44_F3
Difficulty lifting or carrying heavy objects	2/14 (14.3)	“I cannot…carry heavy boxes. And carry cement or something. Cement bags. That’s too heavy for me. Cement bags are too heavy.” M_44_F3
Trouble bending, lifting, or stooping	2/14 (14.3)	“Pain would extend up from my back, and when I walked, when I tried to lean down to get something on the floor, I had pain.” M_44_F3
Trouble walking two or more blocks	2/14 (14.3)	“Walking is difficult…Sometimes even just walking around my house.” NB_19_F2
Sports	1/14 (7.1)	“Before I was diagnosed I was actually in a sword fighting club on my college campus. I have not been able to participate anymore. One, because I don’t have the physical ability to as at the moment. But two, there’s also the fear of during sparring if I get hit the wrong way with my liver being inflamed, is it possible I could get. Hit the wrong way and possibly not be able to recover?” NB_19_F2
Trouble climbing two flights of stairs	1/14 (7.1)	“It’s just hard, very difficult to move around, like, say, when you go up on a flight of stairs, if there’s a little short of breath when you get up there, you can’t even run on the treadmill without being … wounded … however you say.” F_27_F1
Psychological/ emotional impact	14/20 (70.0)	“Yeah, it’s very frustrating and it’s very depressing. It makes you feel kind of less than a person. Not pulling your weight on everything.” F_53_F3
Sadness/low mood	2/14 (14.3)	“I think it’s because you know that the things that you typically did before you can’t, so you get sad, you get angry, you get unencouraged because you’re like, I’m so tired, and I know that I wasn’t tired before. I was active, and now I can’t be as active as I was because I have no energy.” F_35_F1
Anxiety	1/14 (7.1)	“I don’t know. I think maybe probably anxiety… not the sense of throw up, I think that’s probably because of my anxiety because of other things.” M_20_F2
Feel irritable	1/14 (7.1)	“…it’s irritating but not – I live with it. That’s what I do.” F_63_F2
Frustrated	1/14 (7.1)	“The frustration of that, if that’s one. Because I get frustrated because I can’t do what I want to do because of it.” F_63_F2
Have mood swings	1/14 (7.1)	INTERVIEWER: How have NASH symptoms affected your daily life? PARTICIPANT: Mood swings.” F_63_F2
Other: stress (n = 1); worry (n = 2); self-esteem (n = 3)	4/14 (28.6)	“But at the same time, with the constantly being nauseous, it’s causing high levels of stress so I’ve been getting stress headaches more frequently because of this condition.” NB_19_F2 “It worries me, so it’s worrisome, it’s bothersome, you don’t know like what’s going to happen. Am I going to advance into full blown cirrhosis? Am I going to have like metabolic or hepatic encephalopathy? Do I need to take lactulose forever and a day so that I can get them on the level. You know these kinds of things, it bothers my mind.” M_41_F2
Dietary impact	13/19 (68.4)	“…it’s having to peel the skin off my chicken or cut the fat off a good, juicy steak. You know. Oh, yeah. I miss them tastes.” M_54_F2
Bothered by diet limitations	2/13 (15.4)	“It’s a little, I guess, sometimes challenging because the diet and the health changes and the habits that you have to change to try to stop it from continuing to harden, like weight management. Changing your whole lifestyle and diet basically around your illness is kind of challenging because some people are on a set budget for groceries or whatever, and it’s just a little bit tricky because you have to balance everything all over again.” F_35_F1
Unable to eat as much as you would like	1/13 (7.7)	“Like I’m trying to eat less. Talking about quantity, less. And avoiding fried food, eating more vegetables.” F_46_F3
Daily activity impact	13/20 (65.0)	“Yes. If I have an active day before then the following day I’m not going to be active unless I have to be active…. Babysitting sometimes. I make myself do that, but it’s definitely hard. Outdoor activity stuff, helping with my husband do stuff.” F_53_F3
Household chores	8/13 (61.5)	“I mean, just this past year doing anything more active has gotten me tired, you know, doing the vacuum cleaning, running around loading the dishwashers and whatever.” F_71_F3
Day-to-day usual activities	3/13 (23.1)	“To shopping, I don’t know if you who doesn’t like to shop, at least for groceries, you know? You don’t want to get up, and when you, you’re just like, “Can I send my kid in to get it?” F_35_F1
Leisure activities	3/13 (23.1)	“So it’s really disruptive because you can’t do the things that you once enjoyed. It’s hard to get motivated to do it.” F_35_F1
Personal care	2/13 (15.4)	“When I have the headaches then I cannot touch my head or even comb my hair. It’s painful.” F_46_F3
Relationship/ social participation impact	11/19 (57.9)	“ Yes, I don’t have the energy to go out and be social. And then there’s times where I’m so tired and just don’t feel like moving to where I don’t want to see people…Or even have people over.” M_54_F2
Family/children	3/11 (27.3)	“I think when I gave notice when I talked about my situation at first that I have NASH with, for example, with my friends or my family members, I think they treat me more differently, a little, the fact that I used to be. Yeah.” M_20_F2
Partner/spouse/ dating	3/11 (27.3)	“They’ve definitely affected my daily life. I haven’t been able to work as much, so financially it’s put me in a really bad spot…And I really like going and getting coffee with my partner but when you’re broke, you can’t really go out and get coffee either.” NB_19_F2
Friends	2/11 (18.2)	“And I like spending time with my small group of friends. And having a decreased level of energy prevents me from really doing any of those things.” NB_19_F2
Social participation	1/11 (9.1)	“Yes, because, you know, drinking is a very social activity. My family does a lot. Friends of the family do it a lot. And obviously it’s not something I can participate in on a regular basis, due to my condition.” F_29_F2
Economic and burden impact	11/20 (55.0)	“…it does definitely have an economic impact, especially in stuff like insurance and co-pays, because you’re paying, you know, another co-pay, another pharmacy bill, another procedure bill for something else yet again.” F_29_F2
Financial burden	2/11 (18.2)	“I was told, “You need to stay away from carbs, stay away from red meats, go more on a lean diet like the Mediterranean diet.” All things good are expensive, really expensive. It goes from, “Let me spend $150 on groceries for the week,” to now we’re spending $300 a week. It can put a stressor in your pocket…It’s a little hard because you go from limiting your budget to certain things to now I need to expand it.” F_35_F1
Disability	1/11 (9.1)	INTERVIEWER: Are there any impacts to your work productivity as a result of NASH? PARTICIPANT: “I guess, yes. I am on disability.” F_63_F2
Healthcare utilization	1/11 (9.1)	INTERVIEWER: Any physical impacts? PARTICIPANT: “Outside of biopsies to check the progression of the NASH? No.” F_29_F2
Work absenteeism	1/11 (9.1)	PARTICIPANT: “I’m constantly dealing with diarrhea and vomiting every time I eat. And it affects my ability to work…” INTERVIEWER: Have you had to call out of work? PARTICIPANT: “A lot…Probably for about 50% of my shifts.” NB_19_F2
Other (school disruption, reduced work hours)	1/11 (9.1)	“It’s [fatigue] definitely more severe if I’ve had to do something the day before. I work a part time job but I’ve had my hours reduced because of all the medical issues I’ve been having.” NB_19_F2

n number of participants, NASH non-alcoholic steatohepatitis.

Note: The participant code is provided next to each quote for easy identification. It includes the gender (female, F; male, M; non-binary, NB), age, and fibrosis stage (F1, F2, or F3): Gender_Age_Fibrosis stage.

Participants may endorse more than one concept, and only the most relevant sub-impacts of each impact of NASH are presented; as such, the total number of participants endorsing a sub-impact may not add up to the total number endorsing an impact of NASH.

I would say most of the day I feel tired. I don’t have the energy to do anything, so I can’t really do house chores after work.

I cannot do exercise…And walk and exercise, this exercise bicycle, and I couldn’t do that.

Among those who described the psychological/emotional impact of NASH, participants were concerned that NASH would progress into cirrhosis, or they experienced depression or anxiety due to NASH (Table 5). Responses from some participants are as follows:

It worries me…Am I going to advance into full blown cirrhosis? Am I going to have like metabolic or hepatic encephalopathy?

I think maybe probably anxiety…I think that’s probably because of my anxiety because of other things.

Participants’ responses about the impact of NASH on their diet, daily activities, and social participation were as follows:

I’m trying to eat less. Talking about quantity, less. And avoiding fried food, eating more vegetables.

Just this past year doing anything more active has gotten me tired…doing the vacuum cleaning, running around loading the dishwashers and whatever.

Yes, I don’t have the energy to go out and be social. And then there’s times where I’m so tired and just don’t feel like moving to where I don’t want to see people.

Several participants (n = 11/20; 55.0%) described the economic impact and burden that NASH had on their lives (Table 5). An example response is provided here:

…it does definitely have an economic impact, especially in stuff like insurance and co-pays, because you’re paying…another co-pay, another pharmacy bill, another procedure bill for something else yet again.

Of the mentioned impacts, participants chose the three impacts they considered to be most bothersome: relationships or social interactions, n = 10/11, 90.9%; psychological or emotional impact, n = 11/14, 78.6%; economic burden, n = 5/11, 45.5%; physical impact, n = 6/14, 42.9% (Table 4). More than one-third of participants (n = 7/20, 35.0%) described that a good day with NASH was one without any symptoms. Symptoms like fatigue, lack of energy, bloating, pain, lack of focus or low self-esteem represented a bad day for participants (Table 6).

Table 6. Participant descriptions of a good and bad day with NASH.

Description Theme	Total n/N (%)	Example Quotes
Good Day
Lack of symptoms	7/20 (35.0)	“I mean, a good day would be no symptoms, obviously, but I guess with symptoms, it’s mild, it’s manageable, it doesn’t directly impact my ability to function.” M_35_F2
Able to carry out daily activities (e.g. household chores, shopping)	5/20 (25.0)	“A good day is going is like Saturday I went Christmas shopping. I had a good day Saturday. We have ATVs, and we ride those. A good day is going and actually feeling like going riding, just being motivated, doing things.” F_47_F3
Full of energy	3/20 (15.0)	“A good day is not getting tired throughout the day, being able to get things done around the house and actually have the energy to leave the house.” M_54_F2
Able to get work done	3/20 (15.0)	“A good day is I get most if not all of the things I planned to do done, and I’m able to relax at the end of the night so that way the pain that I’m feeling, especially in my back, can have a chance to dissipate.” NB_19_F2
No changes	2/20 (10.0)	“I don’t know what a good day or a bad day because I still feel the same as I always did.” M_53_F2
Bad Day
Experience symptoms	12/20 (60.0)	“I would say just the feeling overall tiredness or no energy, or I’ll… very bad bloating, the discomfort. I would say that that’s the main one.” F_27_F1 “A bad day is I’m not able to get most of the things I planned to do in my day done because I’m in too much pain, I don’t have the energy, or because I’m in and out of the bathroom.” NB_19_F2
Sedentary (e.g. not able to go out, stay in bed)	3/20 (15.0)	“A bad day with NASH, I absolutely won’t go to the store. I can’t get out and walk around. I’ll drive into the store if they want some things.” F_35_F1
Not able to do household chores	2/20 (10.0)	“That I cannot exercise or do my chores.” M_44_F3
Cognition/emotional (e.g. self-esteem, lack of focus)	2/20 (10.0)	“That sense of low self-esteem, and it becomes a little bit more difficult to think that it’s not that big of an issue. It becomes a bit more difficult to understand that I have this. It’s not a normal thing, like a normal day in the past.” M_20_F2
No changes	2/20 (10.0)	“I couldn’t answer that because I, like I said, I wouldn’t have even noticed that I had it. So, I don’t know.” M_53_F2

ATV all-terrain vehicle, n number of participants, NASH non-alcoholic steatohepatitis.

Note: The participant code is provided next to each quote for easy identification. It includes the gender (female, F; male, M; non-binary, NB), age, and fibrosis stage (F1, F2, or F3): Gender_Age_Fibrosis stage.

3.2. NASH conceptual model development

Findings from the TLR were used to develop a preliminary conceptual model, which was subsequently updated to include concepts identified during the qualitative interviews to develop a final conceptual model of key concepts and the impact of NASH (Figure 3). This model includes the concepts identified in the TLR: clinical signs/risk factors (abnormal liver imaging and function, diabetes, dyslipidemia, and hypertension); frequently reported symptoms (e.g. fatigue, pain, sleep problems, and discomfort); impacts (e.g. depression, anxiety, work impairment, and social life); and unmet treatment needs (economic burden, lack of education and disease management, absence of a cure, dealing with NASH symptoms such as fatigue and itching, and limited treatment options). In addition, the model incorporates concepts identified using social media analyses (perceived lack of physician support, or lack of knowledge about disease prognosis or treatments)²⁵. Furthermore, the top symptoms (energy/sleep-related symptoms, cognitive, gastrointestinal, and other symptoms) and impacts (physical, emotional, dietary, social, activity, and economic) described by participants during the qualitative interviews are represented in the conceptual model.

Figure 3. Conceptual model of NASH: participants’ perceptions of NASH clinical signs, symptoms, impact, and unmet treatment needs. F fibrosis stage, GI gastrointestinal, n number of participants, NASH non-alcoholic steatohepatitis. Note: Concepts listed within grey boxes were identified from the targeted literature review; concepts listed within blue (symptoms) and green (impacts) boxes were identified from both the targeted literature review and qualitative interviews.

4. Discussion

Findings from a TLR and qualitative interviews with 20 participants living with NASH were used to develop a conceptual model of NASH including patients’ perceptions of clinical signs, symptoms, impact, and unmet treatment needs. Through concept elicitation interviews, insights around participants’ perspectives on symptoms and the impact of NASH on their daily lives were elucidated. Participants in this study reported experiencing a variety of NASH symptoms and considered most symptoms to be moderately severe. The results of this study build upon findings from other qualitative studies that assessed patients’ perspectives on NASH/NAFLD symptoms^16,19–23. Fatigue and weakness or lethargy were the most frequently reported NASH symptoms^{16,19,20,22,23}, with fatigue affecting patients the most in their daily lives¹⁶. A recent qualitative study by Swain et al. reported that NASH patients considered fatigue, abdominal pain, worry, and food restrictions as some of the most important symptoms/impacts of NASH²³. Consistent with previous studies, participants in the current study also reported impact of NASH on physical functioning, psychological or emotional aspects, diet, daily activities, relationship or social participation, and economic burden^17,18,20,21. Importantly, the psychological or emotional impacts of NASH were considered to be the most bothersome among participants in the current study.

Due to the lack of approved pharmacological options, physicians recommend lifestyle interventions like weight reduction through diet modification and physical activity as first-line therapy for NASH management based on current treatment guidelines^6,14. Physicians have reported the challenges of conveying the importance of lifestyle modifications to patients with NASH due to inadequate patient education materials²⁶. On the other hand, patients with NASH may consider this line of treatment to be insufficient or may perceive it as a lack of interest by their healthcare provider in their disease and its management^19,22. Available evidence suggests that even a 5% to 10% reduction in body weight could induce improvements in NASH histology²⁷. Despite this, many patients are unable to make the required lifestyle modifications. For example, few patients achieve 10% weight reduction in clinical trials²⁷, possibly due to the lack of adequate support for these patients. Nearly half of the patients with NASH are not referred to diet, nutrition, or exercise specialists who can provide personalized advice to help them make the recommended lifestyle modifications²⁸. In the present study, several participants were concerned about being overweight and were bothered by the recommended dietary limitations. In addition, participants discussed the challenges of weight reduction, including low motivation, dietary restrictions, and an inability to exercise due to the impact of NASH on their energy levels. Taken together, these findings suggest that understanding patients’ motivational needs, improving patient education, and providing emotional and lifestyle-related support to patients with NASH might help them achieve their weight reduction goals and consequently help in disease management^19,27.

Previous studies have proposed conceptual models on the symptoms, impacts, and barriers and aids to making lifestyle behavioral changes for patients with NASH^19,20,23. For example, one conceptual model presented patients’ perceptions of NASH symptoms and their impact as identified during concept elicitation interviews²⁰. The model characterized the following: (1) key symptoms (pain, fatigue, itching, cognition, sleep impact); (2) risk factors (diabetes and high BMI); (3) psychological risk factors (attitude, motivation, and eating habits); and (4) physical, social, psychological, and economic impacts of NASH²⁰. Another model focused on the aspects that aid (social support, symptoms, and concerns about adverse outcomes) or prevent (impact on quality of life, competing priorities, and time constraints) patients with NAFLD from making lifestyle behavioral changes¹⁹. The conceptual model proposed by Swain et al. listed the patient-reported signs and symptoms of NASH (such as fatigue, pain, bloating, and pruritus), immediate impacts resulting from NASH symptoms (decreased physical activity, worry, and frustration), and the general impacts of the condition (such as drowsiness, anxiety, and decreased social functioning)²³. The current study proposes a holistic conceptual model that provides comprehensive descriptions of patients’ perspectives of the physical and psychological impact of NASH on their daily lives. This model integrates key concepts such as NASH symptoms (gastrointestinal, energy/sleep-related, and cognitive symptoms) and impacts on patients’ daily activities (physical, emotional, dietary, social, activity, and economic impacts). Furthermore, the model highlights the clinical signs and risk factors of NASH (abnormal liver imaging and function, diabetes, dyslipidemia, and hypertension), and unmet treatment needs and treatment barriers (lack of education and absence of a cure). Therefore, this conceptual model provides additional information to what others have previously described^19,20,23. This model may help guide patient-physician conversations around the disease burden and its impact on patients with NASH, enabling a more targeted and personalized approach to NASH disease management.

Strengths and limitations

The key strength of this study is that it utilized concept elicitation interviews to understand the experiences and perspectives of patients living with NASH. The number of participants interviewed reflects the typical sample size for qualitative research^24,29. The study findings address the gap in the literature around understanding patients’ perspectives of the disease symptoms and the resulting impact on their daily lives. We captured the real-world experiences of people living with NASH and other comorbidities, based on how they felt and functioned in their everyday life, as well as the totality of their lived experience with NASH and other comorbidities.

However, the study has its limitations. A majority of participants were White (75.0%). Only patients with mild (F1) to advanced (F3) fibrosis who had not progressed to liver cirrhosis were eligible for the study. Liver cirrhosis is likely to have a deeper physical, emotional, social, functioning and economic impact due to its severe symptoms³⁰; therefore, the perspectives of participants in this study may differ from the experiences of NASH patients with liver cirrhosis. We further acknowledge there may have been several interactions and some overlap in participant experiences based on their different diagnoses, and participants may not have the clinical expertise to attribute their symptoms and impact specifically to NASH as compared to other conditions. That is the reality of the complexity of NASH, which we sought to characterize in the participants’ own words in this study. Finally, the study only included English-speaking US residents. For these reasons, the findings of the present study may not be generalizable to all patients with NASH.

5. Conclusions

This qualitative study identified key symptoms and gaps in the literature around recognizing patients’ experience of living with NASH and its impact on their daily lives. These findings can serve as a foundation for larger studies evaluating the disease burden of NASH. Understanding patients’ perspectives on NASH symptoms and their disease impact could help better characterize and diagnose patients living with NASH. In turn, this would assist healthcare providers in better treatment-related decision-making for their patients living with NASH.

Transparency

Declaration of funding

This study was sponsored by Eli Lilly and Company (Indianapolis, IN, USA).

Declaration of financial/other relationships

SS, CC, and J-LP are employees and stockholders of Eli Lilly and Company. NT is an employee of Evidera. RW is an employee of PRECISIONheor and was an Evidera employee when this research was conducted. Evidera received funding from Lilly to conduct the research that generated the evidence used to develop this manuscript. SMB is currently an employee of IQVIA, and was an employee of Evidera at the time of this research.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have read and given their approval for this version to be published. All authors contributed to the conception/design, data analyses and interpretation, manuscript writing, and provided final approval of the manuscript.

Acknowledgements

The authors thank Adam Bailey, Fanyang Zeng, Effah Acheampong, Chris Roldan, Hope Paul, and Amira Bakir (Evidera, Bethesda, MD, USA) for assisting with the initial study design, coding/analysis, or report writing. Richa Kapoor, an employee of Eli Lilly Services India Pvt. Ltd., provided medical writing support which was funded by Eli Lilly and Company (Indianapolis, IN, USA).

Data availability statement

The data that support the findings of this study are available from the corresponding author, SS, upon reasonable request.