Comparison of the Simplified sWHI and the Standard CHS Frailty Phenotypes for Prediction of Mortality, Incident Falls, and Hip Fractures in Older Women

Abstract

Background

We compared the simplified Women’s Health Initiative (sWHI) and the standard Cardiovascular Health Study (CHS) frailty phenotypes in predicting falls, hip fracture, and death in older women.

Methods

Participants are from the WHI Clinical Trial. CHS frailty criteria included weight loss, exhaustion, weakness, slowness, and low physical activity. The sWHI frailty score used two items from the RAND-36 physical function and vitality subscales, one item from the WHI physical activity scale plus the CHS weight loss criteria. Specifically, level of physical function was the capacity to walk one block and scored as severe (2-points), moderate (1-point), or no limitation (0). Vitality was based on feeling tired most or all of the time (1-point) versus less often (0). Low physical activity was walking outside less than twice a week (1-point) versus more often (0). A total score of 3 resulted in a frailty classification, a score of 1 or 2 defined pre-frailty, and 0 indicated nonfrailty. Outcomes were modeled using Cox regression and Harrell C-statistics were used for comparisons.

Results

Approximately 5% of the participants were frail based on the CHS or sWHI phenotype. The sWHI frailty phenotype was associated with higher rates of mortality (hazard ratio [HR] = 2.36, p ≤ .001) and falls (HR = 1.45, p = .005). Comparable HRs in CHS-phenotype were 1.97 (p < .001) and 1.36 (p = .03), respectively. Neither phenotype predicted hip fracture. Harrell C-statistics revealed nonsignificant differences in HRs between the CHS and sWHI frailty phenotypes.

Conclusion

The sWHI phenotype, which is self-reported and brief, might be practical in settings with limited resources.

Based on the data from the Cardiovascular Health Study (CHS), a phenotype of geriatric frailty was proposed in which at least three of five indicators (slowness, weakness, fatigue, low physical activity, and body weight loss) were present (1). Despite the CHS phenotype being predictive of adverse outcomes in multiple studies (2–4), implementation of the measure in nonclinical setting is still challenging. Frailty criteria such as slowness and weakness evaluate performance and require specialized training and equipment and therefore might be limited to settings with adequate resources. Using WHI data, we offered an alternative approach in which RAND-36 physical function (PF) scale was used in place of CHS performance measures (5). This modification offered practical advantages for self-administration and allowed self-report. Previously, we demonstrated that self-report WHI measure performed comparably to the more-complex CHS phenotype in predicting important geriatric outcomes such as mortality, hip fracture, and falls (6). These analyses confirmed the value of the WHI phenotype, however concern still exists that multiitem scales might not be efficient for use with large populations, might be cumbersome for over the phone administration, and might not be scalable for dissemination in settings with limited resources.

Others have carried out attempts to simplify frailty instruments for screening, however the resultant measures were either limited by clinical assessment (such as chair stands in SOF phenotype (7)) or included comorbidities (such as in FRAIL scale) (8), although originally frailty was conceptually defined as being independent of coexistent conditions (1). To fill the gap in offering easy to use and valid and reliable screening measure of frailty that is consistent with its original conceptual and biological model and that is independent of comorbidity and disability, we carried out further analyses of the WHI multi-item scales, identifying four items and corresponding thresholds that provided approximation of that scale’s indicator of the presence or absence frailty classification. In item selection, we favored single items within each of the frailty domains that were commonly used in frailty literature (9) and we also selected thresholds within each of the items in the way that frailty prevalence would be consistent with the nonsimplified WHI phenotype estimate.

The aim of the current study was to compare this simplified, 4-item sWHI phenotype with the CHS phenotype for prediction of falls, hip fracture, and death in a subsample of the WHI Clinical Trial (CT) participants aged 65 years and older for whom data on both phenotypes were available. It was hypothesized that the CHS and sWHI phenotypes would have similar predictive abilities.

Sample

The WHI CT (N = 68,132) is a study of postmenopausal women’s health that was designed as a set of randomized clinical trials. Details of the design, data collection methods, and baseline data are available elsewhere (10). Briefly, women aged 50–79 years were recruited from 1993 to 1998 at 40 clinical centers in the United States. Women were excluded for predicted survival of 3 years or less, conditions limiting adherence, or active participation in other trials. A random 25% subsample (n = 6,025) of participants aged 65 years and older attended baseline and Year 1 clinical visits in which self-report and physical performance measures were collected. From this subsample, 3,666 (60.9%) women provided complete data on CHS frailty components (defined later) and 3,974 (66.0%) individuals had nonmissing data on sWHI frailty criteria (defined later); 3,634 (60%) participants who provided complete data on both CHS and sWHI frailty elements constituted the analytical sample used here. Detailed description of data availability per CHS and WHI frailty phenotypes is provided (see Supplementary Figure 1). All WHI participants provided written informed consent and institutional review board approval was obtained at each of the 40 WHI clinical centers and at the Clinical Coordinating Center.

Measurements

The WHI Physical Activity Scale (11) included a self-report of frequency and duration of mild, moderate, and strenuous activities with total expenditure of energy calculated as a metabolic equivalent task score. Comorbidity history of myocardial infarction, angina, congestive heart failure, peripheral arterial disease, arthritis, cancer, treated diabetes, hypertension, and chronic bronchitis/emphysema were collected by self-report at baseline. Independence in activities of daily living (ADL) was measured at the baseline and Year 1 follow-up visit using four items asking about the amount of help (no help, some help, totally dependent) needed to eat, dress and undress, get in and out of bed, and take bath or shower. At the baseline and Year 1 follow-up visit, trained staff also clinically collected anthropometric measurements such as weight, height, and waist circumference. Tests of physical performance included grip strength (using a handheld Jamar dynamometer, expressed in kilogram) and walking speed (time in seconds to walk 6 m at usual pace, expressed as m/s). Two trials were conducted for performance-based measures and scored as the average of the two trials.

CHS Frailty Phenotype

In CHS, frailty was operationally defined as the presence of three or more of the following criteria (1): Shrinking: Objectively measured weight loss of 10 pounds or more or weight loss of 5% or more between the baseline and Year 1 visits. Weakness: Grip strength in the lowest quintile stratified according to BMI categories (Supplementary Table 1). Exhaustion: RAND-36 self-report of being tired or worn out at least most of the time (Supplementary Table 1). Slowness: Gait speed of 0.8 m/s or less, which was found to be a sensitive marker of mobility impairment (12). Low physical activity: WHI Physical Activity questionnaire score in the lowest quintile.

For each frailty component, 1 point was assigned if the participant scored below the criterion-specific cut-point, yielding a score ranging from 0 to 5. Consistent with other studies, frailty was defined as a score of 3 or more; prefrailty as a score of 1 or 2, and nonfrailty as a score of 0.

sWHI Frailty Phenotype

The sWHI operationalization of frailty included the same criteria as the CHS phenotype for shrinking (weight loss of ≥ 10 pounds or ≥ 5% between the baseline and Year 1 visit). PF was measured using a single item from RAND-36 (13) PF scale. The item inquired about the extent of health limitations in walking one block. The response categories included “limited a lot”, “limited a little” and “not limited at all”, and were scored as 2, 1, and 0 points accordingly. One other RAND-36 item (from the Vitality Scale) inquired about how often participant’s felt tired in the previous 4 weeks. The response of being tired most of the time or more was used to indicate the presence of exhaustion. One item from WHI Physical activity inquired about frequency of walking outside the home for more than 10 minutes. Walking outside less than twice a week was used to indicate low physical activity. Similar to the CHS definition, the sum of points ranged from 0 to 5. Women having three or more points were considered to be frail, those with one or two were considered to be prefrail, and those with none were considered to be nonfrail (Table 1).

Table 1.

Definitions of Frailty in the CHS and sWHI Phenotypes

Frailty Criterion	CHS Frailty Phenotype and Cut Point (point assignment)	sWHI Frailty Phenotype and Cut Point (point assignment)
Weakness	Grip strength in the lowest quintile stratified according to BMI categories (1 point)	Single item from the RAND-36 for both weakness and slowness
Slowness	Gait speed of 0.8 m/s or less (1 point)	“How much does your health now limit you in walking one block?”
		“Limit a lot” (2 points); “limit a little” (1 point); “not limit at all” (0 point)
Exhaustion	RAND-36 self-report of being tired or worn out at least most of the time (1 point)	Single item from the RAND-36
		“How much of the time during past 4 wk did you feel tired?”
		>“Most of the time” (1 point)
Low physical activity	WHI Physical Activity questionnaire score in the lowest quintile (1 point)	Single item from the WHI physical activity questionnaire
		“How often do you walk outside the home for more than 10 min without stopping?
		< “2–3 times each week” (1 point)
Shrinking	Weight loss of 10 pounds or more or weight loss of 5% or more in 1 y (1 point)	Weight loss of 10 pounds or more or weight loss of 5% or more in 1 y (1 point)

Note: CHS = Cardiovascular Health Study; sWHI = simplified Women’s Health Initiative

Ascertainment and Adjudication of Death, Hip Fractures, and Falls

Participant deaths (and other outcomes) were ascertained through annual mailed medical updates and periodic checks of the National Death Index for all participants. At the time of this analysis, the latest WHI mortality data were available through December 1, 2013. Hip fractures and falls were also ascertained from the annual medical updates, with WHI physicians adjudicating hip fractures using medical records. Participants reported the number of times they fell or landed on the ground in the interval since the completion of the last medical update form. Two years of follow-up for falls after the Year 1 clinical visit in which a participant was identified as having an incident fall were included if she had reported at least one fall per year. Because the goal was to examine incidence of hip fracture and falls subsequent to ascertainment of frailty, hip fractures and falls reported before the first annual follow-up visit were excluded. Information on fractures was included for the duration of study follow-up.

Statistical Analysis

Year 1 statistics for age and individual frailty criteria were examined using the CHS and sWHI frailty phenotypes. Frequencies were estimated for categorical variables, and means and SD were calculated for continuous variables. A Venn diagrams illustrated the overlap of disability (defined as needing assistance with one or more of the ADL) and comorbidity (defined as 2 or more of the coexistent chronic conditions) with frailty at Year 1 follow-up visit using the CHS and sWHI frailty phenotypes, percentages are based on all frail participants. Cox proportional hazards models were used to estimate effect of the association between frailty and prefrailty criteria according to CHS or sWHI phenotypes on all-cause mortality, hip fractures, or falls, using the nonfrail category as a reference group. Models were adjusted for age. Time to event was defined as the number of years in days from WHI Year 1 follow-up visit to study outcomes. To compare the predictive ability of the CHS and sWHI frailty phenotypes, Harrell C indexes (14), which estimated the probability of concordance between observed and predicted responses for the mortality, hip fracture, and falls models were calculated including each phenotype separately. For the purpose of estimating reliable confidence intervals (CIs), the main analytical sample was randomly divided into derivation and validation sets of equal sizes. Age-adjusted models were run in the derivation set and C-indexes and 95% CIs were then estimated in the validation set (15). Finally, C-index test statistics were compared by estimating their differences, generating a 95% CI of the differences and then specifying whether that CI included 0. All statistical analysis was completed using Stata version 11.2 (Stata Corp, College Station, TX).

Results

Characteristics of the Study Population and Concordance Between the CHS and sWHI Phenotypes

Characteristics of the cohort of 3,634 older women (average age 70.9) are shown in Table 2. Approximately 5% were frail based on the CHS or sWHI phenotype. Comparing individual criteria, slowness was identified in 11% of study participants and weakness in 27%, and total low and intermediate PF was identified in 13% of the sample.

Table 2.

Characteristics of 3,634 Female Participants Aged 65 Years and Older

Characteristics	Value
Age, mean ± SD	70.9 ± 3.7
Frailty status according to CHS phenotype, n (%)
Nonfrail	1,574 (43.3)
Prefrail	1,883 (51.8)
Frail	177 (4.9)
Frailty status according to sWHI phenotype, n (%)
Nonfrail	1,475 (40.6)
Prefrail	1,969 (54.2)
Frail	190 (5.2)
Individual CHS phenotype components, n (%)
Weakness	971 (26.7)
Slowness	387(10.7)
Poor energy	262 (7.3)
Low physical activity	713 (19.6)
Weight loss	645 (17.8)
Individual sWHI phenotype components, n (%)
Low physical function (2 points)a	99 (2.7)
Intermediate physical function (1 point)b	350 (9.6)
Good physical function (0 points)c	3,185 (87.6)
Poor energy	247 (6.8)
Low physical activity	1,665 (45.8)
Weight loss	645 (17.8)
Study outcomes, n (%)
Death	763 (21.0)
Incident hip fracture	161 (4.4)
Incident fall	977 (27.3)

Note: RAND-36 item “How much does your health now limit you in walking one block?” CHS = Cardiovascular Health Study; sWHI = Simplified Women’s Health Initiative.

^a<“limit a lot”, ^b“limit a little”, ^c>“not limit at all.”

Classification of frailty status using the phenotypes was concordant in 2,488 (68%) women. The kappa statistic was 0.4 (p < .001). The Spearman correlation between the CHS and sWHI phenotypes was 0.50 (p < .001) (Table 3).

Table 3.

Concordance Between CHS and sWHI Phenotypes in Levels of Frailty

sWHI Phenotype	CHS Phenotype (n)
	Nonfrail	Prefrail	Frail
Nonfrail	1,051	424	0
Prefrail	513	1,358	98
Frail	10	101	79

Note: CHS = Cardiovascular Health Study; sWHI = simplified Women’s Health Initiative.

κ = 0.42, p < .001.

Overlap of Frailty With ADL Disability and Comorbidity According to Simplified sWHI and CHS Phenotypes

Figures 1 and 2 display overlap between frailty, disability, and comorbidity by two phenotypes. In sWHI phenotype (Figure 1), there was modest concordance between frailty and comorbidity. Of those who were frail, 59% had comorbid disease, 1% had disability, 7% had both comorbid disease and disability, and 33% had neither ADL disability nor comorbidity. In CHS phenotype (Figure 2), similarly, modest concordance between frailty, and comorbidity was observed. Of those who were frail, 55% had comorbid disease, 1% had disability, 3% had both comorbid disease and disability, and 41% had neither ADL disability nor comorbidity.

Figure 1.

Venn diagram displays extent of overlap with activities of daily living (ADL) disability and comorbidity (≥2 diseases) for the simplified Women’s Health Initiative phenotype. Total represented 1,386 participants who had comorbidity and/or disability and/or frailty. n of each subgroup indicated in parentheses. Frail***: overall n = 190 frail participants. Comorbidity**: overall n = 1,302 with 2 or more of the following nine diseases: myocardial infarction, angina, congestive heart failure, peripheral arterial disease, arthritis, cancer, treated diabetes, hypertension, and chronic bronchitis/emphysema. Of these, 125 also were frail. Disabled*: overall n = 64 with an ADL disability; of these, 15 were frail.

Figure 2.

Venn diagram displays extent of overlap with activities of daily living (ADL) disability and comorbidity (≥2 diseases) for the Cardiovascular Health Study phenotype. Total represented 1,403 participants who had comorbidity and/or disability and/or frailty. n of each subgroup indicated in parentheses. Frail***: overall n = 177 frail participants. Comorbidity**: overall n = 1,302 with 2 or more of the following nine diseases: myocardial infarction, angina, congestive heart failure, peripheral arterial disease, arthritis, cancer, treated diabetes, hypertension, and chronic bronchitis/emphysema. Of these, 103 also were frail. Disabled*: overall n = 64 with an ADL disability; of these, 7 were frail.

sWHI Phenotype Versus CHS Phenotype for Prediction of Risk of Falls, Hip Fracture, and Mortality

During an average follow-up of 12 ± 3.9 years after the Year 1 clinical visit, 763 (21%) older women died, and 161 (4%) experienced hip fracture. A more immediate follow-up of an average of 2.6 years yielded an overall incident fall rate of 27%.

All-cause mortality was higher with greater level of frailty using the CHS or sWHI phenotype (Table 4). Point estimates for hazard ratios (HRs) for frailty were higher for the sWHI phenotype model. Specifically, the death rate women in the prefrail group (p < .001) 1.3 times as high as that of the nonfrail women and the rate of those with frailty was 2.4 as high (p < .001). Differences in the predictive ability of models in terms of C index were nonsignificant. The estimates were 0.60 for the sWHI and CHS phenotype (p for comparison = .85).

Table 4.

Age-Adjusted Association Between Frailty Level According to the CHS and sWHI Phenotypes and Estimates of Harrell C Scores and Risk of Adverse Outcomes in WHI Clinical Trial Participants

Phenotype	Mortality Model			Hip Fracture Model			Falls Model
	Deaths/PY	Incidence/1,000 PY	Estimate (95% CI) p Value	Hip Fractures/PY	Incidence/1,000 PY	Estimate (95% CI) p Value	Falls/PY	Incidence/1,000 PY	Estimate (95% CI) p Value
CHS
Nonfrail	277/20,614	13.4	Reference	71/20,224	3.5	Reference	398/4,017	99.1	Reference
Prefrail	435/23,506	18.5	1.36 (1.17–1.59)a < .001	82/23,113	3.5	0.95 (0.69–1.30)a .73	520/4,731	110.0	1.11 (0.98–1.27)a .10
Frail	51/1,906	26.8	1.97 (1.46–2.66)a < .001	8/1,911	4.2	1.04 (0.50–2.16)a .91	59/433	136.3	1.36 (1.03–1.80)a .03
Harrell C statistic			0.60 (0.57–0.63)b .85c			0.64 (0.58–0.70)b .27c			0.54 (0.51–0.56)b .24c
sWHI
Nonfrail	273/19,241	14.2	Reference	68/18,929	3.6	Reference	382/3,749	101.9	Reference
Prefrail	422/24,769	17.0	1.28 (1.11–1.49)a < .001	82/24,330	3.4	1.00 (0.73–1.38)a .98	526/4,970	105.8	1.04 (0.91–1.19)a .53
Frail	68/2,059	33.0	2.36 (1.81–3.09)a < .001	11/1,989	5.5	1.38 (0.73–2.62)a .32	69/462	149.4	1.45 (1.12–1.88)a .005
Harrell C statistic			0.60 (0.57–0.63)b			0.65 (0.58–0.71)b			0.54 (0.51–0.57)b

Note: CI = Confidence interval; CHS = Cardiovascular Health Study; HR = Hazard ratio; PY = Person years; sWHI = simplified Women’s Health Initiative.

^aHazard Ratio (95% CI). ^bC statistics (95% CI). ^cp value for comparison between CHS and sWHI frailty phenotypes.

Frailty identified using the CHS and sWHI phenotypes revealed different but insignificant rates of hip fracture. After adjustment for age, the rate of hip fracture in women with frailty identified using the CHS phenotype was 1.0 times as high (p = .91) and using the sWHI phenotype was 1.4 times as high (p = .32). There was not significant difference in the C index between the two models (p = .27)

Finally, the relationship between higher levels of frailty and rates of falling was similar in the CHS and sWHI phenotypes, so that the hazard of falling in women with frailty according to the sWHI phenotype was 1.5 times as high (p = .005); the hazard according to the CHS phenotype was 1.4 as high (p = .03). The rate of falls in women in the prefrail group based on the sWHI and CHS phenotypes was 1.1 times as high (p > .1 for all). Both models had similarly low C index estimates of 0.54 (p for comparison = .24).

Discusssion

In this large sample of older women, it was demonstrated that a simplified 4-item self-report sWHI frailty phenotype performed at least as well as the more-complex CHS phenotype in predicting important geriatric outcomes. Approximately 5% were judged as frail based on the CHS or sWHI instrument. Both measures concurred that frailty is independent of disability and comorbidity and a subset of 33% and 41% of the study participants with frailty by the sWHI and CHS phenotypes respectively were free of comorbidity and disability. Classification of frailty using the two phenotypes was concordant in almost 70% of participants; the kappa statistic agreement measure nevertheless was only moderate suggesting differences in identifying persons at risk. Overall, HR estimates confirmed the predictive ability of the simplified sWHI phenotype to identify a subset of women at risks for mortality and falls. None of the measures predicted hip fractures.

The WHI and CHS approaches are different in the objective versus subjective evaluation of functional capacity. In the CHS phenotype, functional performance is measured by grip strength and timed walking-speed tests; in the sWHI phenotype, functional capacity is measured by a single item from the RAND-36 scale. Because participant-completed report about levels of difficulty to walk one block rely on self-perception of severity of functional capacity deficits, they may indicate, to a certain extent, unique information about one’s own health that may differ from objective measures. If this is the case, the subjective assessment is not necessarily a disadvantage given a well-established and strong association between self-rated health and adverse outcomes (16–18). This conclusion resonates with a recent analysis demonstrating that operationalization of frailty in which a self-report tool substituted for a slowness objective measure yielded a better prediction of mortality over 5 years of follow-up (9).

Although the C-statistics show that the predictive ability of the two models is similar, the sWHI phenotype discriminatory power was higher in predicting mortality and falls. This finding is not unexpected since mobility limitations are reflected in the self-report measure and these limitations are a strong predictor of mortality and falls (19). Our findings also highlighted that both the CHS and sWHI phenotypes are somehow limited in their ability to discriminate adverse outcomes and, therefore, neither of these measures should be used as the sole tool for screening for risk of mortality, falls, and hip fractures. Nevertheless, the validity of these frailty phenotypes in predicting adverse outcomes was similar to other commonly used risk stratification measures (7–9). The hypothesis that the simplified self-report measures of frailty would be informative in risk assessment was confirmed. Absolute rather than population specific thresholds used to define the extent of mobility limitations may also have contributed to the sensitivity of the sWHI phenotype. The latter is especially important, given that dissemination depends on the perceived ease of use. Short, simple, and self-administered screening measure might be well suited for use in community settings and could lead to more preventive rather than reactive assessment and earlier intervention for managing frailty.

The reasons underlying relatively weak association between frailty and the outcome of hip fracture is not entirely clear. WHI frailty measure predicted incident hip fracture (5,6). Low discriminatory power of sWHI phenotype with regard to fractures might be due to its focus on mobility limitations. Although persons with lower mobility might be at higher risks for fall, the risk of injury and fracture might be mitigated by the fact that these individuals might be also subjected to environmental inspection and hazard-reduction interventions. The participation in these programs led to a lessened rate of injurious falls (20).

This study has several strengths, including a large sample size, careful adjudication of outcomes, and completeness of long-term follow-up. There are also several limitations. First, the item selection in the sWHI phenotype may raise a concern that other constructs such as poor health being measured. To assuage that concern, we matched items within each of the frailty domains with single items that were commonly used in frailty literature and provided head to head comparison in terms of construct overlap between frailty, disability, and comorbidity. Although sWHI measure appeared to be more sensitive to capture the severity of chronic conditions, similar overlap between sWHI and CHS measures with disability, suggests that sWHI measure might be useful to identify groups at risks for future functional impairment and disability. Second, the measures used to define components of the CHS phenotype in this analysis were similar but not identical to those used in the original definition (1). Notably, previously, slowness was based on sample specific cutoff point in earlier studies (12,21) rather than the universal threshold used here. Also, exhaustion items differed somewhat, but were conceptually true to those used in CHS definition. Third, older women with low levels of functioning and health were less likely than women with better functioning to participate in performance-based assessments and complete self-reported questionnaires. Loss to follow up may underestimate the proportion of frail women at risk of adverse events, although rather than determining the epidemiology of frailty, we aimed to provide a head-to-head comparison of the predictive performance of widely used traditional tool and a brief self-report for frailty. Fourth, we compared the predictive ability of the sWHI phenotype, which is short and self-report and is consistent with the proposed biological model of frailty (1), and CHS phenotypes, however several other indexes of frailty have been proposed (4,9) and our findings might not be generalizable across different frailty definitions. Future studies might consider evaluating whether screening measures that also include chronic disease count or dependence in ADL justify departure from conceptualization of frailty as being distinct from comorbidity and disability in terms of their predictive power. Finally, the population studied here, while diverse, was limited to relatively healthy women, largely of white European origin. Future studies including men and having more minority ethnic representation may offer important insights.

In summary, the easily collected simplified self-report sWHI phenotype provides an operational definition of frailty with predictive ability for falls, hip fractures, and mortality at least as good as that of the more-complex CHS phenotype. Therefore, the sWHI phenotype, which does not require direct measurements of physical performance, offers practical advantages for self-administration and might be used in settings with limited resources.

Supplementary Material

Supplementary data is available at The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences online.

Funding

The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through Contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. The funding agencies had no role in the design and conduct of this study, the analysis or interpretation of the data, or the preparation of the manuscript.

Conflict of Interest

The authors declare no conflict of interest.