Frailty does not cause all frail symptoms: United States Health and Retirement Study

Background Frailty is associated with major health outcomes. However, the relationships between frailty and frailty symptoms haven’t been well studied. This study aims to show the associations between frailty and frailty symptoms. Methods The Health and Retirement Study (HRS) is an ongoing longitudinal biannual survey in the United States. Three of the most used frailty diagnoses, defined by the Functional Domains Model, the Burden Model, and the Biologic Syndrome Model, were reproduced according to previous studies. The associations between frailty statuses and input symptoms were assessed using odds ratios and correlation coefficients. Results The sample sizes, mean ages, and frailty prevalence matched those reported in previous studies. Frailty statuses were weakly correlated with each other (coefficients = 0.19 to 0.38, p < 0.001 for all). There were 49 input symptoms identified by these three models. Frailty statuses defined by the three models were not significantly correlated with one or two symptoms defined by the same models (p > 0.05 for all). One to six symptoms defined by the other two models were not significantly correlated with each of the three frailty statuses (p > 0.05 for all). Frailty statuses were significantly correlated with their own bias variables (p < 0.05 for all). Conclusion Frailty diagnoses lack significant correlations with some of their own frailty symptoms and some of the frailty symptoms defined by the other two models. This finding raises questions like whether the frailty symptoms lacking significant correlations with frailty statuses could be included to diagnose frailty and whether frailty exists and causes frailty symptoms.

Enter a financial disclosure statement that  This statement is required for submission and will appear in the published article if YSC is employed by the Canadian Agency for Drugs and Technologies in Health. YSC conducted this study as an independent researcher out of academic curiosity without any material support. No external funding was received for this study. This study is not associated with any patents, products in development or marketed products.   Frailty is associated with major health outcomes. However, the relationships 63 between frailty and frailty symptoms haven't been well studied. This study aims to show the 64 associations between frailty and frailty symptoms. 65

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The Health and Retirement Study (HRS) is an ongoing longitudinal biannual survey in 67 the United States. Three of the most commonly used frailty diagnoses, defined by the 68 Functional Domains Model, the Burden Model, and the Biologic Syndrome Model, were 69 reproduced according to previous studies. The associations between frailty statuses and 70 input symptoms were assessed using odds ratios and correlation coefficients. 71

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The sample sizes, mean ages, and frailty prevalence matched those reported in 73 previous studies. Frailty statuses were weakly correlated with each other (coefficients = 0.19 74 to 0.38, p < 0.001 for all). There were 49 input symptoms identified by these three models.

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Frailty statuses defined by the three models were not significantly correlated with one or 76 two symptoms defined by the same models (p > 0.05 for all). One to six symptoms defined 77 by the other two models were not significantly correlated with each of the three frailty 78 statuses (p > 0.05 for all). Frailty statuses were significantly correlated with their own bias 79 variables (p < 0.05 for all). 80

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Frailty diagnoses lack significant correlations with some of their own frailty 82 symptoms and some of the frailty symptoms defined by the other two models. This finding 83 raises questions like whether the frailty symptoms lacking significant correlations with 84 frailty statuses could be included to diagnose frailty and whether frailty exists and causes 85 frailty symptoms. 86 Frailty is a geriatric syndrome and can be diagnosed with composite criteria that 91 consist of various frailty symptoms. [1][2][3]  The causal relationships between frailty and frailty symptoms can be confirmed 111 based on previously published criteria. 1 Among all criteria, the strengths of associations 112 between frailty and frailty symptoms are important and can be used to assess the impact of 113 frailty prevention programs on frailty treatment and to understand the mechanisms that 114 cause frailty. For example, it has been suggested that cognitive impairment plays an 115 important role for frailty diagnosis and mortality among frail patients.
[3] The confirmation 116 of the causal relationship between frailty and cognitive function has the potential for 117 intervention development. Without extensive reviews of the relationships between frailty 118 and its symptoms, how frailty may influence frailty symptoms is an important question that 119 is unanswered. This study aims to assess the effect of frailty on the occurrence of frailty 120 symptoms using a cohort that have been used to compare three of the most commonly 121 used frailty indices. 122

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The input variables, frailty symptoms, and domains are listed in Table 1 to 3. There were 10, 26, 142 and 14 variables (frailty symptoms, input variables or domains) identified for the 3 models, 143 respectively. In total, there were 57 variables required to produce the frailty indices defined 144 by the 3 models. In addition, there were 4 bias variables induced by the 4 domains in the 145 Functional Domains Model (Table 1), 1 bias variable induced by the Burden Model (Table 2), 146 and 4 bias variables induced by the Biologic Syndrome Model (Table 3).

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The associations between the frailty statuses and itheir nput symptoms were 149 determined with odds ratios and correlation coefficients. Odds ratios were the ratios of the 150 odds that an outcome of developing symptoms occurred among frail individuals, compared 151 to the odds among those not frail.
[13] Odds ratios equaling 1 suggest that the two groups have similar risks of 153 developing symptoms.
[13] The processing to transform non-binomial variables to binomial 154 variables were according to the authors of the Burden Model.
[14] Pearson's correlation 155 coefficients were used to assess the associations between frailty statuses defined by the 3 156 models and frailty symptoms or input variables or domains or bias variables.
[15] Correlation 157 coefficients ranged from -1 to 1, representing completely opposite information and identical 158 information between 2 variables, respectively. We hypothesized that I) frailty statuses were 159 not associated with symptom incidence (odds ratio = 1); ii) frailty statuses were not 160 correlated with frailty symptoms or input variables of the frailty indices (correlation 161 coefficient = 0). Correlation coefficients between 0 and 0.10, 0.10 and 0. In Table 1 to 3, the associations between frailty status (yes or no) and symptom 176 development are shown using odds ratios and correlation coefficients. Overall, most of 177 frailty symptoms were significantly associated with frailty statuses. However, frailty statuses 178 defined by the three models were not significantly associated with all frailty symptoms or 179 input variables or domains. The frailty symptoms or input variables or domains that were 180 not significantly associated with frailty statuses are described below. The correlation 181 coefficients between the three frailty statuses ranged from 0.19 to 0.38 (weak correlations, 182 p < 0.001 for all). 183 In Table 1, the frailty status defined by the Functional Domains Model was not 184 significantly correlated with one input variable, BMI (correlation coefficients = -0.02, 95% CI 185 = -0.04 to 0). 186 Among the frailty symptoms or input variables or domains identified by the other 187 two models, two symptoms, malignant disease and tiredness all the time, were not 188 significantly associated with this frailty status (p of correlations > 0.05 for both symptoms).

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Among the bias variables, one bias variable that was induced by having one of two Center 190 for Epidemiologic Studies Depression (CES-D) items was not significantly associated with this 191 frailty status (correlation p > 0.05).

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In Table 2, the frailty status defined by the Burden Model was assessed for the 193 associations with frailty symptoms, input variables, and domains. One input symptom, 194 tiredness all the time, was not significantly associated with this frailty status (p of 195 correlation > 0.05). One symptom identified by the other two models, self-reported weight, 196 was not significantly correlated with this frailty status (p > 0.05). Among the bias variables, 197 four were not significantly correlated with this frailty status (p > 0.05 for all).

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In Table 3 In Table 1 to 3, the correlations with bias variables are shown for the three frailty 209 indices. Each frailty status was significantly associated with the bias variables induced by 210 their own diagnostic criteria. The frailty statuses defined by the Functional Domains Model, 211 the Burden Model, and the Biologic Syndrome Model, were significantly correlated with 212 four, one, and four bias variables induced by their own models, respectively (p < 0.05 for 213 all). In addition, the frailty status defined by the Functional Domains Model, the Burden 214 Model, and the Biologic Syndrome Model, were significantly correlated with three, four, and 215 two bias variables induced by the other two models, respectively (p < 0.05 for all). 216

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Strengths of the associations are one of the Bradford-Hill criteria to assess whether a 218 disease causes symptoms or outcomes.
[20] Frailty has been promising in establishing causal 219 relationships with major health outcomes, such as mortality and falls, based on frailty's 220 significant associations with them.
[2] However, whether frailty causes frailty symptoms 221 have not been well studied. In this study using the HRS data, three of the most commonly 222 used frailty diagnoses fail to demonstrate significant correlations with some of the frailty 223 symptoms of their own or those defined by the other two frailty diagnoses. When frailty 224 lacks significant associations with frailty symptoms, this suggests frailty diagnoses are made 225 based on so-called frailty symptoms, some of which frailty may not cause them. This needs 226 serious discussion and examination. 227 The pathological changes that are considered related to frailty include sarcopenia, 228 heart disease, and lung disease, depending on the frailty models. correlated not only with their own frailty diagnoses, but also the frailty diagnoses defined by 251 the other two models. How these bias variables affect the correlations between frailty 252 diagnoses and their input symptoms remains a question for further research.

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In sum, the results highlight logic challenges. Frail patients are not more likely to 254 have certain frail symptoms, but these symptoms are necessary to make these diagnoses. It 255 is unclear whether the symptoms that frailty is insignificantly correlated with can be called 256 "frailty" symptom or used for frailty diagnosis. When excluding these symptoms from being 257 used for the diagnosis of frailty, the prevalence of frailty decreases. Many of the published 258 frailty prevalence rates are likely to be overestimated, because we have not identified any 259 studies explicitly examine the significance of the associations between the frailty statuses 260 and frailty symptoms they defined in their own models. We will continue exploring the 261 causal relationship between frailty and frailty symptoms using other data sets in the future. 262