6 Chan DCD (2012)

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6.1 論文

では、RCT の論文を探してみましょう。

Chan DCD, Tsou HH, Yang RS, Tsauo JY, Chen CY, Hsiung CA, & Kuo KN (2012) A pilot randomized controlled trial to improve geriatric frailty. BMC Geriatrics, 12, 1-12.

https://doi.org/10.1186/1471-2318-12-58

Creative Commons Attribution License

BMC Geriatrics とは、オープンアクセス大手の一つ BioMedCentral の老年学に関するジャーナルです。

BioMedCentral 系ジャーナルの特徴として、査読も公開されています。

第一著者 (first author) は Ding-Cheng Derrick Chan で、名前をクリックすると所属 (affiliation) やその他の論文へのリンクがあります。責任著者 (corresponding author) は、メール記号のある Ken N Kuo です。¹

¹ PDF や印刷された論文の場合、責任著者はどのように判断するか？

6.2 用語

pilot study とは、予備試験のことです。予備試験の目的として、より大規模で実験を行うことが可能か検証したり、またその際に必要なサンプルサイを推定するために行われます。²

² Pilot とは何か? また、その目的や役割は?

MMSE は、認知機能のテストです。30点満点で、点数が良い方が認知機能は良いです。

Barthel index は、ADL のテストです。100点満点で、点数が良い方が ADL は良いです。

6.3 Abstract

Background

Few randomized controlled trials (RCTs) report interventions targeting improvement of frailty status as an outcome.

Methods

This RCT enrolled 117 older adults (65-79 years of age) in Toufen, Taiwan who scored 3-6 on The Chinese Canadian Study of Health and Aging Clinical Frailty Scale Telephone Version and then score ≥1 on the Cardiovascular Health Study Phenotypic Classification of Frailty (CHS_PCF). With a two by two factorial design, subjects were randomly assigned to interventions (Exercise and nutrition, EN, n = 55 or problem solving therapy, PST, n = 57) or controls (non-EN, n = 62 or non-PST, n = 60). Educational booklets were provided to all. EN group subjects received nutrition consultation and a thrice-weekly exercise-training program while PST group subjects received 6 sessions in 3 month. Subjects were followed at 3, 6, and 12 months. Primary outcome was improvement of the CHS_PCF by at least one category (from pre-frail to robust, or from frail to pre-frail or robust) from baseline assessments. One hundred and one completed final assessments. Intention-to-treat analysis with the generalized estimating equation model was applied with adjustment for time and treatment-by-time interactions.

Results

Mean age was 71.4 ± 3.7 years, with 59% females. Baseline characteristic were generally comparable between groups. EN group subjects had a higher improvement rate on the primary outcome than non-EN group subjects (45% vs 27%, adjusted p = 0.008) at 3 months, but not 6 or 12 months. They also had more increase of serum 25(OH) vitamin D level (4.9 ± 7.7 vs 1.2 ± 5.4, p = 0.006) and lower percentage of osteopenia (74% vs 89% p = 0.042) at 12 months. PST group subjects had better improvement (2.7 ± 6.1 vs 0.2 ± 6.7, p = 0.035, 6-month) and less deterioration (−3.5 ± 9.7 vs −7.1 ± 8.7, p = 0.036, 12-month) of dominant leg extension power than non-PST subjects. Some secondary outcomes were also improved in control groups (non-EN or non-PST). No adverse effects were reported.

Conclusions

The three-month EN intervention resulted in short-term (3-month) frailty status improvement and long-term effect on bone mineral density and serum vitamin D (12-month) among Taiwanese community-dwelling elders. The effect of PST was less pronounce.

Trial registration

ClinicalTrials.gov: EC0970301

6.4 Background

本文の最初は、Background という見出しになっています。これは Introduction とほぼ同じようです。Background となっている理由としては、このジャーナルの指定テンプレートであるからです。著者が自由に構成できるわけではありません。 ³

³ Backgroud とは、他の多くのジャーナルにおいてどの部分にあたるか?

Frailty is a geriatric condition characterized by loss of reserves (energy, physical ability, cognition, health) that gives rise to vulnerability [1]. The lack of a consensus, however, on the definitions of and measurements for this geriatric condition has limited comparisons on the effectiveness of interventional studies on frail older adults [2]. Numerous instruments were developed to measure frailty. A recent review of on frailty instruments as outcome measures found that instruments could generally fit into 3 dimensions (physical, psychological, and social) with 8 factors (nutritional status, physical activity, mobility, energy, strength, cognition, mood, and social relationship/social support) [3]. However, it is not clear whether these instruments had sound clinimetric properties to be considered as good outcome measures that were responsive to interventions [3]. Another recent review on exercise interventions for management of frailty also pointed out that even all 47 studied enrolled “frail” older adults, validated operationalizations of frailty were only available for 3 studies [4]. None of the studies reviewed used frailty status as an outcome measure [4]. When we conducted a systemic review of frailty intervention focusing on trials that measured outcomes based on their pre-defined frailty indicators, only 11 studies were included [5]. Of the 4 studies [2, 6–8] that enrolled participants based on the Cardiovascular Health Study Phenotypic Classification of Frailty (CHS_PCF) [9], one have not published their study outcome [2], and the rests [6–8] were not able to demonstrate the effects of interventions on indicators from the CHS_PCF.

… The lack of a consensus, however, on the definitions of and measurements for this geriatric condition has limited comparisons on the effectiveness of interventional studies on frail older adults [2]. Numerous instruments were developed to measure frailty. …

いきなり第二文で、フレイルの定義については合意がないと指摘しています。

… When we conducted a systemic review of frailty intervention focusing on trials that measured outcomes based on their pre-defined frailty indicators, only 11 studies were included [5].

著者らは、この論文に先だって系統レビューを行ったようです。系統レビューの目的は、介入によってフレイルが改善するかというものでした。当然、それぞれの論文ではフレイルを定義することになります。⁴

⁴ 系統レビューとともに行われる分析は何か？

Of the 4 studies [2, 6–8] that enrolled participants based on the Cardiovascular Health Study Phenotypic Classification of Frailty (CHS_PCF) [9], one have not published their study outcome [2], and the rests [6–8] were not able to demonstrate the effects of interventions on indicators from the CHS_PCF.⁵

⁵ CHS_PCF の引用文献はどれか？

定義として Cardiovascular Health Study Phenotypic Classification of Frailty (CHS_PCF) に焦点を当てています。これは、わかりにくいですが、Fried LP の Phenotype 定義のことです。実際、引用文献の [9] は、

Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001, 56: M146-M156. 10.1093/gerona/56.3.M146.

となっています。これは、第2章で読んだものですね。

Fried LP のフレイル定義は、わずか 5 項目の簡単な定義です。判定方法としては簡易なものですが、介入で改善しようとするならば簡単ではないかもしれません。系統レビューでは、改善したものはありませんでした。

ここでようやく第１段落が終わりです。

続く第2〜３段落は、他の病因との関係についての先行研究に触れていますが、はっきりとしたことは述べられていません。

Frailty has multiple etiologies, interacting pathogeneses, and often linked with other geriatric conditions and poor outcomes [10, 11]. For example, a recent review found consistent bidirectional associations between depression and frailty in cross-sectional studies, but less consistent associations in cohort studies [12]. Similarly, osteoporosis and frailty shared many common risk factors — such as malnutrition, sarcopenia, physical inactivity, and low vitamin D [4, 13–15] — that would increase the risk of fall and fracture [14].

However, it is not clear whether interventions targeting frailty or other geriatric conditions (eg: depression or osteoporosis) may benefit from each other.

Background の最終段落では、研究の目的が書かれています。

We designed a pilot randomized control trail using validated frailty indicators to enroll 117 community-dwelling older adults with the following aims: 1) To determine whether the proposed interventions may have an impact on dynamic changes of frailty indicators. 2) To determine whether these interventions have impacts on other outcomes including depression, cognition, bone mineral density, physical function, and quality of life. 3) To explore the feasibility and accurate sample size to inform the design and implementation of future large scale clinical trial.

pilot randomized control trail となっています。誤植ですね。

目的は、以下の通りです。

提案する介入が、フレイル指標に効果を及ぼしうるかどうか
提案する介入が、フレイル以外の状態に効果を及ぼしうるかどうか
これは予備試験なので、本試験の実行可能性や必要なサンプルサイズを探索⁶

⁶ サンプルサイズとは何か？また、サンプル数と同じか？

となっています。

この段階で、フレイルの指標を複数用いるのだろうか？という疑問が湧きます。

6.5 Methods

臨床論文では、通常 Methods と Results は過去形で書かれます。⁷

⁷ In a biomedical article, the past tense is usually used to refer to the methods and results of the study being described. (AMA Manual of Style 11th edition p. 432)

A single site randomized controlled trial was conducted with a 3-month interventions and a 12-month follow-up period after baseline assessments on Taiwanese older adults with high frailty risk (Figure 1). The study was approved in 2008 by the Institutional Review Board of the National Health Research Institutes (NHRI), Zhunan, Taiwan.

介入期間は 3 ヶ月、さらに追跡が 12 ヶ月となっています。⁸

⁸ 追跡期間とは何で、何のために設けているのか？

Recruitment and eligibility

Participants were enrolled after a telephone interview screening followed by a hospital screening. Our target population was community-dwelling older adults from 65 to 79 years of age in Toufen Township (N = 6,828). The Chinese Canadian Study of Health and Aging Clinical Frailty Scale Telephone Version (CCSHA_CFS_TV) [1, 16] with satisfactory inter-rater reliability and criterion validity was used for the first stage screening. The instrument was particularly useful in population base screening for its short administration time (<3 min) and its easy implementation even by interviewers without formal training in geriatric care [16]. Eligible participants were those scored 3-6 on the CCSHA_CFS_TV. Exclusion criteria included institutionalizations; communication barriers; and scores of 1, 2, (too healthy) or 7 (too ill) on the CCSHA_CFS_TV.

… Our target population was community-dwelling older adults from 65 to 79 years of age in Toufen Township (N = 6,828). …

対象の母集団としては、頭份市の地域在住の65歳から79歳の 6,828 人となっています。

The Chinese Canadian Study of Health and Aging Clinical Frailty Scale Telephone Version (CCSHA_CFS_TV) [1, 16] with satisfactory inter-rater reliability and criterion validity was used for the first stage screening. …

リクルートの第１段階では、組入れ基準には、CCSHA_CFS_TV というフレイル尺度で３〜６を用いました。この辺りは、abstract にも書かれているとおりです。⁹

⁹ CCSHA_CFS_TV とはどのような尺度か？

Eligible older adults were invited to a local community hospital for second-stage screening during their annual geriatric health exams that included history and physical, blood works such as complete blood counts and blood chemistry. Informed consents were signed after careful explanations of the benefits and risks of proposed study. Participants were also asked to give permissions to use information gathered from the geriatric health exams as well as other blood works (such as 25(OH) vitamin D), or special tests (such as bone mineral density) needed from the study.

その後、病院で第 2 段階を行いました。

第 2 段階における組入基準には、CHS_PCF を用いました。わかりにくいですが、Background に出てきた Fried LP の５段階の基準のことです。

The CHS_PCF was used to select eligible participants [9]. Most cut-points were adapted from the CHS (Please refer to Table 1 for detail). Important modifications were:

ただし、以下のように、一部修正を加えています。

Weight loss of 3 kg (instead of 5 kg) was used to adjust for smaller body size for an East Asian population. The Taiwan IPAQ-SF (International Physical Activity Questionnaire Short Form) [17] instead of the Minnesota Leisure Time Physical Activity Questionnaire [18] was used to measure energy expenditure because the former has been validated in Taiwanese populations [17].

まず、「意図しない体重減少」は 5 kg ではなく 3 kg としています。¹⁰つぎに、「身体活動の低下」は別の質問紙を使っています。なお、「身体活動の低下」については、引用文献があります。つまり、「身体活動の低下」については彼ら独自のものではなく台湾で認められているものと判断できます。

¹⁰ なお、日本は６ヶ月で 2 kg としています。

Exclusion criteria included hearing/visual impairments affecting daily activity; cognitive impairment, as defined by a Mini-Mental Status Exam (MMSE) score of ≤16 [19]; functional impairment, as defined by a Barthel Index (BI) ≤35 [20]; active alcohol-abuse problems, organic mental disorders; history of schizophrenia or a diagnosis of a bipolar disorder; any mental problems (other than depression) under psychiatric care; active suicidal ideation; and a score of 0 on the CHS_PCF [9].

次に除外基準です。

除外基準としては、認知機能テストとして有名な MMSE (30点満点) で 16点以下、ADL 指標のバーゼル指標 (100点満点) で 35 点以下などがあります。

Measurements and procedures

Baseline assessments were completed before randomizations. Outcomes were assessed at the end of intervention (roughly 3 months after baseline assessments), 6 months and 12 months after baseline assessments.

介入期間は３ヶ月です。アウトカム評価は、ランダム化前、介入直後、6ヶ月後、12ヶ月後に行われました。

Baseline assessments

Other than the frailty related characteristics collected from screening stages, comprehensive assessments were performed to collect data on several domains including 1) demographics, 2) health related characteristics, 3) body composition, and musculoskeletal system characteristics, and 4) blood works. Important primary and secondary outcomes were listed below.

少し飛ばして、アウトカムについてみてみましょう。

Primary and secondary outcomes

The primary outcome was improvement of CHS_PCF by at least one category (from pre-frail to robust, or from frail to pre-frail or robust) [9]. Secondary outcomes included interval changes of the following indicators between baseline and repeated assessments. We also categorized secondary outcomes into the above domains. In the frailty index domain, we included each of the 5 indicator from the CHS_PCF [9]. In the health-related characteristics domain, we included the Mini Mental Status Exam (MMSE) [19], Primary Care Evaluation of Mental Disorders (PRIME-MD) score [21], and the Barthel Index (BI) score [20], health care resource utilization, and EQ-5DTM[22]. In the complex body composition and musculoskeletal system domain, we included, body mass index (BMI), fat free mass (FFM) (Inbody 3.0®, as a substitute of lean body mass), lowest T score from either spine or hip bone mineral density (BMD, Norland Excell Bone Densitometer®), left one-leg-stand time, and dominant leg extension power. Finally, for all the blood chemistry we collected, we only reported 25(OH) Vitamin D level as the outcome for this manuscript. Most primary and secondary outcomes were repeated at all follow up visits except for MMSE, BMD, and 25(OH) Vitamin D (only repeated at 12-month). To improve the comparability of the baseline and 12-month 25(OH) Vitamin D samples, we defrosted samples collected at 2 different time-points to run the radioimmunoassay (RIA) on the same kit (DiaSorin®, Minnesota, U.S.A.).

The primary outcome was improvement of CHS_PCF by at least one category (from pre-frail to robust, or from frail to pre-frail or robust) [9]. ¹¹

¹¹ プレフレイルから頑健への移行とはどういうことか？

主要アウトカムは、Fried 基準のフレイルからプレフレイル、あるいはプレフレイルから頑健への移行です。

Secondary outcomes included interval changes of the following indicators between baseline and repeated assessments. We also categorized secondary outcomes into the above domains. …

副次的アウトカムもいくつか設定しているようです。ここでは、あまり深入りしないでおきましょう。

Most primary and secondary outcomes were repeated at all follow up visits except for MMSE, BMD, and 25(OH) Vitamin D (only repeated at 12-month). …

アウトカムは、全てではありませんが、ほぼ追跡時に調査しているようです。

Randomization

Subjects were stratified by age (65-74, 75-79) and gender to achieve balance of baseline characteristics. Within each stratum, a permuted block (4 persons/block) randomization method was used to ensure balanced assignments. The randomization code was generated from the off-site statistical center with a computer random number generator. Random group allocation was managed by a project manager not involved in assessment or intervention. In a 2 × 2 factorial design, subjects were first randomly assigned to an exercise and nutritional program (EN) or non-EN group. Within each group, subjects were further randomized to a problem solving therapy (PST) [23] group or non-PST group. Previous studies have shown that when PST was used, both mental and physical health were improved [23]. The 2 × 2 factorial design would help to determine the individual effect of two interventions on frailty.

ランダム化について詳しく書かれています。じつは、RCT の重要な要素であるランダム化は、RCT 論文でもそれほど詳しく書かれているわけではありません。この論文は、かなり丁寧にランダム化を記述しています。

まず、年齢と性別で層別化されています。これによって、年齢と性別は揃うことになります。なぜなら、もし 10 人の男性と 10 人の女性をそのまま 2 群に分けると、ごく稀に A 群に男性が 10 人というばらつきが出ることがあります。あらかじめ、男性から 5 人ずつ選ぶように層別化しておけば偏りはなくなります。¹²

¹² ランダム化の目的は何か？

The randomization code was generated from the off-site statistical center with a computer random number generator. Random group allocation was managed by a project manager not involved in assessment or intervention.

ランダム化は研究者が行うのではなく、統計センターがコンピュータを使って行っています。海外の大学等ではこのような方式を取られていることを見かけますが、日本の大学等ではどの程度普及しているのか、、、

In a 2 × 2 factorial design, subjects were first randomly assigned to an exercise and nutritional program (EN) or non-EN group. Within each group, subjects were further randomized to a problem solving therapy (PST) [23] group or non-PST group.

今回の介入は２段階で、運動と栄養 (EN) と、問題解決療法 (PST) という二つの介入の有無、合計 4 群となります。

Blinding

The research assistants who performed baseline and outcome assessments were blinded from the randomization status. However, blinding to the intervention research assistants or participants was not possible with the designed interventions.

ベースライン時点では、研究協力者は盲検化 (blinding) されていました。今回のような運動療法では盲検化は不可能なため、介入では盲検化されていません。¹³

¹³ 二重盲検とは何か？

Interventions

Education booklet

The educational booklet on frailty, healthy diets, exercise protocols, and self-coping strategies was given to all participants. Subjects who were randomized into the non-EN, non-PST groups were contacted monthly to check on how much they had read the booklet and how well they had complied with the suggested diet and exercise protocols. For those randomized into EN or PST groups, similar questions were asked during their visits to the study sites for their designated programs

さて、介入はどのような内容でしょうか。まずは、全参加者に教育本を配りました。対照群は月に１回コンタクトをとっています。¹⁴

¹⁴ 対照群はどの群か？

Exercise and nutritional program

The EN group subjects were invited to take a structured exercise course at the participating hospital 3 times a week for 3 months. Each section lasted about 1 h. The exercise program included 15 min warm up with 10 min brisk walks followed by gentle stretching of major joints (cervical and lumbar joints) and muscles (such as biceps, triceps, hamstrings, rectus femoris, gastrocnemius, soleus) for 5 repetitions each. Resistance training (20-30 min) with rubber band and bottled water (0.6-1 L) as weight for major muscles of upper and lower limbs with 10 to 15 repetitions for each (such as deltoids, biceps, triceps, hand grasp, hip and knee flexors and extensors, hip abductors, ankle plantar flexors and dorsiflexors). Postural control activities and balance training were also provided for 10 min by asking participants to perform tandem gaits and one leg standing with eyes open/close (up to ones’ ability), step up and down stairs, toe walking and heel walking. Finally a 5-min cool down session with gentle relaxation movements are done. The research team also inquired about the subjects’ dietary compliance and responded to their dietary questions during the exercise sessions.

EN 群は、３ヶ月間、週３回、1時間の運動を行います。栄養については説明はあまりありません。

The problem solving therapy

The PST group subjects received 6 sessions therapy by trained case managers. It is a brief form of evidence-based psychotherapy that was originally developed in Britain for use by medical professionals in primary care. It teaches people how to solve the “here-and-now” problems contributing to their mood-related conditions and helps increase their self-efficacy [23]. Previous studies have shown that when PST was used to manage mental problems, both mental and physical health were improved [23].

もう一つの介入は、問題解決療法です。

問題解決療法は、６セッションあるようです。３ヶ月なので、月２回ということでしょうか？内容は、「今、ここで」問題を解いて自己効力感を向上させるようです。先行研究では、精神的にも身体的にも健康が改善するようです。

Approaches to analysis

Data were coded to permit blinding to group allocation during statistical analysis. All statistical analyses were conducted using SAS software, Version 9.1 (SAS Institute, Inc., Cary, NC). Analysis was conducted at baseline and at 3-month, 6-month, and 12-month follow-up assessments in accord with the “intention-to-treat” principle (ITT). Summary statistics, including mean and standard deviation, were provided for continuous variables, such as age, MMSE, PRIME-MD, etc. Frequencies and proportions were used to summarize discrete variables, such as CCSHA_CFS TV, CHS_PCF categorization, etc. Missing variables were excluded from analyses. Baseline characteristics were compared between two groups using t-test for continuous variables and chi-square test with Fisher’s exact test when appropriate for categorical variables.

解析は ITT 方式で、欠損値は解析から除外されました。ベースラインでは、数値データは t 検定、カテゴリ検定にはカイ二乗検定または Fisher の正確性検定が用いられました。¹⁵

¹⁵ intention-to-treat を日本語に訳しなさい。

Because of the factorial design, we tested for a possible interaction between the 2 interventions (EN and PST) for each reported outcome. If there was no interaction, we examine the independent effect of one intervention controlling for the effect of the other. If there was significant interaction, we would perform subgroup analysis to report the effect of one intervention with or without the other intervention.

今回、介入が２つあるので、交互作用 (interaction) を解析しました、とあります。¹⁶

¹⁶ The main effect is the effect of one of the factors (drugs) on the outcome inclusive of all the various doses and excluding the effect of the other factors (drugs). Interactions can be tested between factors (drugs) in the same experiment. … When an interaction exists (eg, the interaction variable is statistically significant), the factors have an effect that is greater than what would be expected by the addition of each when they act alone.

ところで、この研究では時間軸もあるので、実際には時間という要因もあります。

どのような解析方法でしょうか？次に書かれています。

In our study, the outcomes of interest (e.g., frailty improvement) were measured at several time points (baseline, the 3rd month, the 6th month, and the 12th month). For estimating the repeated measurements of the intervention effect, the generalized estimating equations (GEE) model was used to compare the between-group frailty improvement with adjustment for time and treatment-by-time interactions. GEE approach is an extension of generalized linear model (GLM) and provides a semi-parametric approach to repeated categorical response. The intervention effect can be reasonably estimated by using GEE even if the covariance structure is not specified correctly. The primary outcome was also adjusted for multiple baseline characteristics, including age, gender, MMSE, healthcare-resource utilizations, EQ-5D, FFM, BMD, one-leg stand and 25 (OH) Vitamin D. Where high co-linearity was found between two potential confounders, only one variable was retained in the final model.

ここでは、一般化推定方程式 (GEE) が使われています。¹⁷

¹⁷ 交互作用 (interaction) を解析する統計手法には何があるか?

一般に、RCT の場合は繰り返しがある交互作用を検定します。この際に用いられる手法には、繰り返しのある２限配置分散分析 (two way repeated measures ANOVA) や一般線形混合モデル (generalized linear mixed model, GLMM) などが用いられてきました。GEE は比較的最近使われる統計手法です。

GEE approach is an extension of generalized linear model (GLM) and provides a semi-parametric approach to repeated categorical response.

GEE とは、generalized linear model (GLM) の拡張と説明しています。GLMM も GLM の拡張ですが、手法が異なります。このあたり、名前がややこしいですね。

The intervention effect can be reasonably estimated by using GEE even if the covariance structure is not specified correctly. …

GEE の強みは、covariance structure が正しく特定されていなくても、合理的に推測できる、とのことです。

Longitudinal changes between groups and changes within a group were analyzed with the use of linear mixed models. However, the between-group BMD differences were compared using logistic regression model at 12 months. Under all circumstances, P < 0.05 was considered to be statistically significant.

縦断的の群間変化と群内変化は、線形混合モデルを用いて解析しました。ただし、群間差はロジスティック回帰を用いたとあります。

RCT では、繰り返しのある二元配置分散分析、線形混合モデル、一般化線型モデルなどが用いられます。

6.6 Results

Participant flow

From the 6,828 target population, the probability-proportional-to-size (PPS) sampling approach was employed to select 2,900 population-representative random samples for first-stage screening. However, only 845 completed the telephone interview, 548 of whom were eligible for second-stage screening. Half (N = 275) signed the informed consents and were screened at the hospital. The recruitment period was roughly 3 months. Following the 2 by 2 factorial design protocol, 117 out of the 151 eligible subjects were randomized into 4 groups: A (EN/PST), B(EN/non-PST), C(non-EN/PST), and D(non-EN/non-PST). Group A and B were combined into the EN group (N = 55) while group C and D were combined into the non-EN group (N = 62). Similarly, Group A and C became the PST group (N = 57) while group B and D were the non-PST group (N = 60). Eighteen of the 55 EN group subjects attended at least 50% of the 36 intervention sessions while 16 of the 57 PST subjects completed the 6 courses. At 12 months, 50 (EN group), 51 (non-EN group), 48 (PST group), 53 (non-PST group) subjects completed final assessments, respectively. The reason for attrition was participant refusal (Figure 1).

Participant flow は、Figure 1 のとおりです。

Baseline characteristics

For the entire cohort (N = 117), mean age was 71.4 ± 3.7; and 69 (59%) were female. Using the CCSHA_CFS TV, 47 (40%) were categorized into category 3 (well, with treated co-morbid diseases), 55 (47%) into category 4 (apparently vulnerable), 13 (11%) into category 5 (mildly frail), and 2 (2%) into category 6 (moderately frail). With the CHS_PCF, 102 (87%) were classified pre-frail, and 15 (13%) as frail at baseline.

Baseline characteristics では、ベースラインでの患者背景が書かれています。

For the entire cohort (N = 117), mean age was 71.4 ± 3.7; and 69 (59%) were female. ¹⁸

¹⁸ N は何を表しているか？

まず、合計 N = 117 より117 人の参加者がいます。平均年齢は 71.4 才で、標準偏差が 3.7 となっています。65歳くらいから、70代後半までいたことがわかります。69 人 (69/117 = 59%) が女性でした。

… With the CHS_PCF, 102 (87%) were classified pre-frail, and 15 (13%) as frail at baseline.

102 人 (102/117 = 87%) がプレフレイルで、15 人 (15/117 = 13%) がフレイルでした。

Even though all subjects were considered at high risk for frailty, subjects enrolled in the trial were relatively healthy with few co-morbidities (3.5 ± 2.2), preserved BI (mean 98.3 ± 4.7) score, MMSE (24.4 ± 3.9) scores, low PRIME-MD (2.5 ± 3.4) score, satisfactory EQ-5D score (0.9 ± 0.1), and few healthcare-resource utilizations (1.6 ± 2.0). The cohort had high prevalence of radiographic vertebral fracture (N = 111, 95%), and high prevalence of osteopenia (n = 92, 80%) from DXA scan. The mean left one leg stand time was 5.8 ± 6.3 s, the mean dominant leg extension power is 25.7 ± 6.1 kg, and the mean 25 (OH) Vitamin D level was 17.5 ± 5.8 (ng/ml).

Most baseline characteristics were similar between EN and no-EN group, also between PST, and non-PST group (Table 2). However, EN group subjects had lower percentage of weakness (60% vs 81%, p = 0.014), higher number of co-morbid conditions (4.0 ± 2.1 vs 3.1 ± 2.2, p = 0.022) (Table 2). Also, PST group subjects higher percentage of slowness (26% vs 12%, p = 0.043).

EN/non-EN 間の差、PST/non-PST 間の差はほとんどありませんでした。これは、ランダム化しているため当然のことです。ただし、わずかながら差が出てしまいました。すべての指標を完全にランダム化するのは難しいためです。

なお、ここはなぜか non- ではなく、no-EN となっています。

Primary outcomes and transition of frailty status

The improvement rates were highest at the end of intervention (3-month) for EN (45%) and PST (44%) groups. Afterwards, there were gradual declines of the improvement rates at 6 (42% EN group, 35% PST group) and 12 (40%, EN group, 35% PST group) months. On the other hands, the improvement rates of the non-EN, or non-PST group subjects were stable around 30%. Therefore, only the 3-month differences between EN and non-EN group (45% vs 27% p = 0.008) was significant after adjusting the effect of PST and other potential confounders (Figure 2).

３ヶ月の介入で、EN 群と PST 群でフレイルに改善割合が高かったようです。ただし、その後の追跡で低下しています。このように介入で改善し介入後に低下することは RCT ではよくあることで、追跡調査が臨床的に重要な理由です。

During the intervention period (baseline to 3-month), 33 (32.4%) of the prefrail participants (N = 102) improved to robust, while 3 (20%) and 6(40%) of the frail (N = 15) participants improved to robust and prefrail, respectively (Table 3). During follow-up periods without intensive interventions, most individual stayed at their original status, the chances for natural transition to better frailty status was a lot fewer. For example, during the 3-6 month follow up period, only 2 (22.2%) of frail individuals (N = 9) improved to prefail status, and only 12 (16.7%) of prefrail individuals (N = 72) improved to robust status.

介入によって、プレフレイル 102 人中、33 人が頑健に変わりました。フレイルか頑健またはプレフレイルに変わって人たちもいました。

3 (20%) and 6(40%) of the frail (N = 15) participants improved to robust and prefrail, respectively.

respecively は「それぞれ」の意味。フレイルのうち、3 人は頑健に、6 人はプレフレイルに、それぞれ改善した。

Secondary outcomes

Individual frailty indicator

In general, no within or between group differences were observed over repeated measures (Table 4).

Health-related characteristics

There were no observable between group changes. However, within group improvements were found for PRIME-MD (non-EN and PST group at 3-month), BI (all 4 groups at 3-month), and EQ-5D (non-EN and non-PST group at 3-month) (Table 4). Body composition, and musculoskeletal system characteristics

In general, there were no observable between group differences except that changes of dominant leg extension power at 6 and 12 months were in favor of the PST group (both p < 0.05). At 12 month, BMI decreased in both EN and PST group, but not the non-EN or non-PST group. However, FFM decreased in all 4 groups. For one leg stand time and leg extension power, changes at different time periods were general more obvious in intervention (EN or PST) than control (non-EN, non-PST) groups (Table 4).

Blood test

Increase of 25 (OH) Vitamin D level was observed in EN, PST, and non-PST groups in 12 months. The difference between EN and non-EN group (4.9 ± 7.7 vs 1.2 ± 5.4, p = 0.006) was statistically significant (Table 4).

Secondary outcomes については、ここでは省略します。

Interaction

Interactions between EN and PST were found for improvement of weight loss and 25 (OH) Vitamin D. Controlling the effect of PST, the effect of EN was more significant in EN/non-PST subgroup (weight loss), and EN/PST subgroup (25 (OH) Vitamin D)(Additional file 1: Table S1). Controlling for the effect of EN, the effect of PST was more significant in PST/EN subgroup (for both variables) (Additional file 2: Table S2).

Interaction とは、交互作用です。¹⁹

¹⁹ ここの interaction は、何と訳すか？

Interactions between EN and PST were found for improvement of weight loss and 25 (OH) Vitamin D.

体重減少と Vitamin D について、EN と PST の交互作用が見られました。

… Controlling for the effect of EN, the effect of PST was more significant in PST/EN subgroup (for both variables) (Additional file 2: Table S2).

EN の効果を制御すると、PST の効果は PST/EN サブグループで有意でした。

この点については、Discussion で詳しく見ましょう。

6.7 Discussion

Our study demonstrates that the three-month exercise and nutritional program resulted in short-term (3-month) frailty status improvement and long-term effect on BMD and serum 25 OH Vitamin D (12-month) among a population-representative sample of frail older adults. The effect of PST on geriatric frailty, mood, and physical performance was less pronounce. We also found some significant improvements in the control (non-EN, non-PST) groups.

Discussion の第１段落は、通常通り結果の要約です。

Our study demonstrates that the three-month exercise and nutritional program resulted in short-term (3-month) frailty status improvement and …

まず、運動栄養介入は、３ヶ月でフレイルを改善しました。しかし、明記されていませんが、追跡時には元に戻っていました。

The effect of PST on geriatric frailty, … was less pronounce.

もう一つの介入である PST は、運動栄養介入ほどはありませんでした。

We also found some significant improvements in the control (non-EN, non-PST) groups.

対照群においても有意な改善が見られました。

これは、RCT においてはあり得ることで、このためにこそ対照群を設定しています。

Many instruments were created to measure frailty and studies with different instruments were difficult to compare with [24]. We chose several recent intervention trials that used modified CHS_PCF for comparison [2, 6–8]. Peterson et al. enrolled 81 older male veterans scored ≥1 on CHS_PCF. Roughly half (N = 39) were randomized into a high intensity physical activity telephone counseling group [7]. After 6-months, 49% and 69% were still classified as frail respectively (p = 0.08). Kenny and colleague reported the effect of 12-month transdermal testosterone patch on 131 older men with low testosterone level, fracture, or low BMD and scored ≥1 on CHS_PCF [6]. Improvements of BMD, and lean mass were found, but not physical performance or frailty indicators [6]. In another RCT, Li et al. enrolled 310 community-dwelling older adults who scored ≥1 on the CHS_PCF [8]. The 6-month individualized multi-factorial care plans after comprehensive geriatric assessments (CGAs) did not improve frailty status. The Frailty Intervention Trial (FIT) [2] used similar CGA with individualized care plans approach but enrolled older adults with ≥3 deficiencies; that study is still in progress and so still lacks published outcome data. To our knowledge, ours is the first study to demonstrate that the CHS_PCF categorization is responsive to intervention to with sound clinimetric properties as an outcome measure [24].

次に第２段落移行です。先行研究との比較を行っています。

まずは、CHS_PCF 基準のフレイルが改善されるかどうか。再確認ですが、CHS_PCF とは Fried 基準です。

… Peterson et al. enrolled 81 older male veterans scored ≥1 on CHS_PCF. Roughly half (N = 39) were randomized into a high intensity physical activity telephone counseling group [7]. After 6-months, 49% and 69% were still classified as frail respectively (p = 0.08). Kenny and colleague reported the effect of 12-month transdermal testosterone patch on 131 older men with low testosterone level, fracture, or low BMD and scored ≥1 on CHS_PCF [6]. Improvements of BMD, and lean mass were found, but not physical performance or frailty indicators [6]. In another RCT, Li et al. enrolled 310 community-dwelling older adults who scored ≥1 on the CHS_PCF [8].

文献 [6] と [7] では、介入によるフレイルの有意な改善はなかったようです。[8] は参加者人数の紹介程度で結果は書かれていません。おそらく有意差はなかったのでしょう。

… To our knowledge, ours is the first study to demonstrate that the CHS_PCF categorization is responsive to intervention to with sound clinimetric properties as an outcome measure [24].

ここで、本研究の独自性の一つが示されます。すなわち、Fried 基準で改善することができました。

When other frailty indicators were considered, several recent reviews found that structured exercise improved physical and psychological determinants, frailty status, and prevented disability in frail older adults [4, 5, 25, 26]. However, many researchers called for more unified definition and operationalization of frailty to enhance comparability of different intervention trials [2, 4, 5, 27].

Expert opinions and the results of clinical trials suggest nutritional consultation as a component in frailty interventions [2, 28, 29]; but rarely does it stand as an independent intervention on frailty. One recent study showed that diet and exercise was more effective than diet or exercise alone in improving frailty indicators among 93 obese and frail older adults [29]. Our study also added new evidence that combination of exercise program and nutritional information had positive impact on frailty.

その次の段落は、運動栄養介入という二つを組み合わせた介入方法についての考察です。

… One recent study showed that diet and exercise was more effective than diet or exercise alone in improving frailty indicators among 93 obese and frail older adults [29]. Our study also added new evidence that combination of exercise program and nutritional information had positive impact on frailty.

先行研究 [29] でも、「運動のみ」や「栄養のみ」よりも、両者を組み合わせた方が良いとしています。

実はこれは当然で、Fried 基準では、歩行速度と握力といった運動介入が効果的な内容と、意図しない体重減少という栄養介入が効果的な内容があるためです。

It is not clear whether exercise and/or nutritional consultation has a positive impact on BMD or 25 (OH) Vitamin D level among frail older adults. In a study of 65 subjects randomized to moderate-intensity on-site exercise training 3 times per week for 9 months,, the subjects’ BMD did not differ from that of 47 subjects randomized to a low-intensity home exercise program [30]. Similar to our study, Villareal and colleagues reported positive effect of diet and exercise on improving or preserving BMD from 2 RCTs of 27 [31] and 93 [29] obese older adults. This research group [31] also found that diet and exercise increased the serum 25(OH) Vitamin D level as in our study.

この段落は副次的アウトカムについてですので、省略します。

In our study, subjects in the PST group had better improvement in frailty and PRIME-MD scores than subjects in the non-PST group; but the differences did not reach statistical significance. Even roughly 40% reported exhaustion from the (CES-D) [32] questions, their mean PRIME-MD score was quite low (average 2 points) indicating low level of depression. The floor effect might explain parts of the lack of effectiveness of PST.

Some observational studies suggested that frailty is a dynamic process and natural transitions to better status may occur without interventions [33–35]. During the intervention period, our degrees of improvement in frailty status were significantly higher than the natural improvement rates reported from observational studies [34]. On the other hand, the improvement rates during the follow up periods were similar to other studies [34]. It was encouraging that frailty status could be reversed with proper interventions. However, the effects might not last long when intensive interventions were discontinued.

介入期間においては、フレイル改善は観察研究よりも高かったようです。しかし、追跡後には、先行研究と同程度になったようです。

効果を持続させるのは、なかなか難しいことがわかりました。

We felt it unethical to enroll older adults in the control group without basic education material to teach them about self-managements even this might mitigate intervention effect. It is encouraging that subjects received education material only also had improvements in functional status, mood, quality of life, and physical performance.

ここでは、倫理的な話題を行っています。²⁰

²⁰ 対照群に何も行わないことは倫理的に問題である。筆者らはどう対処したか？

We \(_V\)felt \(_O\)it \(_C\)unethical to enroll older adults …

この it は、形式目的語です。it の実態は、to enrol older aduls … の部分です。

筆者らは、\(_O\)[教育本を与えずに高齢者を対照群にに割り当てること]を\(_C\)非倫理的であると\(_V\)感じた。

…even this might mitigate intervention effect.

たとえ、これが介入効果を弱めるかもしれないとしても

実際、RCT の倫理的な問題として、対照群が治療を受けられないことが挙げられます。治験等の参加者は、実験であったとしても新しい治療を受けられることを期待して参加しているのに、対照群に割り当てられてしまうことは、非倫理的と捉えられます。

ただし、不思議なことに、ここで倫理的な課題を述べているにもかかわらず、本研究については倫理審査を受けたかどうかは書かれていません。予備研究としても、ちょっと不思議です。

Strengths and limitations of the current study

The probability sampling design enhances the generalizability of this study to community-dwelling frail older adults without significant cognitive or functional impairments. The quick and valid CCSHA_CFS TV saved us tremendous time and resources in conducting the large-scale community-based frailty screening. Our educational material and interventions would be easily replicable in other settings.

次の段落では、一般化可能性 (generalisatbility) について触れています。一般化可能性は、外的妥当性ということもあります。

The probability sampling design enhances the generalizability of this study to community-dwelling frail older adults without significant cognitive or functional impairments. …

サンプル選定デザインを考慮すると、一般化可能性が高いと主張しています。

generalizability はアメリカ表記で、イギリス表記だと generalisability となります。この論文が掲載されている BMC Geriatrics は、イギリスのジャーナルです。しかし、英語についてはイギリス英語である必要はないようです。

次に、研究の限界 (limitation) です。５つ書かれています。

The study also has several important limitations. First, we encountered an unexpectedly low response rate during the telephone-interview stage, with one-third not being reachable after multiple attempts, and another one-third refusing the telephone interviews, which hampers the external validity of the current study.

まず、電話面接での応答率がかなり低かったようです。

Second, compliance with the thrice-weekly exercise sessions and PST sessions were fair. Many participants had problems reaching the study site and other personal issues, such as taking care of their grandchildren which prevented them from on-site intervention. The intervention effect could have been enhanced if better adherence had been reached.

参加率は「普通」のようです。ただ、「普通」では、３回ちゃんときたようにも取れます。一体どの程度だったか気になるところです。

compliance と adherence は、処方などの「遵守」の意味です。compliance に比べて、adherence は患者が主体的に選択する意味合いを含んでおり、adherence の方が好ましいとされています。

fair は、「普通」や「平均」を表します。悪くはないですが、良くもない状態です。

thrice は、「３回」の意味。once、twice と同様に使います。「４回」以降も存在しますが、使われているところを見たことがありません。

第３と第４の限界は、フレイルの基準についてですが、ここでは省略します。

Third, the CHS_PCF instrument does not allow assessment of different degrees of frailty as the CCSHA_CFS_TV. However, we were not able to detect more subtle changes frailty degrees with the later instrument since it was only used at the screening stage.

Forth, we did not have use population specific cut-points in the 5 frailty indicators to enroll study participants. At the time of the study design, Taiwanese frailty cut-points with the CHS_PCF were not available. However, since it is an interventional study with a purpose to identify subjects with certain degree of frailty suitable for interventions, it probabably did not matter which cut-points were used as long as study populations could be clearly and systemicly identified and classified.

Finally, the study sample size is relatively small, though it is comparable or greater than some previous interventional studies of frailty [6, 7, 28–31]. In the review conducted by Thou and colleagues [4], only 13 out of 47 exercise programs had sample size greater than our study which indicating the difficulty enrolling and conducting RCTs in frail older adults. Since there was a lack of previous data to guide estimation of sample size based on our designated primary outcome, one purpose of this study was to determine feasible sample size for future study.

最後は、サンプルサイズ (sample size) が小さかった点です。先行研究と比較すると、本研究より大きかったものは 13 なので、必ずしも小さすぎるということはありません。将来の実行可能なサンプルサイズの推計もこの研究の目的の一つであると反駁しています。

6.8 Conclusions

結論です。

In summary, with proper exercise and nutritional management even a short, 3-month intervention can improve the dynamic frailty process, bone mineral density, and 25(OH) Vitamin D level in frail older adults.

適切な運動栄養療法で、わずか３ヶ月の介入でもフレイル高齢者のフレイルなどを改善することが可能です。

6.9 解答および解説

Q. PDF や印刷された論文の場合、責任著者はどのように判断するか?

A. 責任著者 (corresponding author) は、第一著者または最終著者であることが多い。通常、Correspondant to などで明示されている。明示されていない場合、どちらかの連絡先 (近年ではメールアドレス) が書かれている方。

Q. Pilot とは何か? また、その目的や役割は?

A. 研究プロジェクトを開始する前に、その研究デザインの実現性を見極めるために行う予備的な小規模調査。サンプルサイズを予測することもある。

Q. 系統レビューとともに行われる分析は何か？

A. メタ分析

Q. Backgroud とは、他の多くのジャーナルにおいてどの部分にあたるか?

A. Introduction にあたる。なお、近年では Structured Abstract で、Background と Objectives を指定するジャーナルは多い。

CHS_PCF の引用文献はどれか？

A. Fried LP, Tangen CM, Walston J. et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146–M156. doi: 10.1093/gerona/56.3.M146.

Q. 追跡期間とは何で、何のために設けているのか？

A. 介入効果が介入終了後も持続するかどうかを調べる。

Q. CCSHA_CFS_TV とはどのような尺度か？

A. 電話でフレイルをスクリーニングする尺度。

Q. プレフレイルから頑健への移行とはどういうことか？

A. CHS 基準で 1~2 項目該当していた状態から、0 項目該当になった。

Q. ランダム化の目的は何か？

A. 比較群間の均質性の向上。医師国家試験 110-B22、115-B06、118-B09 などで出題された。

Q. 二重盲検とは何か？

A. 被験者が盲検化されるのが一重盲検。研究者も盲検化されるのが二重盲検。

Q. 対照群はどの群か？

A. 月に１回コンタクトをとるだけの群。

Q. intention-to-treat を日本語に訳しなさい。

A. 治療を意図

Q. 交互作用 (interaction) を解析する統計手法には何があるか?

A. 繰り返しのある二元配置分散分析、線形混合モデル、一般化線型モデルなど

Q. N は何を表しているか？

A. 介入群、対照群を合わせた参加者総数。

なお、通常 N やサンプルサイズという時は、「１群のサイズ（参加者数）」です。２群いると、総数は約２倍となります。

Q. ここの interaction は、何と訳すか？

A. 交互作用

Q. 対照群に何も行わないことは倫理的に問題である。筆者らはどう対処したか？

A. 自己管理のための教材を渡した。