Reliability and Validity of Different Models of TKK Hand

Reliability and Validity of Different Models of TKK
Hand Dynamometers
Cristina Cadenas-Sanchez, Guillermo Sanchez-Delgado,
Borja Martinez-Tellez, José Mora-Gonzalez, Marie Löf,
Vanesa España-Romero, Jonatan R. Ruiz, Francisco B. Ortega
MeSH TERMS
diagnostic equipment
hand strength
muscle strength
muscle strength dynamometer
reproducibility of results
OBJECTIVE. We examined the reliability and validity of the analog and digital models of TKK handgrip
dynamometers using calibrated known weights.
METHOD. A total of 6 dynamometers (3 digital and 3 analog; 2 new and 1 old for each model) were used in
this study.
RESULTS. Intrainstrument reliability was very high; systematic error for test–retest reliability was £|0.3
kg|. The systematic error among different instruments (same model) and between different models (digital
vs. analog) ranged between |0.4 kg| and |0.6 kg|. The systematic error between new and old dynamometers
ranged from |0.8 kg| to |1 kg|. All dynamometers provided lower values for the same known weights than a
SECA scale, with a systematic error ranging from 20.94 to 22.64 kg.
CONCLUSION. This study indicates that clinicians and investigators who provide treatment to address
handgrip strength should use the same instrument and model for repeated measures. Distinguishing meaningful change from dynamometer variability is discussed.
Cadenas-Sanchez, C., Sanchez-Delgado, G., Martinez-Tellez, B., Mora-Gonzalez, J., Löf, M., España-Romero, V., . . .
Ortega, F. B.(2016). Reliability and validity of different models of TKK hand dynamometers. American Journal of
Occupational Therapy, 70, 7004300010. http://dx.doi.org/10.5014/ajot.2016.019117
Cristina Cadenas-Sanchez, MSc; Guillermo
Sanchez-Delgado, MSc; Borja Martinez-Tellez,
MSc; and José Mora-Gonzalez, MSc, are PhD
Students, PROFITH (PROmoting FITness and Health
through physical activity) Research Group, Department of
Physical Education and Sport, Faculty of Sport Sciences,
University of Granada, Granada, Spain; address
correspondence to [email protected]
Marie Löf, PhD, is Senior Researcher, Department of
Biosciences and Nutrition, Karolinska Institutet,
Stockholm, Sweden.
Vanesa España-Romero, PhD, is Lecturer,
Department of Physical Education, School of Education,
University of Cádiz, Puerto Real, Spain.
Jonatan R. Ruiz, PhD, and Francisco B. Ortega,
PhD, are Senior Researchers, PROFITH Research Group,
Department of Physical Education and Sport, Faculty of
Sport Sciences, University of Granada, Granada, Spain,
and Senior Researchers, Department of Biosciences and
Nutrition, Karolinska Institutet, Stockholm, Sweden.
M
uscular strength is considered an important marker of health (Blair et al.,
1989; Ortega, Ruiz, Castillo, & Sjöström, 2008; Ruiz et al., 2009).
Growing evidence indicates that muscular strength is inversely associated
with muscular disorders, back pain, osteoarthritis, and premature mortality
(Bergman et al., 2001; Ortega, Silventoinen, Tynelius, & Rasmussen, 2012;
Timpka, Petersson, Zhou, & Englund, 2013). Szeto and Lam (2007) examined
whether musculoskeletal discomfort was associated with strength factors and
concluded that a weaker left handgrip was strongly associated with neck and
shoulder pain. Furthermore, growing evidence indicates that physical workload
and other occupational factors are a risk factor for many musculoskeletal disorders and discomfort in several parts of the body (Rachiwong, Panasiriwong,
Saosomphop, Widjaja, & Ajjimaporn, 2015; Roquelaure et al., 2009; Szeto &
Lam, 2007). Therefore, the assessment of muscular strength as a health indicator has become important from a clinical, therapeutic, occupational, and
public health perspective.
The handgrip strength test, which is the most reliable and valid field-based
muscular fitness test (Artero et al., 2011; Castro-Piñero et al., 2010), has traditionally been assessed using the Jamar dynamometer and has been recommended by the American Society of Hand Therapists (Shechtman & Sindhu,
2013). Some studies have focused on the reliability and validity of the Jamar
dynamometer (Gerodimos, 2012; Härkönen, Harju, & Alaranta, 1993; King,
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2013; Savva, Karagiannis, & Rushton, 2013; van den Beld,
van der Sanden, Sengers, Verbeek, & Gabreëls, 2006), and
others have used this instrument as a criterion standard to
validate other dynamometers (Bellace, Healy, Besser,
Byron, & Hohman, 2000; King, 2013; Mathiowetz, 2002).
However, several studies have found that the Transducer,
TKK, DynEx, and BTE-Primus dynamometers provide
higher reliability and validity estimates than the Jamar
(Amaral, Mancini, & Novo Júnior, 2012; Shechtman,
Davenport, Malcolm, & Nabavi, 2003; Shechtman, Gestewitz,
& Kimble, 2005).
Our research group has previously determined the
reliability and validity of the Jamar, DynEx, and digital
TKK dynamometers using calibrated known weights
(España-Romero et al., 2010). We observed that the
digital TKK showed the highest test–retest reliability and
the highest criterion-related validity (i.e., smaller mean
difference when compared with known weights). Differences between TKK and Jamar dynamometers showed
that the TKK dynamometer is more reliable and valid
than the Jamar (España-Romero et al., 2010); the grip
span of the TKK dynamometer can be continuously
adjusted to differences in hand size using age- and gender-specific equations (España-Romero et al., 2008; Ruiz
et al., 2006; Ruiz-Ruiz, Mesa, Gutiérrez, & Castillo,
2002; Sanchez-Delgado et al., 2015), whereas the Jamar
has five positions (beside the position of the hand; see
Supplemental Figure 1, available online at http://otjournal.
net; navigate to this article, and click on “Supplemental”).
The TKK dynamometer does not need regular calibration,
but the Jamar requires calibration every year.
On the basis of this evidence, our recommendation is
to use the digital TKK dynamometer. However, the digital
version has a range that measures from 5 to 100 kg, which
might not be useful in populations whose handgrip
strength values can be lower than 5 kg, such as people with
certain pathologies or work-related hand injuries, people
in hand therapy programs, older people, or preschool
children. For these clients, the analog version of the TKK
dynamometer, which measures from 0 to 100 kg, would
be a good alternative. To the best of our knowledge, the
reliability and validity of the analog TKK have not been
examined objectively (i.e., measured with calibrated
known weights). We identified several relevant questions
regarding the reliability and validity of hand dynamometers that still need to be addressed—in particular, how
reliable the handgrip measure is when using two different
instruments of the same model, different models, or a
new dynamometer versus an older one. This information
is important for researchers, clinicians, physiotherapists,
and sport scientists because this measure provides important
information about client prognosis (Savino et al., 2013)
and may be pivotal in task-oriented rehabilitation programs
for chronic patients (da Silva, Antunes, Graef, Cechetti, &
Pagnussat, 2015).
The overall aim of the current study was to examine
the reliability and validity of the digital and analog models
of TKK dynamometers using calibrated known weights.
The specific aims of the study were to determine test–retest
reliability within instruments of the same TKK model
(i.e., intrainstrument reliability), interinstrument reliability
between instruments within the same TKK model (e.g.,
between two digital dynamometers and 2 analog dynamometers), intermodel reliability (digital vs. analog dynamometers), reliability of new TKK dynamometers versus
old ones, and validity of dynamometers against calibrated
known weights.
Method
Instruments
A total of 6 TKK handgrip dynamometers, 3 digital and 3
analog, were used to assess the reliability and criterionrelated validity. The digital handgrip dynamometers (TKK
Model 5401; Takei, Tokyo, Japan) had a range of measure
from 5.0 kg to 100.0 kg, whereas the analog handgrip
dynamometers (TKK Model 5001; Takei, Tokyo, Japan)
had a range of measure from 0.0 kg to 100.0 kg (Supplemental Figure 2, available online at http://otjournal.net;
navigate to this article, and click on “Supplemental”).
Four dynamometers were new (i.e., bought for this
study), and 2 (1 digital and 1 analog) were old (i.e., had
been used for >6 yr in population studies), allowing us to
compare the reliability and validity between new and old
TKK dynamometers. The dynamometers, weights, and
scale were calibrated by the manufacturer at purchase. The
verification of all weights was performed by means of a
new (bought for this study) high-precision SECA scale
(Model 769; SECA, Hamburg, Germany). We assumed
that the SECA scale was perfectly calibrated because we
could not test its validity against a gold standard. However,
we assessed its reliability using known weights from 1 to
70 kg with increments of 1 kg up to 20 kg and increments
of 5 kg thereafter. We observed very high reliability; that is,
the mean difference between the known weights and the
SECA scale measures was 0.004 kg (standard deviation
[SD] 5 0.02 kg; p 5 .300).
Procedures
Known weights were used to analyze the criterion-related
validity (known weights vs. dynamometers) and reliability
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(intrainstrument, interinstrument, and intermodel measures) of the 6 dynamometers (Supplemental Figure 3,
available online at http://otjournal.net; navigate to this
article, and click on “Supplemental”). The dynamometers
were positioned between two wooden supports with the
handle fixed. The known weights were suspended with a
loading belt from the center of the dynamometer’s handle;
the weights ranged from 1 kg to 70 kg, and increments of
1 kg were added up to 20 kg and increments of 5 kg
thereafter. The dynamometer’s handle was marked for
consistent placement of the loading belt with the known
weight. The weights were added in a randomized order,
and each weight measure was repeated twice (test–retest).
The order of testing of the dynamometers was also randomized. As commonly described in the literature, a
5.0-cm grip span was used (roughly corresponding to
Position 3 of a Jamar grip span). The time between trials
was approximately 50–60 s.
Statistical Analysis
The agreement among intrainstrument, interinstrument,
and intermodel trials (i.e., reliability) and the agreement
between the known weights and dynamometer measures (i.e., criterion-related validity) were assessed using
Bland and Altman’s (1986) method. Mean difference
(error) and the 95% limits of agreement (error ± 1.96 of
the difference) were calculated. Results were graphically
examined by plotting the differences against their mean
(Bland & Altman, 1986). One-sample t test was used to
test whether the mean difference (i.e., systematic error)
was significantly different from zero (reference).
On the basis of results from previous studies (Bénéfice,
Fouére, & Malina, 1999; Molenaar, Zuidam, Selles,
Stam, & Hovius, 2008) and a study conducted by our
group in preschool children (ages 3–5 yr; Sanchez-Delgado
et al., 2015), we observed that preschoolers’ handgrip
strength is likely to be less than 15 kg. To gather information about how reliable and valid the dynamometers would be in people with hand injuries, older adults,
and preschoolers, we used one-way analysis of variance
(ANOVA; with intertrial mean difference as the dependent variable) to test whether the intertrial mean
differences of the dynamometers studied were significantly different at weights £15 kg versus >15 kg.
Heteroscedasticity, or whether the variability (error)
increases or decreases as the magnitude of the measures
changes, is an important dimension of an instrument’s
reliability and validity. To calculate the heteroscedasticity,
the negative values of the difference (both reliability and
validity analyses) were changed to positive (i.e., multiplied by 21) and fitted into a one-way ANOVA model,
with weight groups as the fixed factor (i.e., light weights
£15 kg and heavier weights >15 kg). A significant difference (p < .05) between light and heavier weights would
confirm heteroscedasticity.
An exploratory analysis was performed to know
whether the selection of the grip span influenced the reliability of the dynamometers. We measured known
weights (5, 10, 20, 30, 40, 50, 60, and 70 kg) at several
grip spans (4.0, 4.5, 5.0, and 5.5 cm). The measures were
performed once for each model of dynamometer (new
digital and new analog). For all the analyses, the level of
significance was set at p < .05.
Results
Reliability
Table 1 presents the mean differences among repeated
measures with the same instrument (intrainstrument reliability), different instruments of the same model (interinstrument reliability), different models (i.e., digital
vs. analog; intermodel reliability), and old versus new
dynamometers. Regarding intrainstrument reliability,
the mean difference ranged from |0.04 kg| to |0.25 kg| for
the digital dynamometer and from |0.09 kg| to |0.33 kg|
for the analog dynamometer. The systematic error between different instruments within the same model (e.g.,
digital 2 vs. digital 1; interinstrument reliability) was |0.6 kg|
for both the digital and analog dynamometers. Systematic error ranged from |0.24 kg| to |0.35 kg| for the
comparison between different new models (i.e., digital vs.
analog). The systematic error between old and new digital
dynamometers was |1.08 kg| for the digital and |0.78 kg|
for the analog dynamometers. All reliability estimates did
not differ between weights £15 and >15 kg (p > .05).
We tested for heteroscedasticity for all the comparisons shown in Table 1 and observed that the intrainstrument variability between measures increased as the
magnitude increased for the new analog 1 (£15 kg 5
0.14 ± 0.21; >15 kg 5 0.60 ± 0.65; p 5 .014) and new
analog 2 (£15 kg 5 0.14 ± 0.29; >15 kg 5 0.49 ± 0.56;
p 5 .041) dynamometers. No significant heteroscedasticity
was observed for the rest of the dynamometers. Reliability
analyses are graphically shown using Bland–Altman plots
in Figures 1 and 2. Plots are shown for one dynamometer
only per model; similar plots were obtained for the other
dynamometers (data not shown). In the exploratory analyses, we observed that the differences among grip spans
(from 4.0 to 5.5 cm) ranged from |0.00 kg| to |0.66 kg|
and from |0.00 kg| to |0.75 kg| for the new digital and new
analog dynamometers, respectively (Supplemental Table 1,
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Table 1. Differences in Reliability Among TKK Dynamometers
General
M ± SD
Dynamometer
pa
Weights £15 kg, M ± SD
Comparison using the same instrument (intrainstrument reliability: retest minus test)
0.04 ± 0.58
New digital 1
0.04 ± 0.60 .742
Weights >15 kg, M ± SD
Difference Between Weights, pb
0.04 ± 0.64
1.000
New digital 2
20.06 ± 0.55
.613
20.16 ± 0.26
0.01 ± 0.67
.449
Old digital
20.25 ± 0.65
.063
20.30 ± 0.48
20.22 ± 0.75
.769
New analog 1
0.09 ± 0.65
.437
0.06 ± 0.25
0.13 ± 0.90
.784
New analog 2
20.22 ± 0.53
.034
20.13 ± 0.30
20.31 ± 0.69
.365
Old analog
20.33 ± 0.69
.013
20.13 ± 0.48
20.53 ± 0.81
.112
20.54 ± 1.13
20.23 ± 0.64
20.67 ± 2.50
21.06 ± 1.70
.876
.087
Comparison between different instruments of the same model (interinstrument reliability)
New digital 2 minus new digital 1
New analog 2 minus new analog 1
20.62 ± 2.03
20.64 ± 1.33
.140
.013
Comparison between different models (intermodel reliability)
New digital 1 minus new analog 1
20.35 ± 1.51
.260
20.01 ± 0.92
20.57 ± 1.80
.372
New digital 2 minus new analog 2
20.25 ± 1.72
.499
20.31 ± 0.63
20.19 ± 2.19
.865
Comparison of old vs. new dynamometers
Old digital minus new digital 1
Old analog minus new analog 1
1.08 ± 2.02
.014
1.00 ± 1.44
1.13 ± 2.38
.876
20.78 ± 1.32
.003
21.13 ± 0.84
20.43 ± 1.62
.153
Note. M 5 mean; SD 5 standard deviation.
a
One-sample t test. The intertrial difference was entered as a dependent variable; p value indicates whether the mean difference is significantly different from 0 for
all measures from 1 kg to 70 kg. bOne-way analysis of variance. The intertrial difference was entered as a dependent variable, and weights £15 kg vs. >15 kg as a
fixed factor; p value indicates whether the mean difference is the same or different for weights £15 kg (i.e., people with lower handgrip strength, such as adults with
work-related hand injuries or preschoolers) compared with weights >15 kg (i.e., people with higher handgrip strength, such as healthy children age >6 yr,
adolescents, and adults).
available online at http://otjournal.net; navigate to this article, and click on “Supplemental”).
Validity
Criterion-related validity for the dynamometers against
known weights is provided in Table 2. A negative systematic error (underestimation) was observed for the new
digital (range 5 22.64 kg to 22.02 kg) and new analog
(range 5 22.15 kg to 21.51 kg) dynamometers as
well as for the old digital and analog dynamometers
(20.94 kg and 22.29 kg, respectively). The systematic
error increases as the magnitude of the measures increases
(heteroscedasticity) in all of the dynamometers except the
old digital one. Most had a mean difference range from
0.97 to 1.83 kg for weights £15 kg and from 2.22 to
3.62 kg for weights >15 kg.
Discussion
The current study provides several major findings. First,
the intrainstrument test–retest reliability was excellent for
all of the dynamometers. The combined systematic error
of £0.3 kg is relatively low for digital and analog devices,
especially for the analog dynamometer, which has a
precision of measure of 0.5 kg. Second, the systematic
error between different instruments of the same model
and between different models (digital vs. analog) ranged
between |0.3 kg| and |0.6 kg|, which we consider acceptable.
Third, the systematic error between new and old dynamometers ranged from |0.8 kg| to |1.1 kg|, which in our
opinion is a relatively large error. Finally, all dynamometers
provided lower values than known weights.
The main message drawn from these findings is that
whenever possible, clinicians should use the same dynamometer in repeated measures to minimize the systematic
error inherent in the apparatus. If repeated measures are
taken using different instruments (e.g., new digital 2 minus
new digital 1) or different models (e.g., new digital minus
new analog), the systematic error is expected to range from
0.3 to 0.6 kg, with higher errors of measure observed
between old and new dynamometers (both digital and
analog). This finding is in accordance with the finding by
Härkönen et al. (1993) that older Jamar dynamometers
were less accurate than newer ones. This fact raises a point
of caution when interpreting results of handgrip strength
levels in long-term follow-up studies because slight improvements (roughly 1 kg) or impairments in hand therapy or exercise programs could be attributable to a systematic
error between new and old dynamometers. Thus, these
findings should be interpreted and generalized cautiously
because the systematic error might differ depending on
the frequency of use, the way the dynamometer is used,
and how old the dynamometer is.
The heteroscedasticity analysis showed significant
differences in the new analog dynamometers between light
and heavier weights, which indicates that the test–retest
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Figure 1. Reliability of TKK dynamometers versus known weights: (A) Intrainstrument reliability within the same digital dynamometer; (B)
Intrainstrument reliability within the same analog dynamometer; (C) Interinstrument reliability between different digital dynamometers; (D)
Interinstrument reliability between different analog dynamometers. The central line represents the mean difference (error) between known
weights and different trials. Upper and lower broken lines represent the 95% limits of agreement (mean difference 6 1.96 of the
differences).
error increases as the client’s handgrip strength increases.
A practical implication of this finding is that when assessing handgrip strength using the analog TKK dynamometer in a specific population (e.g., people with
certain pathologies or hand injuries, preschoolers) with
very low handgrip strength, the systematic error will be
very small (i.e., <0.2 kg). This error is smaller than that of
the digital version (i.e., 0.5 kg), which supports the use of
analog TKK dynamometers in populations with very low
handgrip strength, with the additional advantage that the
analog dynamometer measures less than 5 kg, whereas the
digital one does not. In contrast, when assessing older
children and adolescents or healthy and young adults, the
digital version would be a better choice because of its high
reliability and lack of heteroscedasticity. Our exploratory
analyses indicate that the same grip span should be used
when testing the same person repeatedly because mean
differences among grip spans might be up to 0.8 kg.
The criterion-related validity analyses suggest that all
dynamometers studied provide lower values than the SECA
scale (20.94 to 22.64 kg), which could be interpreted as a
slight underestimation. This result is in contrast with what
we observed in our previous study, in which the TKK
(only the digital model) overestimated handgrip strength
levels (0.49 kg; España-Romero et al., 2010). The difference between studies could be partially attributed to the
model of the weight scale used (SECA 769 vs. 861) or to
interinstrument error (described in this study). Nevertheless, we believe this last finding is not very relevant because
handgrip strength will never be measured using a body
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Figure 2. Reliability of TKK dynamometers versus known weights. (A) Intermodel reliability between the digital model and the analog
model. (B) Old versus new digital 1 dynamometer. (C) Old versus new analog 1 dynamometer. The central line represents the mean
difference (error) between known weights and different trials. The upper and lower broken lines represent the 95% limits of agreement
(mean difference 6 1.96 of differences).
weight scale. In addition, and in line with previous research (Mullany, Darmstadt, Khatry, Leclerq, & Tielsch,
2007), we assumed that the SECA scale was the gold
standard, and therefore we calibrated the weights using this
scale; however, we could not know how valid the SECA
scale is because no better gold standard was available to test
it. Consequently, we can conclude only that the TKK
dynamometer provides values 1–2 kg lower than the
SECA scale. Overall, heteroscedasticity analysis showed
significant differences for the digital and analog dynamometers indicating that the error of the measures increased as the magnitude of the measures increased, as
previously described (España-Romero et al., 2010).
Our results strongly support the use of the same instrument in repeated measures to minimize the systematic
error to 0.3 kg or less. If different instruments, models, or
dynamometers of different ages are used in repeated
measures, the systematic error might increase up to 1 kg.
This information is useful for studies in which the aim is to
compare handgrip strength levels over different time
periods (e.g., before and after a hand therapy program, in
intervention or follow-up studies). For example, in the
AVENA and HELENA studies, Moliner-Urdiales et al.
(2010) analyzed secular trends in adolescents’ healthrelated physical fitness between 2001 and 2007. Adolescents showed a change of 4 kg in strength values
measured by the handgrip strength test. If the researchers
used the same dynamometer 6 yr later, the expected error
would be 1 kg. Some additional variance would be
attributable to the biological variability of each participant, but the 4 kg of secular change reported is likely
to reflect a real change in strength.
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Table 2. Differences Between TKK Dynamometers and Known Weights
General
Dynamometer
M ± SD
pa
Weights £15 kg, M ± SD
Weights >15 kg, M ± SD
Difference Between Weights, pb
New digital 1
New digital 2
22.02 ± 2.60
22.64 ± 2.73
.001
.001
20.73 ± 1.03
21.27 ± 0.90
22.89 ± 2.99
23.56 ± 3.17
.040
.037
Old digital
20.94 ± 3.05
.135
0.27 ± 1.29
21.75 ± 3.62
.105
New analog 1
21.51 ± 1.73
.001
20.71 ± 0.27
22.31 ± 2.18
.009
New analog 2
22.15 ± 2.20
.001
20.93 ± 0.60
23.37 ± 2.54
.001
Old analog
22.29 ± 1.27
.001
21.83 ± 0.83
22.75 ± 1.48
.047
Note. M 5 mean; SD 5 standard deviation.
a
One-sample t test. The intertrial difference was entered as a dependent variable; p value indicates whether the mean difference is significantly different from 0 for
all measures from 1 kg to 70 kg. bOne-way analysis of variance. The intertrial difference was entered as a dependent variable, and weights £15 kg versus >15 kg as
a fixed factor; p value indicates whether the mean difference is the same or different for weights £15 kg (i.e., people with lower handgrip strength, such as adults
with work-related hand injuries or preschoolers) compared with weights >15 kg (i.e., people with higher handgrip strength levels, such as healthy children age
>6 yr, adolescents, and adults).
The main strength of the current study is that we used
TKK dynamometers, which have been shown to be reliable and valid and also to be sufficiently precise to detect
minimum changes in comparison with other dynamometers (e.g., Jamar). A limitation of this study is the
absence of a group of people with different characteristics
to examine the reliability of different models of dynamometers. Further studies involving human samples and
different types of dynamometers (e.g., Jamar, DynEx) are
needed to confirm our findings.
Implications for Occupational
Therapy Practice
The results of this study have the following implications
for occupational therapy practice:
• The TKK dynamometer is a useful tool for hand grip
assessment with good reliability and validity and higher
precision, reliability, and validity than other dynamometers such as the Jamar (España-Romero et al., 2010).
• Practitioners providing hand therapy should use the
analog version of TKK, rather than the digital version,
because it allows assessment of handgrip strength in
patients with very low strength levels.
• Findings support the recommendation to use the same
instrument to measure hand strength because interinstrument reliability adds a certain amount of error.
• This study provides objective estimates of systematic error
so that practitioners, researchers, and anyone who needs
to compare data from two different time points can
distinguish between the variability of the instrument itself
and a meaningful change in handgrip strength attributable to an intervention program or hand therapy. s
Acknowledgments
The study took place under the umbrella of the ActiveBrains project funded by the Spanish Ministry of Econ-
omy and Competitiveness (Reference DEP2013–47540).
We thank Christine Delisle for her help with the English
proofreading. Cristina Cadenas-Sanchez is supported by
a grant from the Spanish Ministry of Economy and
Competitiveness (BES–2014–068829). Jonatan R. Ruiz
and Francisco B. Ortega are supported by grants from
the Spanish Ministry of Science and Innovation (RYC–
2011–09011 and RYC–2010–05957, respectively). In
addition, the costs related to this project were covered
with support from the Spanish Ministry of Science and
Innovation (RYC–2011–09011). This work is part of a
PhD thesis in biomedicine at the University of Granada,
Granada, Spain. All authors declare that they have no
conflicts of interest to disclose.
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