4.4.1 Methods for assessment of FFM
The field of body composition in medical research has grown rapidly the last decades and brought valuable insight about the impact of body composition on morbidity and mortality in cancer patients. To date, body composition methodology encompasses a large number of methods that differ with regard to precision, costs and availability. Advanced imaging techniques such as DXA, CT and MRI are considered gold standard methods for assessment of FFM due to their ability to precisely measure different tissues within FFM, such as skeletal muscle, fat, bone and organs. However, access to these methods is often limited in clinical practice and BIA is considered a more available alternative to assess FFM. Since BIA
estimates FFM indirectly, it is less precise compared to the gold standard methods. In the current work, BIA and DXA were chosen to assess FFM, and certain methodological aspects regarding these methods will be discussed in the next sections.
Although all are considered gold standard methods, the imaging techniques DXA, CT and MRI have their strengths and limitations, and it is important to note that they measure different compartments of the human body. In order to discuss DXA as a reference method for FFM assessments, it is relevant to compare the method in light of the other gold
standard methods. CT and MRI allow for segmentation and quantification of different tissues from either cross sectional area in single images or series of images that encompass entire organs. Within these cross sectional images, the amount of skeletal muscle (including psoas, paraspinal muscles, transversus abdominus, external and internal obliques and rectus
abdominus) and adipose tissues (including the subcutaneous, visceral and intramuscular adipose tissues) can be precisely determined. For CT, images from the third lumbar (L3) vertebra has been defined as the landmark of interest since the composition of skeletal muscle and adipose tissue at this area is found to be highly representative for whole-body tissue quantities [33, 34]. The cross-sectional areas (m2) can be computed for each tissue by the use of specific CT imaging software, and further incorporated into prediction equations to estimate whole-body skeletal muscle mass and adipose tissue [145-147].However, use of CT in body composition assessment is limited due to the high radiation exposure, and only images taken as part of routine care may be utilized for this purpose. Furthermore, the
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estimation of whole-body tissue quantities is based on regression equations developed in a selected patient population and may hence not be valid in all populations. In contrast to CT, MRI is based on for whole-body assessments and repeated measurements than CT.
However, there are also some limitations related to the use of MRI in clinical practice. It is less available, requires high technical competence and the analysis is time consuming.
4.4.2 DXA
DXA was originally developed to measure bone density and is primarily used to diagnose osteoporosis. DXA is now also used to characterize body composition as the method also allows for whole-body and regional determination of FFM, bone mass, and FM. The sum of lean soft tissue (i.e. FFM without bone) in arms and legs is referred to as total appendicular skeletal muscle. With its high precision is considered one of the gold standard methods for measurement of fat and lean mass. In contrast to CT, the radiation exposure is very low, and DXA is thus more suitable for repeated measurements. The repeatability is found to be very high [148]. Since we had access to a DXA device in our research setting and considered DXA as the most suitable imaging method for assessment of fat-free mass, DXA was used as reference method in the validation study in paper 3. There are, however, some
methodological aspects related to DXA that need to be further discussed. Similar to BIA, also DXA is based on an assumption that lean soft tissue is constantly hydrated at 73 %. Thus, the DXA estimates may be less reliable in patients with fluid and electrolyte disturbances. Small variations in hydration status (i.e. 68-78 %) are however not considered to significantly influence the estimates [149]. On the other hand, severe overhydration such as ascites and edema, may have substantial effect on the measurements. In paper 3, only 12 % of the patients were observed with edema and only four of the patients had a hydration status exceeding the normal range for the ration between total body water (TBW) measured with BIA (i.e. the segmental BIA) and FFM measured with DXA (data not shown). Hence, severe overhydration was not a major concern in our study and had minimal impact on the interpretation of our results.
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4.4.3 BIA
Compared to imaging techniques such as CT, MRI and DXA that directly measure lean body mass with high precision, BIA measures these compartments indirectly by measuring the impedance of a low-voltage current passing through the body. The impedance consists of two components, the resistance, which is the opposition of an ionic solution in both intra- and extracellular spaces and the reactance representing the capacitance from the cell membranes [37]. The resistance and reactance values are further incorporated in linear regression equations to calculate TBW or FFM.
These equations have been developed in different populations and combine BIA impedance data with variables such as height, weight data, age and gender to calculate the various body compartments. One of the main limitations with BIA is related to the complexity of these equations. Although a prediction equation is developed and validated in a specific
population it will not necessarily suit other populations. In addition to the equations incorporated in the various BIA devices, there are a large number of published equations available in the literature. It is therefore confusing for the clinicians to know which equation should be used in which patient. Moreover, BIA relies on several assumptions such as normal body composition and normal fluid and electrolyte status. Since the validity of BIA is mainly tested in healthy populations where these assumptions are met, the clinical value of BIA in patient populations has in general been considered limited.
The existing BIA devices are either based on a whole-body approach or a segmental approach. With the whole-body BIA approach, the human body is viewed as cylindrical conductor with a uniform cross-sectional area. This model is demonstrated to be valid in healthy individuals with BMI in the range 16.0-34.0 kg/m2, provided that hydration is normal and the BIA equation used is applicable to the population studied [150]. In contrast to the whole-body BIA, the segmental BIA devices measure impedance in the various segments, such as arms, legs and trunk.
BIA has several advantages compared to DXA, CT and MRI. It is relative cheap, requires minimal operator training and provides the results immediately. Some BIA devices are portable and may be used in settings where DXA, CT and MRI is not available, such as in
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primary care, hospital wards and institutions such as elderly care and nursing homes. BIA may unquestionable be an easy accessible and useful tool for body composition analysis in clinical practice, given that the various devices and equations are valid.