Bioelectrical impedance breast attachment device and methods of using thereof

Abstract

Attachment devices for analyzing the density of breast tissue are described herein, as well as methods of using thereof which rely on bioelectrical impedance analysis. Use of such techniques can be used to pre-screen individuals with dense breast tissue which are at higher risk for breast malignancies and direct them toward other breast screening tests.

Description

[0001] BIOELECTRICAL IMPEDANCE BREAST ATTACHMENT DEVICE AND METHODS OF USING THEREOF

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 644,363, filed May 8, 2024, incorporated herein by reference in its entirety.

[0004] FIELD OF THE INVENTION

[0005] This invention is generally in the field of determining the density of breast tissue using bioelectrical impedance analysis.

[0006] BACKGROUND OF THE INVENTION

[0007] One in eight women in the United States will be diagnosed with breast cancer in her lifetime. Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among women. Up until recently, breast cancer screening guidelines by the US Preventive Services Task Force (USPSTF) recommend mammograms begin at age 50 years for breast cancer screening. Recent updates have lowered the screening age to 40 years. However, the uptake of mammography is limited by many factors, including lack of knowledge regarding screening guidelines, lack of insurance, insufficient insurance, low-income precluding even small copayments, and lack of physical access to mammography devices in rural and remote areas. The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides breast cancer screening services to low-income, uninsured women aged 40-64 (after which, most women have coverage for screening through Medicare). Nevertheless, a recent study showed that up to 59% of low-income uninsured women aged 40-64yrs and 56% of women age 50-64 yrs did not receive screening (Howard, et al. Cancer Causes Control. May 2015;26(5):657-68). Another study estimated that by 2014, even after implementation of the Affordable Care Act's major insurance expansion provisions, 1.7 million women still fell into a gap and did not have coverage for breast cancer screenings (Levy, et al., Prev Chronic Dis. 2012;9:E159). This number continues to increase as women age into the target screening age range.

[0008] There is a critical untapped group of individuals, particularly from underserved backgrounds, that present with more aggressive and later stage breast cancers due to lack of screening, such as Hispanic / Latina, American Indian / Alaska Native, and African American, in part because they were not old enough at the time of presentation to meet the USPTFS screening guideline age of 50 years (prior screening recommendation). Hispanic and African American women also represent a larger proportion of the uninsured and underinsured populations compared to non-Hispanic white women. Indian Health Service facilities are typically under resourced for our American Indian / Alaska Native population. Preventive screenings may also be out of reach due to co-pay costs in those with insurance.

[0009] Therefore, there remains a need for low cost devices for examining breast tissue which are useful for public health “pre-screenings” of breast tissue with minimal training.

[0010] Therefore, it is the object of the present invention to provide devices which can be used for examining breast tissue to evaluate risk, such as for breast cancer.

[0011] It is a further object of the present invention to provide methods of using such devices.

[0012] SUMMARY OF THE INVENTION

[0013] Attachment devices for use with bioelectrical impedance analysis (BIA) devices are described herein. The attachment devices and BIA devices can be used to evaluate and quantify the density of breast tissue, where the higher the density of the breast tissue the higher the risk factor for breast cancer.

[0014] In one non- limiting instance, an attachment device for analyzing breast density includes: a cup for placement onto a subject’s breast; a plurality of positive and negative electrodes embedded in the cup; where the plurality of positive and negative electrodes can each be independently connected to a bioelectrical impedance analyzer.

[0015] The attachment devices described herein can be used with BIA devices to evaluate and quantify the density of breast tissue. Accordingly, in some non- limiting instances, a method for analyzing breast density of a subject includes the steps of:

[0016] (i) placing an attachment device, as described herein, on a subject’s breast; where the plurality of positive and negative electrodes are connected to a bioelectrical impedance analyzer;

[0017] (ii) applying an alternating electrical current from the bioelectrical impedance analyzer, at one or more frequencies, through tissue of the subject’s breast using the plurality of positive and negative electrodes;

[0018] (iii) measuring the impedance, which is a sum of resistance (R) and reactance (Xc) of the subject’s breast tissue, at the one or more frequencies with the bioelectrical impedance analyzer; and

[0019] (iv) analyzing the impedance using an algorithm to determine density of the subject’s breast tissue.

[0020] Breast density calculated according to the methods described can be used to categorize the analyzed breast tissue as dense or non-dense, in view of standardized mammography cut points or MRI-derived percent density. Based on the BIA-based methods described, the determination that a woman has dense breasts can be used to advise them they have an additional risk factor of dense breasts and recommending to the subject to pursue a mammography screening, or other common screening study.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Non-limiting embodiments are described by way of example with reference to the accompanying Figures.

[0023] FIG. 1 shows a non-limiting illustration of an attachment device for analyzing breast density 100. The device includes a cup 110 for placement onto a subject’s breast, a plurality of positive electrodes 120 and negative electrodes 130 embedded in the cup, a positive electrode wire 125 and a negative electrode 135 wire each connected to the plurality of positive and negative electrodes, respectively, an optional component 140 which can combine the electrode wires into a single connection wire 150, and a connector 160 which can be connected to a bioelectrical impedance analyzer.

[0024] FIG. 2 shows a non-limiting illustration of a device for analyzing breast density 200, where the device includes the attachment device for analyzing breast density 100 connected to a bioelectrical impedance analyzer 210. The bioelectrical impedance analyzer 210 can include an on / off switch 220, a connection port 230 (which can receive connector 160), a display unit 240, and at least one controller 250 for the device.

[0025] FIG. 3 shows a non- limiting timeline or flow of a proposed clinical study of the use of device 200 for analyzing breast density in test subjects.

[0026] DETAILED DESCRIPTION OF THE INVENTION

[0027] Attachment devices for analyzing breast density are described herein, as well as methods of using thereof.

[0028] I. DEFINITIONS

[0029] The term “subject,” as used herein, refers to a mammal, such as a human.

[0030] The term “impedance,” as used herein, refers to the opposition that biological tissues present to the flow of an electrical current. Impedance is the sum of resistance (R) and reactance (Xc).

[0031] The term “resistance (R),” as used herein, refers to the opposition to the flow of an electrical current through biological tissue.

[0032] The term “reactance (Xc),” as used herein, refers to the ability of biological tissues to store and release electrical energy as electrical current alternates.

[0033] "Malleable,” as used herein generally refers to a material's ability to be easily shaped or molded onto different forms with limited or without breaking or fracturing. The numerical ranges disclose individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of sub-ranges encompassed therein. For example, in a given current range of 50 kHz to 100 kHz, the range also discloses 60, 73, and 99 kHz, as well as any subrange between these numbers (for example, 50 kHz to 75 kHz), and any possible combination of ranges possible between these values.

[0034] Use of the term "about" is intended to describe values either above or below the stated value, which the term “about” modifies, to be within a range of approximately + / - 10%. When the term "about" is used before a range of numbers (z.e., about 1-5) or before a series of numbers (z.e., about 1, 2, 3, 4, etc.) it is intended to modify both ends of the range of numbers and / or each of the numbers recited in the entire series, unless specified otherwise.

[0035] II. Attachment Devices for Bioelectrical Impedance Analysis

[0036] Bioelectrical impedance analysis (BIA) has been used to assess body composition by whole body devices using validated equations to determine fat, water, and fat free mass for decades and many devices are available in the marketplace. It operates on the principle that tissues differentially conduct electricity (e.g. fat is a poor conductor). High frequency electrical current is thus variably impeded by different tissues. However, BIA devices on the market today are not known to be used to analyze breast tissue.

[0037] Described herein are attachment devices for use with bioelectrical impedance analysis (BIA) devices. The attachment devices and BIA devices can be used to evaluate and quantify the density of breast tissue, where the higher the density of the breast tissue the higher the risk factor for breast cancer. Accordingly, use of the attachment device and BIA devices can be used for, for example, to “pre-screen” for high breast tissue density which could be used to direct higher risk individuals to perform other higher demand screening and diagnostic techniques, such as mammography, to check for the presence of cancerous or pre-cancerous growths in the breast tissue.

[0038] In one non- limiting instance, an attachment device for analyzing breast density includes: a cup for placement onto a subject’s breast; a plurality of positive and negative electrodes embedded in the cup; where the plurality of positive and negative electrodes can each be independently connected to a bioelectrical impedance analyzer.

[0039] As shown in Figure 1, such an attachment device 100 can include a cup 110 for placement onto a subject’s breast, a plurality of positive electrodes 120 and negative electrodes 130 embedded in the cup, a positive electrode wire 125 and a negative electrode 135 wire each connected to the plurality of positive and negative electrodes, respectively, an optional component 140 which can combine the electrode wires into a single connection wire 150, and a connector 160 which can be connected to a bioelectrical impedance analyzer device.

[0040] In some instances, the cup is formed of a malleable material, such as silicone (i.e., a Liquid Silicone Rubber (LSR)). Other art known malleable materials are also suitable, such as but not limited to, thermoplastic elastomers, polyurethane gels, mineral oil gels, or any material which can be molded to varying thicknesses or weights. In some instances, the cup formed of the malleable material has a thickness to prevent or minimize tearing of the cup but is sufficient to permit molding of the cup and embed electrode(s) within the cup. The thickness of the cup may be uniform or non-uniform throughout. The cup can be formed from any suitable material and can have any suitable shape or size for facile placement on the breast of the subject. Accordingly, the cup can be formed to have a size based on standard breast cup sizing, such as A, B, C, D cup sizes, or larger. The breast cup sizing standard is a system used in the lingerie industry to categorize the size of women's bras based on the volume of the breasts. The cup size represents the difference in volume between the bust measurement and the underbust measurement. The cup size indicates the volume of the breasts relative to the band size. In some instances, the cup size is determined by calculating the difference between the bust measurement (the fullest part of the breasts) and the underbust measurement (the band size). There may be differences in specific sizing charts, grading systems, and terminology where some countries or regions may have their own unique sizing standards. In some instances, the cup may include a hole to center the cup onto the breast. The cup can be easily placed on the breast without significant training and sterilized between uses.

[0041] The cup has a plurality of positive and negative electrodes which are embedded within the cup. In some instances, the plurality is distributed in a radial pattern, as shown in Figure 1. However, there are no particular restrictions on the pattern of the electrodes as long as the pattern does not negatively impact the ability of the density of the breast tissue of the subject to be determined. In some instances, there may be at least one positive and one negative electrodes, however, there are more typically at least two, three, four, or five positive and negative electrodes used. The number of positive and negative electrodes are usually equal. In other words, there may be equal pairs of positive and negative electrodes, such as one, two, three, four, five, or more pairs of electrodes, used In some instances, one of the electrodes may be designated as a superior (or top) electrode which can be used in orienting the cup for placement onto the breast. In some instances, the plurality of positive and negative electrodes are embedded at variable distances from a center point defined on the cup. In some instances, the plurality of positive and negative electrodes are embedded at variable distances from each other in the cup. For example, there may be a minimum distance between positive and a negative electrodes or between any two given electrodes, such as in a range of about 0.1 (0.25 cm) to about 5 inches (13 cm) or about 0.1 (0.25 cm) to about 3 inches (7.6 cm), as well as individual values or subranges contained within. In certain instances, the plurality of positive and negative electrodes can include an exposed contact surface which can directly contact the subject’s breast tissue, where the exposed contact surface can facilitate cleaning of the electrodes after use.

[0042] The plurality of positive and negative electrodes embedded within the cup can be made of any suitable electrode materials known, such as metal electrodes or metal alloy electrodes (i.e., Au / Ag). Other suitable known electrode materials can include, without limitation, Au / Ag, Ag / AgCl, Au / Cr, Au / Ti, Ti / Cu / Ni / Au, stainless steel, carbon nanotubes, graphene, graphite, metallic nanowire, conductive nanomesh, conductive nanoparticles, nanobelt with or without elastic polymer, and conductive polymers. The positive and negative electrodes can each be connected to a positive and negative electrode wire, respectively. In some instances, these electrode wires may be connected directly to a bioelectrical impedance analyzer device. However, in some instances, the electrode wires may be combined into a single connection wire (containing both electrode wires), such as with a suitable component, and the single connection wire includes a connector which can be connected to a bioelectrical impedance analyzer device, as shown in Figure 2.

[0043] The attachment device described can be made by the skilled person using art known manufacturing processes and from art known materials. For example, the cup can be made of a Liquid Silicone Rubber (LSR) which is poured into a designed custom 3D printed mold.

[0044] III. Methods of Using the Attachment Devices

[0045] As noted above, the attachment devices described herein can be used with BIA devices to evaluate and quantify the density of breast tissue. The use of such attachment devices with BIA devices can be used for, for instance, to “pre-screen” for high breast tissue density which could be used to evaluate the risk of individuals for breast cancer and encourage them to perform other higher demand screening and diagnostic techniques, such as mammography, in order to check for the presence of cancerous or pre-cancerous growths in the breast tissue. Accordingly, the attachment devices can be used for non-invasive, inexpensive, comfortable, and portable testing in subjects, particularly those in underserved communities, in age groups lower than screening guidelines (but where a higher risk, such as among some racial and ethnic groups, exists), and areas with limited access to breast cancer screenings. Moreover, the use of the attachment devices in combination with BIA devices, as described, can help avoid unnecessarily exposing subjects to radiation, physical discomfort, and expense of other screening techniques (such as mammography) until an appropriate and recommended time. Pre-screening with the device can be done by existing preventive health care workers and processes, e.g. community health workers in clinics or at health fairs, clinicians during routine visits, radiology technicians or their support staff at clinical centers.

[0046] As shown in Figure 2, a device for analyzing breast density 200 includes attachment device 100 connected to a bioelectrical impedance analyzer 210. The bioelectrical impedance analyzer can include an on / off switch 220, a connection port 230 (which can receive connector 160), a display unit 240, and at least one controller 250 for the device. Although only a single attachment device is show, it is understood that two attachment devices can be present to allow for simultaneous analysis of two breasts. The bioelectrical impedance analyzer device can be a commercially BIA device, such as a RJL Quantum BIA analyzer. Other BIA analyzer devices are commercially available, such as, Biodynamics BIA 450 Bioimpedance Body Composition Analyzer (50kHz); Mint Biodynamics BIA 310 Bioimpedance Body composition Analyzer (50kHz); and Maltron BioScan (5, 50, 100, 200 kHz), which have FDA clearance for safe use on the human body to collect BIA data. The BIA analyzer devices can be single or multi frequency BIA and BIS (bioelectrical impedance spectroscopy), bioelectrical impedance spectroscopy, where an example device would be the Xitron 4200 device (5 kHz- 1000 kHz). Such BIA analyzer devices are typically portable and can be powered by battery or plugged into a power source.

[0047] It is believed that the principles of bioelectrical impedance (BIA) are appropriate for breast density estimates, as BIA relies on a two-component model of body composition (fat and fat free mass, FFM). Some aspects of BIA include:

[0048] • Theory: the volume of a conductor is related to its length (L) and its impedance (Z)

[0049] • Impedance of the body is affected by the specific resistivity and volume of the conductor

[0050] • The conductor of the electrical current water. There is more water in FFM than fat.

[0051] • Volume of the conductor (fat- free tissue) can be predicted as follows: V = p (L2 / Z)

[0052] • p = specific resistivity of the fat-free tissue or the water

[0053] • L = length of the conductor

[0054] • Z = impedance of the conductor • Impedance is the sum of resistance (R) plus reactance (Xc) of the body as follows: Z= (R2+ XC2) ; since Xc is much smaller than R, Z ~ R.

[0055] • Thus, V = p (L2 / R), i.e. volume of a conductor estimated from its length and resistance. (Book: ACSM’s Body Composition Assessment, eds. Timothy G. Lohman and Laurie A Milliken 2020, p77-86)

[0056] In the case of breast density, the dense tissue is the better conductor, as compared to the fatty tissue of the breast, and therefore the volume of the conductor would be a proxy for breast density. Therefore, following placement of the attachment device on the breast and running the BIA device, output can be used to calculate / estimate breast density.

[0057] Accordingly, in some non-limiting instances, a method for analyzing breast density of a subject includes the steps of:

[0058] (i) placing an attachment device, as described herein, on a subject’s breast; where the plurality of positive and negative electrodes are connected to a bioelectrical impedance analyzer;

[0059] (ii) applying an alternating electrical current from the bioelectrical impedance analyzer, at one or more frequencies, through tissue of the subject’s breast using the plurality of positive and negative electrodes;

[0060] (iii) measuring the impedance, which is a sum of resistance (R) and reactance (Xc) of the subject’s breast tissue, at the one or more frequencies with the bioelectrical impedance analyzer; and

[0061] (iv) analyzing the impedance using an algorithm to determine density of the subject’s breast tissue.

[0062] In some instances, step (iii) can be substituted with a step of individually measuring resistance (R) and reactance (Xc) at the one or more frequencies with the bioelectrical impedance analyzer to determine impedance.

[0063] For the methods described herein, the analysis of breast density of a subject can be carried out on one breast at a time. In some instances, a BIA device and two attachment devices may be used to concurrently or sequentially evaluate both of the subject’s breasts.

[0064] In some instances, the one or more frequencies are in a range from about 5 to 1000, 10 to 1000, 25 to 1000, 50 to 1000, 75 to 1000 kHz, 10 to 100, 25 to 100, 50 to 100, or 75 to 100 kHz, as well as individual values or sub-ranges contained within the aforementioned ranges. In some instances, the one or more frequencies is at about 50 kHz or 60 kHz. In some instances, the one or more frequencies are selected to be greater than about 1, 2, 3, 4, or 5 kHz. In some instances, the alternating current provided by the BIA device to the plurality of electrodes is in a range of about 1 to 4 amps, as well as individual values or sub-ranges contained within the aforementioned ranges. The electrical current and frequencies delivered to the breast tissue are not typically felt by the subject.

[0065] The bioelectrical impedance analyzer device is able to analyze the impedance data and can apply one or more algorithms to determine the density of the subject’s breast tissue. Standard algorithms known for whole body BIA can be adapted for understanding output from the BIA device (resistance, reactance or computed impedance using those variables) and the data obtained using the attachment device. In some instances, a suitable algorithm will take into account the following elements, such as: resistance and reactance which can be used to predict MRI or mammogram determined breast density in the context of demographic, and anthropometric data; independent variables, such as age, BMI, breast cup size, race, ethnicity, resistance, reactance. In some instances, the algorithm for calculating the density of the subject’s breast tissue is carried out according to the following formula:

[0066] Breast Density = [intercept + 0i x (cupsize2 / R) + 02 x BMI + 03 x Xc + 04 x age + 0s x Ethnicity + 06 x Race] wherein the intercept and 0 values (0i ; 02 ; 03 ; 04 ; 05 ; 0o) are determined from the data produced by the BIA device upon use; wherein R= resistance;

[0067] Xc = reactance;

[0068] BMI is the body mass index of the subject (weight, kg / height, cm2);

[0069] Age is the subject’s age;

[0070] Cupsize is an integer value from 1-4 (wherein A cup = 1, B cup = 2, C cup = 3, or D cup = 4);

[0071] Ethnicity is an integer value from 0-1 (wherein if the subject is not hispanic = 0 and if the subject is hispanic =1; and

[0072] Race categories numbered 1-z depending on participants.

[0073] Race is issued as an integer number, where, for example, 1 can be African American, 2 can be white, 3 can be Asian, etc. or some other order, “z” represents the endpoint of any statistical list when one is uncertain of how many groups there will be. In some other instances, it is possible to assign Race a value of 0 vs 1 for every category, e.g. white = 1 and not white = 0, African American = 1 and not African American = 0, and so on. If this alternative approach is used, then each additional categories would be added to the equation in place of the current single 06 x race.

[0074] In some instances, the methods can be used to categorize density according to standardized mammography categories and used as a continuous or categorical variable to determine BIA readings that correspond to them. For example, in some instances, the method further comprises step (v), following step (iv), of classifying the calculated density of the subject’s breast tissue on a four-level class scale, wherein:

[0075] (a) fatty, (b) scattered fibroglandular density, (c) heterogeneously dense, or d) extremely dense.

[0076] Accordingly, in some instances, breast density calculated according to the aforementioned method can be used to categorize the analyzed breast tissue as non-dense or dense based on standardized mammography categories of A) Fatty or B) scattered fibroglandular density = 0 (non-dense) and C) Heterogeneously dense or D) Extremely dense = 1 (dense). Density may also be compared to MRI-based breast density measurements, where a 70% dense area is considered dense breasts, such that those with <70% will = 0 (not dense) and > 70% = 1 (dense). The above equation and appropriate values can be used to predict if breast tissue analyzed by the method will be in the dense or non-dense category based on a mammogram (or >70% dense area on MRI), where mammography and / or MRI are used to confirm the finding of dense or non-dense indicated. It is understood that the above categorizations (A-D) for dense and non-dense determinations based on the BIA -based methods described are not particularly limiting and other categorizations may be used, as appropriate.

[0077] When the BIA -based methods described, and accompanying equation, are implemented and the determination is made that a woman has dense breasts, then such women can be advised they have the additional risk factor of dense breasts and they should prioritize gold-standard testing, per the USPSTF guidelines (mammogram), if they are younger than 40y they should discuss with their primary care provider the potential for earlier screening. In some instances, when the density of the subject’s breast tissue is classified as C or D = dense the method further comprises step (vi): recommending to the subject to pursue a mammography screening study. In some other instances, when the density of the subject’s breast tissue is classified as dense or non- dense, such as by mammogram or >70% dense area by MRI, the method further comprises step (vi’): recommending to the subject to pursue a mammography screening study.

[0078] In some instances, the cup of the attachment device is placed by a technician. In some other instances, the cup of the attachment device can be self-placed by the subject and placement confirmed by a technician.

[0079] The device for analyzing breast density can collect and measure impedance data radially and at varying depths of the breast. The device may provide, in addition to density information of the breast, information on the fat, fat free mass (FFM), and total water of the breast. A. Proposed Study Protocols

[0080] Custom designed cups for breast bioelectrical impedance analysis can be fabricated of, for example, custom silicone and the breast cups are used to measure the bioelectrical impedance of test subjects’ breast tissue. The cups will be fabricated, for example, from Liquid Silicone Rubber (LSR) poured into a custom designed 3D printed mold to cure at room temperature. Once the molds are fabricated they can be used to produce multiple cups requiring only the LSR compound, or other suitable material(s), for fabrication. One or more molds can be utilized for each of the breast cups sizes of A, B, C and D cups. In one instance, the mold(s) can be designed to accept four pairs of reusable Au / Ag electrodes with attached wires. The wires can be attached to a connector to allow for easy connection from the breast cup electrodes to a Bioelectrical Impedance Analyzer. The BIA unit can be a unit manufactured by RIL Systems, Inc. However, other commercial BIA units are known and could be used. It is also possible to make a single mold, fabricate one or more breast cups, install the electrodes, wiring and connector(s) so that the system can be evaluated for form, fit, and function.

[0081] In a proposed Phase I Study, the following non-limiting parameters can be used to selected test subjects:

[0082] N = 30 women

[0083] Blocked by cup size (B, C, D only for initial testing)

[0084] Inclusion criteria:

[0085] > 35 years of age

[0086] 6th - 10th day of menstrual cycle or > 12 months since last menstruation (i.e. post-menopausal)

[0087] No vigorous physical activity in prior 48hrs

[0088] No diuretic current use

[0089] No advanced heart disease, kidney disease, or heart failure

[0090] No valvular disease requiring surgery

[0091] No uncontrolled diabetes or endocrine disease

[0092] No clinically relevant fluid retention (i.e. edema, lymphedema) No implanted devices that use 50Hz.

[0093] Such a study can proceed according to the following parameters. In some instances, measures can be taken within 6th - 10th day of menstrual cycle or >12mo since last menstruation 2 x adapted RJL BIA analyses. Additional electrodes added to the device and fixed in the malleable breast cup. Source electrodes introduce current, preferred an alternating current at 50 Khz, once on each breast of the subject to determine the density of the breast as described using the attachment device and methods herein. After BIA analysis using the device, one standard mammogram or one MRI imaging study of the subject’s breasts are taken. Following, assessment of the correlation between device determined breast density vs gold standard imaging Mammographic density grade C&D or MRI fibroglandular density of >70% is made to validate the device determined breast density. Figure 3, shows a non-limiting exemplary flow diagram of the proposed study over a 1-2 day period. The study may vary from the flow diagram, as needed.

[0094] Further analyses may be made, such as, of the descriptive statistics for participant (subject) characteristics; intraclass correlation coefficients (ICC) to evaluate the reliability of the density estimates made from the BIA device tested, Pearson correlation coefficients between BIA device estimates of tissue density and gold standards, univariate analyses to assess value of each characteristic (i.e., age, race / ethnicity, BMI, cup size) and BIA device values for prediction of gold standard breast density; variables reaching p <0.10 to be selected for multivariate models, separate multivariate linear regression models can be derived to predict breast density by mammogram and MRI from the BIA variables and participant characteristics meeting the criteria, adjusted R2combined with the standard error of the estimate (SEE) and Akaike information criterion (AIC) can be used to select the best model for predicting breast density, the selected model can be internally validated using 500 bootstrap samples by the rms package in R, including correction of potential over-fitting and calibration, where model diagnostics based on residuals can be performed on the selected model to identify any potential violation of the assumptions behind the model, and confirmation can be made of the model hypothesized to optimally predict breast density: independent variables = age, BMI, breast cup size, race, ethnicity, BIA resistance, and BIA reactance; dependent variable either MRI or mammographic density grades, as noted above.

[0095] The invention can be further understood in view of the following non- limiting paragraphs.

[0096] 1. An attachment device for analyzing breast density, the device comprising: a cup for placement onto a subject’s breast; a plurality of positive and negative electrodes embedded in the cup; wherein the plurality of positive and negative electrodes can each be independently connected to a bioelectrical impedance analyzer.

[0097] 2. The attachment device of paragraph 1, wherein the cup is formed of a malleable material, such as silicone. 3. The attachment device of any one of paragraphs 1-2, wherein the cup has a size determined based on the subject’s breast cup size.

[0098] 4. The attachment device of any one of paragraphs 1-3, wherein the plurality of positive and negative electrodes is embedded radially in the cup.

[0099] 5. The attachment device of any one of paragraphs 1-4, wherein the plurality of positive and negative electrodes is embedded at variable depths in the cup.

[0100] 6. The attachment device of any one of paragraphs 1-5, wherein the plurality of positive and negative electrodes comprise an exposed contact surface which can directly contact the subject’s breast tissue.

[0101] 7. A method for analyzing breast density of a subject, the method comprising the steps of:

[0102] (i) placing the attachment device of any one of claim 1-6 on the subject’s breast; wherein the plurality of positive and negative electrodes are connected to a bioelectrical impedance analyzer;

[0103] (ii) applying an alternating electrical current from the bioelectrical impedance analyzer, at one or more frequencies, through tissue of the subject’s breast using the plurality of positive and negative electrodes;

[0104] (iii) measuring the impedance, which is a sum of resistance (R) and reactance (Xc) of the subject’s breast tissue, at the one or more frequencies with the bioelectrical impedance analyzer; and

[0105] (iv) analyzing the impedance using an algorithm to determine density of the subject’s breast tissue.

[0106] 8. The method of paragraph 7, wherein the bioelectrical impedance analyzer is a commercially available bioelectrical impedance analyzer.

[0107] 9. The method of any one of paragraphs 7-8, wherein the one or more frequencies are in a range from about 5 to 1000 kHz.

[0108] 10. The method of any one of paragraphs 7-8, wherein the one or more frequencies is at about 50 kHz.

[0109] 11. The method of any one of paragraphs 7-10, wherein the algorithm for calculating the density of the subject’s breast tissue is based according to the following formula:

[0110] Breast density = [intercept + 1 x (cupsize2 / R) + 02 x BMI + 03 x Xc + 04 x age + 05 x Ethnicity + 06 x Race] wherein the intercept and 0 values (0i ; 02 ; 03 ; 04 ; 05 ; 06) are determined from the data produced by the BIA device upon use; wherein R= resistance;

[0111] Xc = reactance;

[0112] BMI is the body mass index of the subject (weight, kg / height, cm2);

[0113] Age is the subject’s age;

[0114] Cupsize is an integer value from 1-4 (wherein A cup = 1, B cup = 2, C cup = 3, or D cup = 4);

[0115] Ethnicity is an integer value from 0-1 (wherein if the subject is not hispanic = 0 and if the subject is hispanic =1; and

[0116] Race categories numbered 1-z depending on participants.

[0117] 12. The method of any one of paragraphs 7-11, the method further comprises step (v), following step (iv), of classifying the calculated density of the subject’s breast tissue on a four- level class scale, wherein:

[0118] (a) fatty, (b) scattered fibroglandular density, (c) heterogeneously dense, or d) extremely dense.

[0119] 13. The method of paragraph 12, wherein when the density of the subject’s breast tissue is classified as (c) or (d) and the method further comprises step (vi): recommending to the subject to pursue a mammography screening study.

[0120] 14. The method of any one of paragraphs 7-11, the method further comprises step (v), following step (iv), of classifying the calculated density of the subject’s breast tissue as dense or non-dense.

[0121] 15. The method of paragraph 14, wherein when the density of the subject’s breast tissue is classified as dense or non-dense and the method further comprises step (vi): recommending to the subject to pursue a mammography screening study.

[0122] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

[0123] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific instances of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMSI claim:

1. An attachment device for analyzing breast density, the device comprising: a cup for placement onto a subject’s breast; a plurality of positive and negative electrodes embedded in the cup; wherein the plurality of positive and negative electrodes can each be independently connected to a bioelectrical impedance analyzer.

2. The attachment device of claim 1 , wherein the cup is formed of a malleable material, such as silicone.

3. The attachment device of claim 1, wherein the cup has a size determined based on the subject’s breast cup size.

4. The attachment device of claim 1 , wherein the plurality of positive and negative electrodes is embedded radially in the cup.

5. The attachment device of claim 1, wherein the plurality of positive and negative electrodes is embedded at variable depths in the cup.

6. The attachment device of claim 1 , wherein the plurality of positive and negative electrodes comprise an exposed contact surface which can directly contact the subject’s breast tissue.

7. A method for analyzing breast density of a subject, the method comprising the steps of:(i) placing the attachment device of any one of claim 1-6 on the subject’s breast; wherein the plurality of positive and negative electrodes are connected to a bioelectrical impedance analyzer;(ii) applying an alternating electrical current from the bioelectrical impedance analyzer, at one or more frequencies, through tissue of the subject’s breast using the plurality of positive and negative electrodes;(iii) measuring the impedance, which is a sum of resistance (R) and reactance (Xc) of the subject’s breast tissue, at the one or more frequencies with the bioelectrical impedance analyzer; and(iv) analyzing the impedance using an algorithm to determine density of the subject’s breast tissue.

8. The method of claim 7, wherein the bioelectrical impedance analyzer is a commercially available bioelectrical impedance analyzer.

9. The method of claim 7, wherein the one or more frequencies are in a range from about 5 to 1000 kHz.

10. The method of claim 7, wherein the one or more frequencies is at about 50 kHz.

11. The method of claim 7, wherein the algorithm for calculating the density of the subject’s breast tissue is based according to the following formula:Breast density = [intercept + 1 x (cupsize2 / R) + 02 x BMI + 03 x Xc + 04 x age + 05 x Ethnicity + 06 x Race] wherein the intercept and 0 values (0i ; 02 ; 03 ; 04 ; 05 ; 06) are determined from the data produced by the BIA device upon use; wherein R= resistance;Xc = reactance;BMI is the body mass index of the subject (weight, kg / height, cm2);Age is the subject’s age;Cupsize is an integer value from 1-4 (wherein A cup = 1, B cup = 2, C cup = 3, or D cup = 4);Ethnicity is an integer value from 0-1 (wherein if the subject is not hispanic = 0 and if the subject is hispanic =1; andRace categories numbered 1-z depending on participants.

12. The method of claim 7, the method further comprises step (v), following step (iv), of classifying the calculated density of the subject’s breast tissue on a four-level class scale, wherein:(a) fatty, (b) scattered fibroglandular density, (c) heterogeneously dense, or d) extremely dense.

13. The method of claim 12, wherein when the density of the subject’s breast tissue is classified as (c) or (d) and the method further comprises step (vi): recommending to the subject to pursue a mammography screening study.

14. The method of claim 7, the method further comprises step (v), following step (iv), of classifying the calculated density of the subject’s breast tissue as dense or non-dense.

15. The method of claim 14, wherein when the density of the subject’s breast tissue is classified as dense or non-dense and the method further comprises step (vi): recommending to the subject to pursue a mammography screening study.

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