Abstract:
Methods for assessing a patient&#39;s risk of having or developing coronary heart disease based on lipoprotein measurements include: (a) generating an NMR spectroscopic signal of a blood plasma or serum sample of a patient; (b) measuring the values of a plurality of selected lipoprotein subclass constituents in the sample; (c) analyzing the measured values of the lipoprotein subclass constituents according to predetermined test criteria to identify when there is an increased and/or decreased risk of having and/or developing coronary heart disease associated with the measured lipoprotein subclass constituent values; (d) outputting the measured lipoprotein subclass values onto a report; (e) providing a plurality of risk analysis portions that depicts the identified risk of the measured lipoprotein subclass values from the predetermined test criteria analysis, a respective one for each measured lipoprotein subclass value, wherein each risk analysis portion defines a plurality of risk segments that are associated with lower, negative, or decreased risk and higher, positive, or increased risk, each risk segment associated with predetermined ranges of measured numerical values; (f) positioning the respective risk analysis portions in the report adjacent its measured corresponding lipoprotein subclass value; and (g) drawing a selectively adjustable perimeter line on the report so that it has an increased size, intensity and/or contrasting color for the risk segment associated with the measured lipoprotein subclass value relative to the non-associated risk segments for each risk analysis portion to visually enhance the identified risk and provide a contemporaneous risk assessment guide useful for interpretation of the risk associated with the measured values.

Description:
RELATED APPLICATIONS  
       [0001]    This application is a continuation of U.S. patent application Ser. No. 09/258,740, filed Feb. 26, 1999, the contents of which are hereby incorporated by reference as recited in full herein. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    The present invention relates generally to reporting and analyzing information related to patient-specific measured lipoprotein results.  
         BACKGROUND OF THE INVENTION  
         [0003]    Recently, a significant advance in measurement techniques used to analyze blood plasma lipoprotein samples was achieved. Lipoproteins are the spherical particles that transport cholesterol, trigylcerides, and other lipids in the bloodstream. The advanced measurement technique employs NMR spectroscopy to provide additional (higher order) increased patient-specific information over the types of information typically provided under routine conventional analysis methods. See U.S. Pat. No. 4,933,844 to Otvos, entitled “ Measurement of Blood Lipoprotein Constituents by Analysis of Data Acquired From an NMR Spectrometer”  and U.S. Pat. No. 5,343,389 to Otvos, entitled “ Method and Apparatus for Measuring Classes and Subclasses of Lipoproteins.”  The contents of these documents are hereby incorporated by reference as if recited in full herein. Unlike conventional “routine” type laboratory lipoprotein blood tests, the lipoprotein analysis provided by the NMR spectral analysis now more easily provides lipoprotein subclass information, which had, until this advance, been generally inaccessible to clinicians. This subclass information can provide information corresponding to the sizes of the lipoprotein particles that make up a person&#39;s lipoprotein constituents.  
           [0004]    Lipoprotein subclass information is not part of conventional lipid panels. The conventional panels typically only provided information concerning total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol (generally a calculated value), and high-density lipoprotein (HDL) cholesterol. In contrast, the NMR analysis can provide information about (a) the concentrations of six subclasses of very low density lipoprotein (VLDL), four subclasses of LDL (including intermediate-density IDL), and five subclasses of HDL, (b) average LDL particle size (which can be used to categorize individuals into LDL subclass pattern-determined risk), and (c) LDL particle concentration.  
           [0005]    The subclass information now available with the NMR spectral analysis can be a more reliable indicator of a patient&#39;s risk to develop coronary heart disease. Indeed, recent scientific research has shown that various subclasses of lipoproteins may provide more reliable markers of the metabolic conditions that predispose individuals to a greater or lesser risk of heart disease. However, the NMR spectral analysis can also provide higher-order information about the levels of variously atherogenic or antiatherogenic subclasses that make up each of the major lipoprotein classes.  
           [0006]    This subclass information can provide a clear indication about a patient&#39;s propensity to develop coronary heart disease. Unfortunately, this additional information can confuse a reviewer as to the meaning of the data, and further, the additional information can be difficult to analyze in a readily discernable manner. For example, a typical NMR lipoprotein analysis can include at least fifteen more values of lipoprotein concentration and size than is provided by standard lipoprotein panels. There is, therefore, a need to analyze and present the lipoprotein-based information in a manner or format which is visually easy to read and understand.  
         OBJECTS AND SUMMARY OF THE INVENTION  
         [0007]    It is therefore an object of the present invention to provide a lipoprotein profile analysis with subclass information with an easily read display format.  
           [0008]    It is also an object of the present invention to provide a lipoprotein-based risk assessment which analyzes a patient&#39;s measured major lipoprotein constituent values and selected subclass information and presents them in a format in which a patient&#39;s specific values are presented in a reader-friendly format.  
           [0009]    It is a further object of the present invention to provide a method of generating a custom report at a commercial volume and which can analyze and/or report a patient&#39;s risk factors for certain diseases based on NMR spectra of lipoprotein constituents and constituent subclasses.  
           [0010]    These and other objects of the present invention are provided by a method for providing and presenting or displaying a customized patient-specific lipid analysis profile with a risk assessment portion for the measured results. In particular, a first aspect of the present invention is directed to a method for providing personalized lipoprotein-based risk assessment information. The method includes the step of generating NMR-based lipoprotein measurement values for a patient&#39;s blood plasma or serum sample, the lipoprotein measurement values including at least one subclass variable value. The at least one patient lipoprotein subclass measurement variable value is compared with predetermined test criteria to determine whether the at least one subclass variable value is associated with a higher or lower risk of developing coronary heart disease. The method also identifies what the level of coronary heart disease risk is for the at least one measured subclass variable value. The lipoprotein measurement values are presented in a two-dimensional window such that each of the lipoprotein measurement values are visually enhanced. A risk analysis portion is provided adjacent to the measured lipoprotein values, the risk analysis portion displaying information related to a range of values corresponding to higher and lower coronary heart disease risk. The measured value is visually enhanced in the risk analysis portion to indicate the level of risk associated therewith to thereby provide a contemporaneous reference guideline for interpretation of the measured value. Preferably, the lipoprotein measurement values are presented such that each of the lipoprotein measurement values is substantially vertically aligned and the risk analysis portions are also substantially vertically aligned.  
           [0011]    Another aspect of the present invention is directed to a method of presenting NMR derived lipoprotein subclass information in a two-dimensional window. The method includes the steps of obtaining lipoprotein information having a plurality of lipoprotein subclass variable values associated with NMR derived lipoprotein analysis and identifying a risk level associated with coronary heart disease for each of the obtained subclass variable values. The obtained lipoprotein information with subclass values is analyzed to determine the associated risk level. Each of the obtained lipoprotein subclass variable values is arranged in a display format which positions the lipoprotein subclass values adjacent to a corresponding risk analysis portion. The risk analysis portion characterizes the subclass variable value&#39;s determined risk level and visually enhances the subclass variable value within the respective risk analysis portion such that the risk associated with the lipoprotein subclass variable value is readily apparent.  
           [0012]    An additional aspect of the present invention is an automated lipoprotein report including data corresponding to NMR-derived measurements. The report comprises a first lipid profile segment comprising a plurality of NMR derived major lipoprotein constituent values, each major lipoprotein value having an associated risk analysis portion and a second subclass profile segment comprising a plurality of NMR-derived subclass variables, each subclass variable having an associated risk analysis portion which is configured to visually enhance the risk of developing coronary heart disease for each of said plurality of subclass values, wherein the lipoprotein report is generated at a commercial volume by a computer based on NMR derived patient-specific values.  
           [0013]    In a preferred embodiment, each of the major constituent lipoprotein risk analysis portions identifies three risk categories associated therewith. It is also preferred that the risk analysis portion for a plurality of the subclass values is presented as a horizontally extending linear bar graph which graphically represents the subclass value relative to a continuum of low to high risk of developing CHD.  
           [0014]    Similar to the above-described aspect, another aspect of the present invention is directed to an automated lipoprotein subclass report which is generated at a commercial laboratory. The subclass report is based on and includes data corresponding to NMR-derived measurements and comprises a subclass profile segment with a plurality of patient-specific NMR derived subclass variables. Each subclass variable has a value and has an adjacently positioned associated risk analysis portion which visually identifies in graphic and verbal form, a risk level associated with the subclass value.  
           [0015]    In a preferred embodiment, the lipoprotein subclass report subclass profile segment includes the average of the LDL size. The associated risk analysis portion presents the LDL size as one of three patterns, Pattern A corresponding to lower risk, Pattern B corresponding to higher risk, and Pattern AB corresponding to an intermediate risk. The LDL size classification is identified in the risk analysis portion by visually enhancing the respective pattern associated with the patient-specific LDL size value.  
           [0016]    Another aspect of the present invention is directed to computer program products for providing personalized lipoprotein-based risk assessments and reports. The computer program product comprises a computer readable storage medium having computer readable program code means embodied in the medium, the computer-readable program code means comprises computer readable program code means for generating NMR-based lipoprotein measurement values for a patient&#39;s blood sample, the lipoprotein measurement values including at least one subclass variable value. The computer program product also includes computer readable program code means for comparing the at least one patient lipoprotein subclass measurement variable value with predetermined test criteria for determining whether the at least one subclass variable value is associated with a higher or lower risk of developing coronary heart disease. The product additionally includes computer readable program code means for identifying, for the at least one measured subclass value, the corresponding risk level associated with coronary heart disease and computer readable program code means for providing a risk analysis portion adjacent the measured lipoprotein values, the risk analysis portion displaying information related to a range of values and corresponding to higher and lower coronary heart disease risk. The risk analysis program code means is configured to present the measured value such that it is visually enhanced in the risk analysis portion to visibly indicate the level of risk associated therewith to thereby provide a contemporaneous reference guideline for interpretation of the measured value.  
           [0017]    Another aspect of the present invention is directed to a computer program product for providing a lipoprotein subclass report.  
           [0018]    Preferably, for the reports, methods, and computer program products directed to lipoprotein information, the measured lipoprotein values include (a) the major lipoprotein constituents of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides and (b) the LDL size and the levels of LDL particles, large HDL cholesterol, and large VLDL triglyceride.  
           [0019]    The present invention is advantageous because it provides NMR-derived lipoprotein results with associated risk information in a format that is easy to understand and aesthetically pleasing. Further, the patient&#39;s specific subclass profile is presented in the risk assessment report in a graphically enhanced or visually emphasized format so the clinician or layman can easily understand the risk category associated with one or more of a patient&#39;s subclass values. Further, the customized report is provided in a computer program product allowing mass or commercial level automated production of a summary report which includes a risk analysis portion which can be customized to report the patient&#39;s results in a visually enhanced format. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0020]    [0020]FIG. 1 illustrates a lipoprotein summary report according to the present invention.  
         [0021]    [0021]FIG. 2 illustrates a risk assessment report according to one embodiment of the present invention which may be included in or provided separate from the lipoprotein summary report of FIG. 1.  
         [0022]    [0022]FIG. 2A illustrates an alternative embodiment of the risk report shown in FIG. 2.  
         [0023]    [0023]FIG. 3 illustrates a lipid profile segment of the lipoprotein summary report of FIG. 1.  
         [0024]    [0024]FIG. 4 illustrates a subclass profile segment of the lipoprotein summary report of FIG. 1.  
         [0025]    [0025]FIG. 5 illustrates a supplemental risk factor segment of the risk assessment report of FIG. 2.  
         [0026]    [0026]FIG. 6 illustrates a subclass level risk assessment segment for the risk assessment report of FIG. 2.  
         [0027]    [0027]FIG. 7 illustrates a primary prevention risk assessment segment of the risk assessment portion of FIG. 2.  
         [0028]    [0028]FIG. 7A illustrates a prevention risk assessment segment having positive risk factors identified as negative numbers to be added to negative risk factors having positive numbers such as those shown in FIG. 7 to provide an overall adjusted risk assessment according to the present invention.  
         [0029]    [0029]FIG. 8 illustrates a secondary risk segment including information regarding high-risk medical conditions for the risk assessment report of FIG. 2A.  
         [0030]    [0030]FIG. 9 is a graphic illustration of alternative embodiment of subclass information and associated positive or negative risk with coronary heart disease.  
         [0031]    [0031]FIG. 10 is a flow chart of a method which analyzes and presents NMR derived lipoprotein information according to the present invention. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0032]    The present invention now will be described more fully hereinafter with reference to the accompanying drawings, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like numbers refer to like elements throughout.  
         [0033]    Referring now to FIG. 1, a preferred embodiment of a NMR lipoprotein profile summary report  10  is shown. Preferably, the lipoprotein profile summary report  10  is divided into at least three horizontally oriented segments  20 ,  30 ,  40 . The first segment  20  of the summary report  10  includes patient identification data  21  such as a name, identification number, and any relevant personal history such as age, smoking status, and other related medical history. As shown, the first segment  20  can also include physician data  22  and a comment section  23 . The second segment  30  of the summary report  10  presents the lipid profile analysis and will be discussed further below. The third segment  40  of the summary report  10  presents the subclass profile analysis and will also be discussed further below.  
         [0034]    As shown in FIG. 2, the summary report  10  can also include a risk assessment report  10 ′ containing information targeted to a more detailed risk assessment. Of course, the summary report  10  and the risk assessment report  10 ′ as well as individual segments of each can be individually reported, presented or provided. In any event, as shown, the risk assessment report  10 ′ includes a fourth segment  50  which presents supplemental risk factors, and a fifth segment  60  containing individual lipoprotein subclass levels. The summary report  10  can also include an optional sixth segment  70  which can incorporate primary prevention risk assessment information which can predict long term (i.e., 10 year) coronary heart disease (CHD) risk percentages.  
         [0035]    As shown in FIG. 2A, a risk assessment report  10 ″ can also include a seventh segment  80  directed to secondary prevention guidelines which can summarize high risk conditions and characterizations, such as atherosclerotic vascular disease and diabetes, and general lipid management goals. This secondary prevention information may be help assist medical personnel in alternative treatment and to alert as to potential high-risk behavior or conditions. As shown, the risk assessment report is rearranged to present the fourth segment  50 , the sixth segment  60 , and the seventh segment  80 . The information in this sample risk assessment report  10 ″ is from a different patient than the results shown in FIGS. 1 and 2.  
         [0036]    In a preferred embodiment, the major lipoprotein constituent values and the selected subclass values are generated via the NMR spectral analysis discussed above. The data are typically obtained by processing a blood plasma or serum sample obtained from a subject. As such, as used herein the terms “blood” and “plasma and “serum” sample are interchangeable, as each is suitable for obtaining the desired NMR spectroscopy signal.  
         [0037]    Turning now to FIG. 3, a preferred embodiment of the lipid profile or second segment  30  of the summary report  10  is shown. The patient-specific lipid value results of total cholesterol  31 , LDL cholesterol  32 , HDL cholesterol  33 , and triglycerides  34  are listed and arranged in aligned order from a top portion  30   a  of the second segment to a bottom portion  30   b  of the second segment. Preferably, alongside the listed order of the total cholesterol, LDL, HDL, and triglycerides,  31 ,  32 ,  33 , and  34 , respectively, the associated actual measured values  31   a ,  32   a ,  33   a , and  34   a  are also serially aligned. Preferably, the values  31   a ,  32   a ,  33   a ,  34   a  are each displayed in a box  31   b ,  32   b ,  33   b ,  34   b . Of course, the values  31   a ,  32   a ,  33   a , and  34   a  may otherwise be presented, but are preferably presented in a visually enhanced format (such as via bold, italics, shaded, font (size, type), circled, underlined, colored or highlighted by other visual enhancement means) to provide ready visual recognition of the patient-specific results.  
         [0038]    As is also shown in FIG. 3, the second segment  30  also preferably includes risk assessment guidelines  35  which represent a relative reference, guideline, or “yardstick” of the patient&#39;s value as compared to targeted values. Preferably, the risk assessment guidelines  35  divide the respective measured patient value for each of the total cholesterol  31 , LDL  32 , HDL  33 , and triglycerides  34  into three different categories  36  of risk associated with a predetermine range of values (shown as measured in mg/dL). These predetermined range of values are based on predetermined test criteria.  
         [0039]    As shown, the three categories for total cholesterol  31  and LDL  32  are labeled desirable  36   a , borderline-high  36   b , and high  36   c . As shown, for total cholesterol  31 , the desirable  36   a  category is defined as a value less than 200. For LDL  32 , the desirable category  36   a , is defined as a value less than 130. The borderline-high category  36   b  is defined as a range of values between 200-239 for total cholesterol  31  and between 130-159 for LDL  32 . The high category  36   c  is defined as 240 or greater for total cholesterol  31  and 160 or greater for LDL  32 .  
         [0040]    Referring again to FIG. 3, the HDL categories  36  are labeled as negative risk factor  36   d , intermediate  36   e , and positive risk factor  36   f . The negative risk factor  36   d  is defined as a value of 60 or greater, the intermediate risk category  36   e  is defined as a value between and including 35-59, and the positive risk factor  36   f  is defined as a value less than 35.  
         [0041]    The triglycerides categories  36  are labeled as normal  36   g , borderline-high  36   h , and high  36   i . The normal category  36   g  is defined as a triglyderides value  33  of less than 200, the a borderline-high category  36   h  is defined a value between 200-400, and the high category  36   i  is defined as a value greater than 400 (but typically below 1000).  
         [0042]    Preferably, the predetermined test criteria or targeted or ranges of values associated with each category of risk  36   a - 36   i  are defined to correspond to current National Cholesterol Education Program (NCEP) guidelines for primary prevention of coronary heart disease. See National Cholesterol Education Program,  Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults  ( Adult Treatment Panel II ), Circulation 1994; 89:1329-1445. Of course, other suitable values or definitions can also be used, such as population based norms or other targeted based norms.  
         [0043]    Preferably, as shown in FIGS. 1 and 3, the risk category  36  which corresponds to the patient value is visibly enhanced so that a reader can readily discern the category associated with the patient specific result (i.e., a visually enhanced risk category  38 ). For example, a person reviewing the patient-specific results shown in FIG. 3 can readily discern that the patient results indicate that the patient is “high risk” in one category (LDL cholesterol  32 ), intermediate/borderline in two categories (cholesterol  31  and HDL cholesterol  33 ), and desirable in the other category (triglycerides  34 ). Further, a reviewer could readily discern how close the measured value is to the next adjacent risk category for each value  31 ,  32 ,  33 ,  34 , which can also facilitate a more complete understanding of the results.  
         [0044]    Preferably, as shown, the risk assessment  35  is formatted so that the three risk categories  36  for each measured value are similarly sized and configured and are arranged serially over or under the adjacent measured value. In this way, each of the categories  36  for each measured value is positionally vertically aligned. The “low” or “negative/good” risk values  36   a ,  36   d ,  36   g  are positioned on one edge of a risk bar  36 ′ and the “high” or “bad/positive” risk values  36   c ,  36   f ,  36   i  are positioned at the opposing edge of the risk bar  36 ′. This presentation yields an aesthetic, easily readable format and informational horizontal continuum of risk characterization associated with the patient&#39;s results. As is also shown, the summary report  10  (or one or more of the segments  20 ,  30 ,  40 ) can include a descriptive comment portion  39  which discusses slight differences which may be observed from NMR spectral measurements compared to conventional or standard tests.  
         [0045]    Turning now to FIG. 4, a preferred embodiment of the third segment  40  of the summary report  10  presenting the subclass profile is shown. The third segment  40  preferably includes four measured subclass variables, the subclass variables being labeled as LDL size  41 , LDL particles  42 , large HDL cholesterol  43 , and large VLDL triglyceride  44 . The LDL size value  41   a  is shown as measured in nanometers (nm). The LDL particles value  42   a  is shown as measured in nano-moles per liter (nmol/L) while the large HDL cholesterol value  43   a  and the large VLDL triglyceride value  44   a  are measured in milligrams per deciliter (mg/dL).  
         [0046]    As for the lipid profile results discussed for the second segment  30  above, each of the measured values  41   a ,  42   a ,  43   a ,  44   a  are preferably presented in a visually enhanced manner  41   b ,  42   b ,  43   b ,  44   b  (the results are shown as visually enhanced or offset by a frame or box).  
         [0047]    In a preferred embodiment, the third segment  40  also includes a risk assessment portion  46  where the measured results  41   a ,  42   a ,  43   a , and  44   a  are visually enhanced and related or compared to predetermined criteria or values. For example, the LDL size result  41   a  is associated with three risk categories  46   a ,  46   b ,  46   c . The risk categories  46   a ,  46   b ,  46   c  are defined by a pattern (A, AB, or B, respectively) associated with the particle size. The first category  46   a  is Pattern A, which is defined as a lower risk pattern associated with large particle sizes of 20.6-22.0. The second category  46   b  is Pattern AD which is defined as an intermediate risk and corresponds to a particle size of 20.4-20.5. The third risk category  46   c  is Pattern B and is defined as a higher-risk category and corresponds to smaller particle sizes of between 19.0-20.3.  
         [0048]    As shown, the remaining subclass measured values  42   a ,  43   a ,  44   a , are displayed on a horizontally oriented line graph  46 ′. Preferably, each line graph  46 ′ plots the patient&#39;s results to illustrate whether the result indicates a higher or lower risk of CHD. In the embodiment shown, the graph is used to compare the patient measured result against a percentage of the general population having higher or lower levels of the measured value. Preferably, as shown, the line graphs  46 ′ are plotted such that the results show a greater risk aligned at the right edge of the graph  46 ′. Stated differently, whether a higher or lower value indicates a higher risk of CHD, each of the line graphs  46 ′ are defined to present the measured value such that the higher risk of CHD is at the same edge of the line graph and the higher and lower risks are thus visually aligned.  
         [0049]    For example, the LDL particles  42   a  and the large VLDL triglyceride values  44   a  are graphed corresponding to percentage of the population having lower values  42   c ,  44   c  while the large HDL value  43   a  is graphed corresponding to the percentage of population having a higher value  43   c . Nonetheless, as shown, the line graphs  46 ′ are oriented and plotted such that the higher risk of CHD is aligned along the right end portion of the line graph. As shown, the patient results illustrate that 94% of the population has a lower LDL particle value  42   a,  71% of the population has a higher large HDL value  43   a , and 78% of the population has a lower large VLDL trigylceride  44   a  level.  
         [0050]    In a preferred embodiment, the population values are based on scientific results obtained from subjects in the Framingham Offspring Study. See Wilson et al.,  Impact of National Guidelines for Cholesterol Risk Factor Screening. The Framingham Offspring Study,  JAMA, 1989; 262: 41-44. Of course the values presently defined for the risk assessment  36 ,  46  portion of the summary may change over time and more or alternate risk categories may be added. Further, the actual ranges or definitions associated with the risk category values of one or more of the lipid panels or subclass categories may change over time and the present invention is not intended to be limited thereto.  
         [0051]    The order of the measured values  31   a ,  32   a ,  33   a ,  34   a ,  41   a ,  42   a ,  43   a , and  44   a  may be alternately arranged in the summary report  10 . In addition, the layout of the results may be alternately oriented (such as in vertical segments). Of course, the second segment  30  (lipid profile) or the third segment  40  (subclass profile) may be provided alone depending on a customer&#39;s specifications.  
         [0052]    It is also preferred that the report include a discussion of “flagged” or potential increased risk factors identified by the subclass values  41   a ,  42   a ,  43   a ,  44   a  as compared to predetermined risk assessment criteria. For example, as shown in FIG. 5, a supplemental risk factor segment  50  can be included in the summary report  10 ′. The supplemental segment can include a preliminary informational introduction  50   a  which notes that coronary heart disease risk can significantly increase when there is a clustering of metabolic abnormalities not detected by standard lipid measurements. The supplemental risk segment  50  summarizes the presence of a metabolic profile associated with a higher level of risk than indicated by the LDL cholesterol value  32   a . In a preferred embodiment, the “clustering” is indicated by a mark  51   a ,  52   a ,  53   a ,  54   a  in a corresponding subclass box  51   b ,  52   b ,  53   b ,  54   b.    
         [0053]    As shown, this supplemental risk factor segment  50  includes a summary  50 ′ for subclass values indicating abnormalities which indicate increased risk, i.e., Pattern B small LDL  51 , elevated number of LDL particles  52 , low level of large HDL  53 , and elevated level of large VLDL  54 . As shown, if the summary  50 ′ is selected (shown as positive with a “check mark” proximate to the category), then the CHD risk is increased. An informational guideline  51   c ,  52   c ,  53   c ,  54   c , for the abnormal values is positioned proximate to the subclass box.  
         [0054]    In an alternative embodiment (not shown), a computer program can be configured to provide the analysis and risk assessment in a manner in which it can suppress non-abnormal results and provide only abnormal results in this segment  50 ′. Thus, if a patient has two “abnormal” or elevated risk values associated with the subclass readings, then only those two subclasses will be printed on this segment  50  of the summary report  10 .  
         [0055]    In any event, as indicated for the small LDL variable  51 , small LDL size (Pattern B) is a hallmark of the “atherogenic lipoprotein phenotype” and confers approximately a three-fold higher risk compared to the large LDL trait (Pattern A). There is evidence that suggests that small LDL particles may be inherently more atherogenic than large LDL. As regards an elevated number of LDL particles  52  (shown as for a value corresponding to the upper 33% of the population), unlike LDL cholesterol, LDL particle concentration (related closely to plasma apo B level), may be the single best indicator of LDL-associated CHD risk and the best target of risk reduction therapy. See Lamarche et al., Circulation 1996; 94:273-278. The supplemental risk factor segment  50  can also indicate the presence of low levels of large HDL  43 . Low levels of large HDL  43  (shown as a value corresponding to the lower 33% of the population) may be a positive risk factor, as only larger HDL subclass particles appear to protect against CHD—whereas small HDL may even be atherogenic. Therefore, large HDL, rather than total HDL cholesterol, may be a more sensitive risk factor. See Freedman et al., Arterioscler. Thromb. Vasc. Biol. 1998; 18:1046-53. Similarly, as shown, elevated levels of large triglyceride rich VLDL particles  54 , appear to be associated with coronary artery disease (CAD) severity, substantially independent of plasma triglycerides. High concentrations of large VLDL in fasting plasma may be a marker for delayed chylomicron clearance (postprandial lipemia).  
         [0056]    As shown in FIGS. 2 and 6, the summary report  10  may also include a fifth segment  60  showing a graphical representation of the subclass levels provided by NMR analysis. Referring to FIG. 6, the fifth segment  60  divides the information into three groups of subclasses, VLDL triglyceride subclasses  61 , LDL cholesterol subclasses  62 , and HDL cholesterol subclasses  63 . Each of the three subclasses  61 ,  62 ,  63  are further divided to graphically portray selected or grouped results. As shown, the VLDL triglyceride subclass  61  is divided into three groupings, a large VLDL subclass  61   a  (shown with a concentration or value of 30), a medium VLDL subclass  61   b  (shown with a value of 74), and a small VLDL subclass  61   c  (shown with a value of 4). The LDL subclasses  62  shown in FIG. 6 include an IDL cholesterol subclass  62   a  (shown with a value of 9), a large LDL cholesterol subclass  62   b  (shown with a value of 31), a medium LDL cholesterol subclass  62   c  (shown with a value of 15), and a small LDL cholesterol subclass  62   d  (shown with a value of 110). The HDL subclasses shown are large HDL cholesterol  63   a  (shown with a value of 21) and small HDL  63   b  (shown with a value of 21 For each subclass level shown  61   a - c ,  62   a - d ,  63   a - b , the level measured in mg/dL are provided in text form at the top of the respective bar. The height of the bar gives the percent of population with lower levels of the graphed value. Advantageously, the HDL cholesterol subclass grouping can visually indicate the breakdown of the constituents of the overall HDL class  33  (value 42) shown on the summary report  10  to indicate the correspondence between the two subclasses to the overall HDL number. As shown, the results indicate an even amount of small HDL cholesterol  63   b  versus large HDL cholesterol  63   a . Of course, other groupings or different subclass information may be separated out such as the separable subclass information shown in FIG. 9, as will be discussed further below.  
         [0057]    The risk assessment report  10 ′ may also include a sixth segment  70  addressing the primary prevention risk assessment for an individual. Referring to FIG. 7, the sixth segment  70  incorporates certain behavioral and medical background of an individual with the lipid profile and subclass values. For example, a patient&#39;s age, smoking history, blood pressure, LDL value  32  and HDL value  33 , and whether he or she has diabetes, and/or other risk pertinent information such as whether a blood relative has diabetes or CHD. A risk factor value is assigned to each of these parameters. Additionally, positive risk factors can be assigned a negative risk value (FIG. 7A). Examples of positive risk factors include whether the patient actively exercises at least three days per week, has a high HDL cholesterol level  33   a , has a Pattern A LDL size  41   a , and has elevated levels of large HDL  43   a ). The positive and negative risk factors can be added to yield an overall risk value. In any event, a percentage based predictive CHD risk is generated corresponding to the total calculated risk. A target norm for the patient&#39;s age and gender can also be provided. In a preferred embodiment, the relative “negative” risk factors and predictive analysis is generated as described by Wilson et al., in  Prediction of Coronary Heart Disease Using Risk Factor Categories,  May 12, 1998 (copyright 1998 American Heart Association, Inc.).  
         [0058]    As also shown in FIG. 7, the risk of coronary heart disease is presented in several different percentage-based risk evaluations. A first risk  76   a  is as indicated by the risk point total. A second risk  76   b  is a “desirable risk”, i.e. the risk associated a non-smoking, non-diabetic person of the same gender and age having optimal blood pressure (less than 120/80), LDL cholesterol of 100-129 mg/dL, and HDL cholesterol of 55 mg/dL. A third risk  76   c  is a “projected” risk to provide an age accounting balancing of risk (age typically being the single largest risk contributor as indicated in the risk factor chart). Thus, the third risk  76   c  evaluation can help provide a helpful basis for managed care assessment. A fourth risk  76   d  can also be included to provide a desirable risk at age 60 (one indicative of only age-related risk conditions). The age standard for persons under the 60 year mark can establish a more clear assessment of the risk a person with the measured values has for coronary heart disease. Advantageously, a patient may take more immediate steps to attempt to reduce the indicated exposure risk when presented with a longer-term standard reference risk.  
         [0059]    The summary report  10 ″ may also include a seventh segment  80  which is directed toward secondary prevention guidelines. As shown in FIG. 8, the sixth segment presents a discussion  80   a  on special risk considerations for patients with established coronary heart disease, other atherosclerotic vascular disease, or diabetes. These patients are considered to be at particularly high risk as measured by the NCEP guidelines. For patients having one or more of these conditions, the present recommendations are lipid management to reduce LDL cholesterol to under 100 mg/dL. The corresponding NMR LDL particle concentration target is 1100 nmol/L. For patients with small LDL (Pattern B) and a clustering of the supplemental risk factors  50  discussed above, it can be especially important to reach these LDL goals. Smoking cessation, increased exercise, healthy diet, and blood pressure control can also be considered important treatment goals.  
         [0060]    [0060]FIG. 9 graphically illustrates some of the subclass information provided by NMR analysis according to the present invention. This graph also shows the present medical understanding of the relationship between various lipoprotein subclass levels and CHD risk. The plus signs represent a positive association with disease (larger size signs indicating subclasses conferring higher risk). The higher levels indicating a higher risk. The minus signs represent a negative association, higher levels equals a lower risk. In a preferred embodiment, certain of the individual subclass information shown is combined with other subclass information shown to provide the subclass groupings described above for FIG. 6.  
         [0061]    As discussed above, a preferred embodiment of the summary report  10  includes portions of the subclass information shown in FIG. 8 ( 42 ,  43 ,  44 ) and also includes LDL size  41 . Of course, the summary report  10  can include other subclass information within the scope of this invention. Advantageously, the instant reporting system and product can be used to provide important patient-specific information in an easy to assess manner and can be generated on a mass commercial production basis. Of course, some or part of this information may be presented in a computer readable medium or hard or paper report.  
         [0062]    [0062]FIG. 10 illustrates a flow chart of methods, apparatus (systems) and computer program products according to the invention. It will be understood that each block of the flowchart illustration, and combinations of blocks in the flowchart illustrations, can be implemented by computer program instructions. These computer program instructions may be loaded onto a computer or other programmable data processing apparatus to produce a machine, such that the instructions which execute on the computer or other programmable data processing apparatus create means for implementing the functions specified in the flowchart block or blocks. These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instruction means which implement the function specified in the flowchart block or blocks. The computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions specified in the flowchart block or blocks.  
         [0063]    Accordingly, blocks of the flowchart illustrations support combinations of means for performing the specified functions and program instruction means for performing the specified functions. It will also be understood that each block of the flowchart illustrations, and combinations of blocks in the flowchart illustrations, can be implemented by special purpose hardware-based computer systems which perform the specified functions or steps, or combinations of special purpose hardware and computer instructions.  
         [0064]    As shown in FIG. 10, lipoprotein measurement values are obtained from a patient or subject, the values include at least one subclass value (Block  810 ). Preferably, an NMR spectral analysis is performed on a blood plasma sample and the lipoprotein values measured include the major lipoprotein constituents (total cholesterol, HDL, LDL, and triglycerides) as well as selected subclass values. The patient specific at least one subclass value is compared to predetermined test criteria to determine whether the value is associated with a higher or lower risk of developing coronary heart disease (Block  820 ). Preferably, the test criteria employed for the lipoprotein results (including the lipoprotein subclass values) correspond to a defined level of risk (low to high) of developing CHD. Preferably, the predetermined test criteria are based on scientific target “norms” or population based norms associated with higher or lower risks of CHD. These values may change over time or can be alternately identified for patients with increased secondary risk factors.  
         [0065]    For example, if a patient has established CHD, athersclerotic vascular disease, and/or diabetes, the “risk” criteria and values of certain constituents or subclasses may be lowered on the summary report relative to a patient without said identified diseases such that a “high” risk value may be associated with a lower value (optional Block  830 ). This report&#39;s ability to automatically adjust or lower the risk value based on preexisting conditions can help alert the physician that this patient is subject to stricter lipid management or protocol by visually indicating the lower risk factor value targeted for this individual. Generally, the test criteria may be set in a controlled revision software format which can be updated as NCEP guidelines or current medical analysis updates risk related information or values.  
         [0066]    As shown in FIG. 10, the next step is to determine the level of risk associated with the lipoprotein subclass value(s) (i.e., whether it is identified as being associated with increased-risk (and/or reduced-risk) of developing coronary heart disease) (Block  840 ). The NMR spectroscopy measured lipoprotein results are presented with a risk category associated with the measured result visually enhanced in a two-dimensional window for easy recognition thereof (Block  850 ). The two-dimensional window can be a display section on a computer screen, display monitor, or electronic or hard copy or a commercial report portion or segment. Advantageously, the customized display or report can be automatically generated or mass produced such as at a commercial facility or laboratory. As shown in FIG. 1, it is preferred that each of the risk analysis information associated with the measured value be presented such that the “high” or elevated risk information is visually enhanced and aligned along one side (the same side as the other risk information for the other values) of the report or display.  
         [0067]    Optionally, as indicated by Blocks  870 ,  875 ,  880  and  885 , additional risk assessment information can also be provided. For example, a supplemental risk assessment for selected abnormal or higher risk subclass results can be provided (Block  870 ). This supplemental risk assessment can customize the report to provide more detailed information regarding selected subclass variables (such as LDL size or particles, large HDL, and/or large VLDL triglycerides). Similarly, a subclass level risk assessment can provide a graphic and textual breakdown of certain subclass groupings or selected subclass data (Block  875 ).  
         [0068]    Alternatively, or additionally, a primary prevention risk assessment prediction assessment can be provided based on risk factors assigned to one or more of behavioral, medical, and/or selected lipoprotein measured constituent and/or subclass values (Block  880 ). As another alternative or addition, a secondary prevention guideline corresponding to recognition of the patient&#39;s diagnosis with certain high-risk medical conditions can be provided (Block  885 ).  
         [0069]    Preferably, the method of the instant invention subdivides the major lipoprotein constituents and the LDL pattern separately into at least three risk categories each. It is also preferred that, the LDL particles  42 , the large HDL value  43  and the large VLDL triglyceride value  44  are compared to a population based-norm and a line graph illustrates the actual measured result compared to the population with higher or lower levels of the measured value.  
         [0070]    The behavioral or medical input can be electronically input or input via a user at the lab or report site (for example, at a blood depository or lab where the blood or plasma sample is taken from a patient). It is typical that an identification number (bar-coded) is assigned to the vials for tracking. Accordingly, a hard copy or electronic data can also be identified such as with the same identification number. Once received at the central processing facility or NMR spectroscopy laboratory, the electronic data can be entered into the facility computer and matched with the lipoprotein measurements, and a customized patient profile summary report can be conveniently generated (either in one or more of soft or hard copy). In one embodiment, the summary report can be encrypted and emailed in electronic format to a physician&#39;s address for contemporaneous data reporting. Of course, the patient can be identified by a “permanent” number to track trend or drug therapy or other treatment impact over time. Additionally, a data base can be kept to analyze population trends (age, location, etc., versus one or more of the identified risk factors represented by a subclass and/or constituents) to provide important indicators of the population for medical use.  
         [0071]    As will be appreciated by one of skill in the art, the present invention may be embodied as a method, data processing system, hard copy report or program product. Accordingly, the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment or an embodiment which combines software and hardware aspects. Furthermore, the present invention may take the form of a computer program product on a computer readable storage medium having computer readable program code means embodied in the medium. Any suitable computer readable medium may be utilized including for example, hard disks, CD-ROMs, optical storage devices, or magnetic storage devices.  
         [0072]    A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner, LipoMed, Inc., of Raieigh, N.C., has no objection to the facsimile by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all rights whatsoever.  
         [0073]    The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. In the claims, means-plus-function clauses are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be construed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the appended claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.