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J Gen Intern Med. 2012 February; 27(2): 213–219.
Published online 2011 July 26. doi:  10.1007/s11606-011-1804-8
PMCID: PMC3270234

Differential Diagnosis Generators: an Evaluation of Currently Available Computer Programs

William F. Bond, MD, MS,corresponding author1,2 Linda M. Schwartz, MDE,2 Kevin R. Weaver, DO,1 Donald Levick, MD, MBA,3,4 Michael Giuliano, MD, MEd, MHPE,5 and Mark L. Graber, MD6



Differential diagnosis (DDX) generators are computer programs that generate a DDX based on various clinical data.


We identified evaluation criteria through consensus, applied these criteria to describe the features of DDX generators, and tested performance using cases from the New England Journal of Medicine (NEJM©) and the Medical Knowledge Self Assessment Program (MKSAP©).


We first identified evaluation criteria by consensus. Then we performed Google® and Pubmed searches to identify DDX generators. To be included, DDX generators had to do the following: generate a list of potential diagnoses rather than text or article references; rank or indicate critical diagnoses that need to be considered or eliminated; accept at least two signs, symptoms or disease characteristics; provide the ability to compare the clinical presentations of diagnoses; and provide diagnoses in general medicine. The evaluation criteria were then applied to the included DDX generators. Lastly, the performance of the DDX generators was tested with findings from 20 test cases. Each case performance was scored one through five, with a score of five indicating presence of the exact diagnosis. Mean scores and confidence intervals were calculated.

Key Results

Twenty three programs were initially identified and four met the inclusion criteria. These four programs were evaluated using the consensus criteria, which included the following: input method; mobile access; filtering and refinement; lab values, medications, and geography as diagnostic factors; evidence based medicine (EBM) content; references; and drug information content source. The mean scores (95% Confidence Interval) from performance testing on a five-point scale were Isabel© 3.45 (2.53, 4.37), DxPlain® 3.45 (2.63–4.27), Diagnosis Pro® 2.65 (1.75–3.55) and PEPID™ 1.70 (0.71–2.69). The number of exact matches paralleled the mean score finding.


Consensus criteria for DDX generator evaluation were developed. Application of these criteria as well as performance testing supports the use of DxPlain® and Isabel© over the other currently available DDX generators.

Electronic supplementary material

The online version of this article (doi:10.1007/s11606-011-1804-8) contains supplementary material, which is available to authorized users.

KEY WORDS: differential diagnosis, clinical decision support systems, diagnostic errors, evidence-based medicine, computer-assisted diagnosis


Diagnostic error can lead to inappropriate or absent therapeutic interventions, and thus has substantial human costs for patients. It is one of the most common reasons for malpractice lawsuits and accounts for the largest dollar losses amongst these cases1,2. Diagnostic error remains one of the more challenging areas of patient safety because of the hidden nature of cognitive processing and the many factors (affective, patient-related, environmental, and systems-related) that influence medical decision making3,4. The challenge to practicing clinicians is to prevent misdiagnosis in real time, and to teach this skill to trainees. Thus, any proactive support system that would help clinicians in teaching or executing the medical diagnostic decision-making process would be welcome5.

Differential diagnosis (DDX) generators are computer programs that assist the clinician by combining symptoms, findings, and other factors to suggest a list of possible diagnoses for consideration. Computer-assisted differential diagnosis generation has been available since the mid-1980s6. One of the most important works evaluating the performance of DDX generators was conducted by Berner et al. in 1994. That landmark study pitted four programs against 105 “diagnostically challenging” cases that were created through a consensus process by experts. At that time the simple presence of the primary case diagnosis within the possible choices of the DDX program list varied in proportion from 0.73 to 0.91 and the proportion of correct diagnoses when the test cases were applied ranged from 0.52 to 0.71. This measure of the correct diagnosis with test case application is akin to sensitivity. Scores were generated for correct or closely related diagnoses found by the programs, comprehensiveness of the diagnosis list, relevance of the diagnosis list and the presence of useful but previously unconsidered diagnoses. By addressing relevance of the diagnostic list, Berner et al. were touching upon the concept of specificity. However, the programs are designed to generate diagnostic possibilities, and therefore by nature are focused on sensitivity (presence of the diagnosis for the case) rather than specificity (absence of irrelevant diagnoses). The programs were judged to be roughly equivalent in their usefulness. At the time, it was noted that their ability to be useful in practice had yet to be proven7,8.

A more recent study showed that when presented with the key findings of difficult cases from the New England Journal of Medicine, a modern DDX generator suggested the correct diagnosis 96% of the time9. Advances in computer software and hardware have made the new DDX generators far more powerful than earlier programs. Likewise, the ability to integrate more factors in patient presentation, such as geography, demographics, and past diagnoses, makes their suggested diagnosis list more accurate and useful. The most recent developments allow for at least partial integration into the electronic health record (EHR) so that the DDX generator is drawing upon real-time information about the patient and hence requires less manual data entry10.

Because of these recent advances, the authors felt that a review of the current state of the technology was in order. The findings of this review may help drive research and/or product development agendas. We also seek to highlight the most helpful features along with those barriers and challenges that remain from the perspective of practicing clinicians. The review uses consensus criteria to compare and contrast the DDX generators most relevant to the generalist facing an undiagnosed patient.


Our author group consisted of a medical librarian with expertise in search strategies in evidence-based medicine, and physicians with expertise in computerized decision support, cognitive error, patient safety and education in the diagnostic process. The specialty areas of pediatrics, emergency medicine, and internal medicine were represented in the authorship group. Thus, the perspective was that of generalists faced with undiagnosed patients in the emergency department, inpatient, and office-based settings.

Consensus was achieved on the inclusion and exclusion criteria (listed in Table 1) before the search for DDX generators. The search was conducted in Pubmed and Google® (see online Appendix 1 for details). Clinical decision support systems were defined as “any computer program(s) designed to help healthcare professionals to make clinical decisions.”11 Wyatt & Spiegelhalter included a criterion that such programs “use two or more items of patient data.”12 The authorship team built upon this starting definition through a series of consensus-building meetings via web teleconferencing. We defined DDX generators as programs which assist healthcare professionals in clinical decision making by generating a DDX based on a minimum of two items of patient data. These included signs, symptoms, disease characteristics and/or other patient data.

Table 1
Inclusion and Exclusion Criteria for DDX Program Review

After preliminary review of identified programs, consensus ensued on factors (Table 2) to include in the evaluation round. These factors were then assessed for each DDX generator by two independent evaluators. In cases of disagreement on review criteria, a consensus discussion ensued. When information was not available to the reviewer, the company producing the software was queried for clarification. In cases where we had no response from a vendor on a particular question, and the answer was not clear from publicly available reference materials, we listed the item as unknown.

Table 2
Evaluation Criteria

The evaluation criteria were built upon work by Musen, Shahar and Shortliffe who characterize clinical decision support systems based on five dimensions: the system’s intended function, the advice mode, the communication style, the underlying decision-making process and the factors related to human-computer interaction11. These criteria were considered and refined through consensus discussion into the evaluation criteria listed in Table 2. The method of inputting data into the system was considered one of the most important criteria, as was the ability to refine the criteria after the initial input. The underlying technique for generating the differential diagnosis by the program was recorded to the degree that the program creator reveals how the program works. Additional features incorporated into the study for descriptive and comparison purposes included: the pricing model, frequency of updating, usage tracking, ability to access further information via references, and other features deemed by the reviewer to be subjectively important. The ability to integrate with the EHR was incorporated as an evaluation criteria, but actual EHR integration was not tested due to resource limitations. With increasing federal emphasis on interoperability of EHRs, adherence to Health Level 7 (HL7) interoperability standards was also considered.

We conducted basic performance testing by entering 20 cases into the four DDX generators. Ten consecutive diagnosis-focused cases chosen from an arbitrary start date were selected from 2010 editions of the Case Records of the New England Journal of Medicine (NEJM)© and from the Medical Knowledge Self Assessment Program (MKSAP)©, version 14, of the American College of Physicians (see online Appendix 3 for case list and scores). Without knowledge of the diagnosis, up to 10 key findings for each case were selected by one of the authors (MLG). These key findings were then entered into the DDX generators by research assistants who were trained to enter as many of the findings as the program would allow, and who were also unaware of the final diagnosis until after the searches were conducted. One research assistant entered the case across all four ddx generators to reduce variability in the method of input of the findings. The results generated were then reviewed to see if the correct diagnosis was listed in the first 20 suggestions or the first screen of DiagnosisPro® suggestions (not strictly one page due to formatting) using a 0–5 scoring system:

  1. The actual diagnosis was suggested on the first screen or in the first 20 suggestions.
  2. The suggestions included something very close, but not exact.
  3. The suggestions included something closely related that might have been helpful.
  4. The suggestions included something related, but unlikely to be helpful.
  5. No suggestions close to the target diagnosis.

In cases where a research assistant was uncertain as to the grading level, the case was discussed with one of the authors (MLG). The use of assigned scores allowed comparison of the results using parametric statistics by analysis of variance with Dunnett T3 correction for multiple comparisons (SPSS© 15.0, Chicago, IL). We also totaled the number of exact matches from each program as an additional marker of performance.


A total of 23 programs were identified during our initial search. After the application of the exclusion criteria, 11 programs were excluded because of specialty-specific focus (see online Appendix 3 for all excluded programs). Another eight programs were excluded after an initial review for reasons that included: inability to compare diagnoses, inability to enter two symptoms or characteristics, a static tree structure with cross linking of internal reference points, and no ranking of the diagnoses. Four programs were reviewed fully with the evaluation criteria listed in Table 2. The general information for each of the programs is listed in Table 3. Information regarding data elements available for input and input methods are listed in Table 4, and information regarding DDX content sources are listed in Table 5.

Table 3
General Information
Table 4
Input Elements and Methods
Table 5
Content Sources and Linking

Knowledge regarding the mechanism of generating the DDX results is limited to the information shared by the vendors. For DiagnosisPro® the underlying logic was not specified. The diagnoses are presented in disease categories. The results are not rank ordered in terms of disease prevalence or other criteria and the program offers no advice on how to further refine the suggestions. These factors limited the program’s usefulness. One differentiating feature is that DiagnosisPro® progressively truncates the list of suggestions as additional findings are entered. Conversely, with the other generators, the lists are re-prioritized, but remain large.

DXPlain® rank ordered results from most to least likely within two categories: common vs. rare diseases, based on disease prevalence. The mechanism is presumed to be a propriety algorithm from the description that follows. An importance rank is given based on criticality of potential diagnosis. Findings are assigned two attributes: one relating to the frequency of the finding in the disorder, and one expressing how strongly it suggests that disease. Ranking is related to findings that are both important and suggestive of a disorder. Rank of a given disease will be lowered if findings commonly seen in the disease are stated to be absent. The attributes are used to generate an ordered list of diagnoses associated with some or all of a given set of findings. Of note, DXPlain® allows occupation as a finding, the input of negative findings such as “no fever,” and has a side-by-side disease comparison feature. The program displays supportive findings and guides the user to other findings which, if present, support or refute the disease.

Isabel© was the only program to accept natural language queries and the only product allowing the user to input all of the key findings at once. The program uses a “natural language processing” search engine to match entered clinical features with similar terms in the diagnostic data set. Each diagnosis has a complete description of the clinical features with the differential ranked by the strength of the match to the entered clinical features. With each clinical feature addition, the differential diagnostic output reconfigures the list, taking into account all the clinical features entered. Isabel has links to databases, knowledge sources and validation studies.

PEPID™ lists diagnoses based on a proprietary scoring system related to the number of selected signs/symptoms consistent with each potential diagnosis. Additionally, each sign/symptom is assigned a unique score/weight relative to its importance in differentiating among specific diagnoses. Classic or cardinal disorders in which selections strongly suggest a disease or are pathognomonic are indicated. Critical diagnoses with immediate life or limb threat are indicated. Worthy of note is that the overall PEPID™ product, of which the DDX generator is only one piece, incorporates a laboratory testing manual, a drug interactions generator, a drug database covering 7,500 drugs, approximately 400 interactive clinical calculators, an IV compatibility tool, an acute care / life support reference section, and 700 evidence based topics (primary care module).

None of the vendors allowed for unfettered access to institutional library resources or PubMed Linkout for full text from subscribed content, although both Isabel and DxPlain® do provide for Pubmed searching. DiagnosisPro® and Isabel report that they integrate with major EHR vendor products to some degree, but we did not test the ability to integrate any of the products into an EHR. It is noteworthy that DiagnosisPro® has English, French, Spanish, and Chinese interfaces.

Aggregated results and mean scores (with 95% confidence intervals) from entering published cases into each of the differential diagnosis generators are shown in Table 6. ISABEL© and DxPlain® performed well with means of 3.45 for both. Post-hoc analysis with correction for multiple comparisons revealed that only the difference between DxPlain® and PEPID™ reached statistical significance (P = 0.04, mean score difference 1.75, 95% C.I. 0.05 to 3.45) None of the generators included the correct diagnosis for two of the MKSAP cases (acquired von Willebrand’s disease related to aortic stenosis, and metformin-induced peripheral neuropathy). Certain scores for returned suggestions such as “pancreatitis” for autoimmune pancreatitis and “cardiomyopathy” for methamphetamine-induced cardiomyopathy were scored only “3” (or “might have been helpful”) because the broad category of diagnosis was clear from the presentation and the DDX generator did not help elucidate the root cause. Compared to the three other generators which appeared to have large vocabularies, PEPID™ was unable to recognize many of the key findings. The number of exact matches was DiagnosisPro® = 5, DxPlain® = 10, Isabel© = 9, and PEPID™ = 4.

Table 6
Scores for Case Testing


This evaluation is intended to raise awareness of the existence of the DDX generators for clinical use and teaching. It also serves as a framework for institutions to use in considering purchase or subscription. Differential diagnostic generators have matured significantly and have begun to leverage access to the EHR, the internet and, to the degree allowed by vendors, subscription-based resources. Potential barriers to the use of DDX generators include access due to subscription models for the generators themselves, lack of the EHR with which to integrate, limitations of the user interface and lack of access to linked content (both EBM and non-EBM). In regard to adoption, we should note that two of the four programs tested by Berner et al.7. are no longer sold, and that DXPlain® is not available to the individual physician. Overall, all of the programs put forth for the final review and testing were deemed subjectively assistive and functional for clinical diagnosis and education.

While DDX generators have been shown to solve very complex cases9, the question of helpfulness among experts in real time clinical diagnosis remains. The expert goes through a series of hypothesis refinement in complex cases13, much the way the diagnosis becomes more refined as more items are added to the DDX generator input. Studies are needed to test these systems’ ability to render final diagnosis more quickly and to support safety in the diagnostic process without overburdening alarms. Berner et al.7. discussed the issue of diagnostic relevancy and the fact that long lists of diagnoses may be unusable by the practicing clinician and challenging for students18. This paper did not specifically address the relevancy or length of the diagnostic lists; in addition, the signal-to-noise problem is difficult to avoid in this setting. For example, the progressively truncated lists generated by DiagnosisPro® improve the diagnostic specificity, but at the expense of sensitivity. We share the concern that, especially in novice clinicians, the lists could lead to increased diagnostic testing with concomitant risk for increased costs and/or iatrogenic injury. Such a factor would be very difficult to quantify in practice. Still, the more urgent consideration is that human memory dictates that the list of diagnoses considered at any one time will be limited, and that the risk of not considering the diagnosis (sensitivity) is the greater concern.

While all of the programs provide a means for manual entry of findings, only two have reached the level of populating this information from various EHRs (Isabel© and DiagnosisPro®). We did not engage in EHR integration testing, which would require fees and an integration process. Also, we did not test the programs in clinical practice with the incumbent workflow and time pressures, something highly recommended prior to purchase or integration decisions. Healthcare systems with significant EHR usage and with single vendor EHRs across multiple settings may find integration more cost effective. We would caution that consideration of whether or not these programs add to an institution’s ability to meet “meaningful use” criteria set by the Health Information Technology for Economic and Clinical Health (HITECH) Act was beyond the scope of this evaluation.

Those DDX generators that can be integrated with the EHR are currently limited in their connectivity to the assigned fields shared with the generator. A different strategy would take all potentially relevant data and share it with the DDX generator in real time; new products that take this integrative approach are currently in development and testing (Lifecom©)14. In this manner, the DDX generator hypothesis is evolving in real time by updating the known problem set. This may help overcome one of the classic problems of cognitive error—the challenge of knowing when to use decision support. Because errors are made in simple as well as complex cases, if DDX generators are accessed only by active choice in cases known to be diagnostic challenges, then many cognitive diagnostic errors will proceed unmitigated in the current paradigm.

DDX generators can serve as helpful adjuncts in education. Bowen et al. recently described how a detailed review of the learner’s DDX using a compare and contrast strategy leads to the development of illness scripts which serve as anchor points in the learner’s memory15. Students and preceptors alike believe the ability to reflect upon the reasoning process is one of the most valuable pieces of the educational encounter16,17. One approach is to have students generate an independent DDX and compare it to the list from a DDX generator. Thus, the preceptor gains insight into the learner’s reasoning process and can identify and correct cognitive errors.

None of the programs allow institutions to leverage their current journal subscriptions for full text versions of articles provided in references, although many provide access to PubMed. Vendors should provide a means of allowing institutions to use their library’s customized PubMed URL to provide the full text of articles referenced. This linking to EBM resources can seamlessly move the clinician from considering a diagnosis to considering the test, and test properties, for investigating the diagnosis. None of the programs support standard solutions such as the digital object identifier and an open URL link resolver would be another welcome feature.

Limitations of our evaluation include the use of an iterative process rather than a formal Delphi method for achieving consensus regarding inclusion and evaluation criteria. In addition, performance testing was not directed at specificity and comparison of performance between programs was limited in statistical power; however, the results of comparisons using our graded scoring system was very similar to the “exact match” comparison, adding some reassurance as to the validity of our findings that DxPlain® and Isabel© performed the best in identifying the correct diagnosis.

Electronic supplementary material

Appendix 1(11K, docx)

Search Criteria for finding DDX Programs. (DOCX 10 kb)

Appendix 2(13K, docx)

Cases Used for Testing the DDX Generator. (DOCX 13 kb)

Appendix 3(12K, docx)

Excluded Programs. (DOCX 12 kb)


The authors would like to thank medical students Genine Siciliano, Agnes Nambiro, Grace Garey, and Mary Lou Glazer for entering the findings into the DDX generators for testing.

Sponsors: This study was not funded by an external sponsor.

Presentations: This information was presented in poster format at the Diagnostic Error in Medicine Conference 2010, Toronto, Canada.

Conflict of Interest None disclosed.


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