How to Develop a Differential Diagnosis: Clinical Reasoning Skills for Med Students

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Overview:

Building a strong differential diagnosis is a critical skill for medical students learning clinical reasoning. Whether you’re on clinical rotations or preparing for board exams, knowing how to systematically approach symptoms, rule out conditions, and prioritize potential diagnoses is essential for patient care.

In this blog, we’ll break down how to develop a differential diagnosis, key clinical reasoning techniques, and common mistakes to avoid. By mastering this process, you’ll improve your diagnostic accuracy, enhance your problem-solving skills, and build confidence in your clinical decision-making.

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Congratulations! You’ve made it through the first two years of medical school, which were packed with lectures, textbooks, Step 1 or Level 1, and plenty of Sketchy.

Now, as a brand-new third-year medical student who’s hitting the wards for the first time, you’re stepping into the hospital, where you’ll be expected to apply everything you’ve learned to real patients. But here’s the challenge: real patients don’t present like textbook cases. 

As an aside, the point above is one reason why we do rigorous clinical training in both medical school and residency. Medical school will prepare you to think critically, analyze, and put into practice your extensive “book knowledge.”

But, while the textbook case is a slam dunk, real-life cases require you to consider alternative diagnoses and refine your clinical reasoning skills in medicine. And, even if the diagnosis ends up being exactly what you expected, humans are unique and like to present the same condition in a thousand different ways.

Obviously exaggerating but the point being, it’s one thing to learn to take an H&P, and it's another to generate a differential diagnosis, but it's all about building your clinical acumen to, for lack of a better word, sense (or commonly joked as “smell”) when something is different. 

Now, back to clerkships—you’re doing your first rotation and you just beautifully presented a patient’s H&P to your attending. Suddenly, you're asked, "What’s on your differential?" and your mind floods with every disease you’ve ever read about.

Clinical reasoning involves applying the knowledge and skills to collect, integrate, and do something with the information (such as the history, labs, or imaging) in an appropriate manner to apply interventions (e.g., medications), solve clinical problems (e.g., why is this person acutely confused?), and ultimately influence patient outcomes¹.

This blog will walk you through the essential strategies to transition from book knowledge to clinical reasoning skills for medical students.

Understanding Clinical Reasoning: From Books to Real Patients

Your first instinct might be to recall everything you watched in Sketchy or read in First Aid, but clinical reasoning skills in medicine isn’t just about memorizing facts—it’s about thinking like a doctor. There are two main ways physicians approach problems:

As a new MS3, your focus should be on developing structured reasoning habits while learning to recognize common patterns over time. Beware of these common pitfalls:

• Anchoring Bias: Sticking with your first impression despite new information.
• Premature Closure: Jumping to a diagnosis too quickly without considering alternatives.
• Availability Heuristic: Over-focusing on diseases you recently studied (you will think everything is vasculitis at some point).

The Foundations of a Strong Differential Diagnosis

When coming up with differential diagnoses, avoid the "Oh no, I can’t think of anything!" moment by using structured tools. One classic framework, and the one I learned in medical school, is the VINDICATE mnemonic, which ensures you don’t overlook key disease categories:

• Vascular (Stroke, MI, PE)
• Infectious (Pneumonia, UTI, Sepsis)
• Neoplastic (Cancer)
• Degenerative (Osteoarthritis, Alzheimer’s)
• Iatrogenic (Medication side effects, Surgery complications)
• Congenital (Cystic fibrosis, Congenital heart disease)
• Autoimmune (Lupus, RA, MS)
• Toxic/Metabolic (DKA, Hyperkalemia, Alcohol withdrawal)
• Endocrine (Hypothyroidism, Adrenal insufficiency)

Let’s apply this to a sample case. For example, the causes of shortness of breath are myriad, but using VINDICATE we get:

• Vascular - Pulmonary embolism, Congestive heart failure
• Infectious - Pneumonia, COVID, Influenza
• Neoplastic - Lung cancer
• Degenerative - COPD, emphysema, pulmonary fibrosis
• Iatrogenic - Opiates, sedatives, chemotherapy medications
• Congenital - Cystic fibrosis, Congenital heart disease
• Autoimmune - Lupus, Sarcoidosis
• Toxic/Metabolic -  DKA, Carbon monoxide poisoning
• Endocrine - Obesity hyperventilation syndrome

Now that you’ve worked through what could be going on, it’s time to narrow it down. Because, as much as it’s rewarding to find a “zebra” or diagnose something very rare, it’s simply not common. One of my go-to phrases is “common things are common.”

Traditionally on rounds your resident or attending will expect you to mention at least three potential diagnoses. Here is how I chose to structure that conversation:

1. Most Likely Diagnosis – What makes the most sense based on the patient’s story? 
2. Most Dangerous Diagnosis to Rule Out First – What would be life-threatening if missed?
3. Less Likely but Possible Diagnosis – The “just in case” consideration. This is usually around 2-3 serious contenders, but may be more. 

Let’s practice again by considering the following case: A 47-year-old male presents with severe epigastric pain and nausea.

• Most Likely: Pancreatitis (history of alcohol use or gallstones, severe epigastric pain radiating to the back, nausea, vomiting).
• Most Dangerous to Rule Out First: Abdominal Aortic Aneurysm (AAA) rupture (hypotension, pulsatile abdominal mass, severe back or flank pain).
• Less Likely but Consider: Peptic ulcer disease (burning pain, relieved by food/antacids, NSAID use).

There is another popular structure for considering your differentials called “Worst First.” As someone going into Emergency Medicine, this is a method I’m accustomed to. You still want to have a most likely condition, a few “this is possible” conditions, but include one to two life-threatening conditions that you absolutely cannot miss.

Simply put, it’s the same list you generated, but when presenting, you mention the scary stuff first. Your attending will know that you’re considering these can’t miss diagnoses, while also recognizing that there is likely something else going on that won’t kill the patient. 

Step-by-Step Approach to Clinical Reasoning

Alright, so now we know what clinical reasoning is, how to use the VINDICATE mnemonic, and how to structure your differential diagnosis in a presentation. But, before we can apply these mnemonics and frameworks, we need data.

Data comes in the form of the history, physical, labs, and imaging. To me, clinical reasoning falls along this timeline: Gather a history (asking questions to rule-in & rule-out conditions), perform a thorough physical exam, decide what testing or imaging you would use (or not at all!), generate a differential diagnosis based on the chief concern, and then integrate these data points to narrow your differential. Let’s walk through it step-by-step.

Step 1: Gather a High-Quality History

The best diagnosticians aren’t the ones who order the most tests—they’re the ones who ask the right questions. When gathering a history, think in terms of:

• "What am I trying to confirm or rule out?"
• "What are the key red flags?"

After asking open-ended questions, such as "Tell me about your chest pain," try targeted questions with a purpose:

• "Does it change with movement or deep breaths?" (Musculoskeletal vs. PE)
• "Does it radiate to your jaw or arm?" (ACS)
• "Have you had recent long flights or leg swelling?" (PE)

It can be helpful to “prime” patients by giving them a glimpse into your decision-making. For example, “I’m going to ask you some specific questions that might seem all over the place, but they help guide me to what is most likely going on.”

Step 2: Perform a Targeted Physical Exam

As with the targeted questions you ask during a history, your exam should be hypothesis-driven—what findings will help confirm or refute your suspected differentials?

For example, for our shortness of breath patient from earlier:

• General - How do they look to you, sick? Struggling? Bent over? Can’t speak more than a few words at a time?
• Cardiac - Along with auscultation, check JVD (ruling out CHF), peripheral edema (CHF), and pulses. 
• Pulmonary - Auscultation (Crackles? Think pneumonia vs. CHF), percussion, special maneuvers.

Step 3: Choosing High-Yield Diagnostic Tests

Before you order a test, ask yourself:

1. Will this change my management?
2. Is this the best test for this situation?

Laboratory tests or imaging can provide an insight into the inside of the body as well as identify things that patients cannot put into words. It’s hard for a patient to say, “I feel hypokalemic.” But, when their potassium comes back quite low, that could be a reason for why they’re feeling so tired. 

One place where medical students and those less comfortable with their H&P skills get caught up is what’s called “shotgunning” tests—ordering a broad panel of tests without a clear diagnostic strategy. Consider, once again, our shortness of breath patient. If they are middle-aged, on oral contraceptives, had cancer, just got off a trans-atlantic flight, and have a bedside POCUS concerning for DVT, then PE should be at the top of your differential diagnosis (and at the top of worst-first too!). 

Do you need a D-dimer in this patient? Or can you skip straight to imaging? Using the Wells’ Criteria for Pulmonary Embolism, you should skip the D-dimer and proceed directly to a CT scan. Don’t forget that every test you order involves (1) many hospital staff and resources, (2) potential pain for the patient, and (3) costs incurred that the patient may have to bear!

Building Your Clinical Reasoning Skills Through Practice

All of the above information is important, but practice makes perfect. Ideally you can apply these methods on real patients in the hospital or clinic. Some active-learning tips include:

• Thinking Out Loud: When presenting patients, explain your reasoning step by step. This gives insight into the cogwheels moving in your brain and shows you are a critical thinker. 
• Teaching Your Peers: Nothing solidifies learning like explaining a concept to a fellow medical student. 
• Using Clinical Calculators & Guidelines: MDCalc has amazing acute management checklists and built-in calculators to guide decision-making.

Conclusion

Developing clinical reasoning takes time, but every patient you see will sharpen your skills. As a medical student, your goal isn’t to be perfect—it’s to think systematically, ask the right questions, and learn from every case.

• Use frameworks like VINDICATE to build differentials.
• Always ask yourself: What is the most dangerous thing this could be?
• Don’t underestimate the importance, and value provided, of a thorough history and physical exam.
• Don’t order every test under the sun. Think about what would give you meaningful data to enhance your clinical understanding of the patient.
• Engage in active learning and case-based practice to refine your skills.

^{1 Delavari S, Barzkar F, M. J. P. Rikers R, Pourahmadi M, Soltani Arabshahi SK, Keshtkar A, et al. (2024) Teaching and learning clinical reasoning skill in undergraduate medical students: A scoping review. PLoS ONE 19(10): e0309606. https://doi.org/10.1371/journal.pone.0309606}