hematology case study with answers

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Hematopoiesis Case Studies

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Case studies are board-style questions with explanations and links to related articles featured in  Hematopoiesis , an e-newsletter that is sent to hematology trainees on a quarterly basis.

• A 73-Year-Old Man With Extensive Bruising
• A 2.5-Year-Old Girl With Fever and Pancytopenia
• 21-Year-Old With Duodenal Adenocarcinoma and a History of T- cell Lymphoma
• 78-Year-Old Woman with Thrombocytopenia and Splenomegaly
• 48-Year-Old Woman With Weight Loss, Hepatomegaly, and Splenomegaly
• Diagnosis of a 64-Year-Old Man With Anemia and Thrombocytopenia
• Prenatal Management of 21-Year-Old Woman to Reduce Risk of Severe Thrombocytopenia and Intracranial Hemorrhage
• Three-year-old Boy With Pancytopenia
• COVID-19 Management in Patients With Hematologic Malignancies
• 25-Year-Old Woman Referred to Clinic for Erythrocytosis
• 60-Year-Old Woman With Headache and Blurred Vision
• Chronic Immune Thrombocytopenia Purpura
• New Therapies for Acute Myeloid Leukemia
• Sickle Cell Disease – A 25-Year-Old in Transition
• Supportive Care in Multiple Myeloma
• Managing Toxicities in CAR T Cell Therapy
• Bicytopenia and Syndromic Features in a Four-Year-Old Child
• Emerging Therapies in Hemophilia
• 47-Year-Old Woman With New-Onset AML and Leukostasis
• The Smart Choice for Prevention of Recurrent Venous Thromboembolism
• 36-Year-Old Man with Severe Low Back Pain and BCP-ALL
• 52 Year-Old Woman with Fatigue and Neuropathy
• 29-Year-Old Woman with Postpartum Hemorrhage
• 30 Year-Old Female with Pancytopenia and Fatigue
• Progressive Fatigue and Cytopenias in a 70-Year-Old Man
• 32-year old man with neurologic changes and cytopenias
• 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia
• Unexplained Thrombocytopenia in a Child
• Neutropenia in a Patient with Rheumatoid Arthritis
• 50-Year-Old Woman with Fibrous Capsule after Breast Augmentation
• 32-Year-Old Female with Multiple Ecchymoses
• 32-Year-Old Female with Anemia and Confusion
• GI Bleed in a Patient with Amyloidosis
• 32-Year-Old Man Admitted to Hospital With Diffuse Lymphadenopathy
• Image Challenge: 54-Year-Old Man With Abnormal Circulating Lymphocytes
• Image Challenge: Hematology Consult - Middle-Age Woman With Neutropenia and Splenomegaly
• Image Challenge: Hematology Consult - Middle-Age Man With Neuropathy and Splenomegaly
• Image Challenge: Bone Marrow Aspirate (August 2012)
• 65-Year-Old with History of Waldenström Macroglobulinemia (May 2012)
• Cervical Adenopathy, Weight Loss, and Night Sweats (February 2012)
• 12-Year-Old Boy With Normocytic Anemia and Bone Pain (August 2011)
• Putting Two and Two Together (May 2011)
• Four-Year-Old Male with Red Urine and Fever (February 2011)
• Intermittent Epistaxis in a Young Boy
• Prognostic Factors in Acute Lymphocytic Leukemia
• 55-Year-Old Male With Multiple Myeloma and Prognosis of Undetermined Significance
• 24-Year-Old Woman With Dark-Colored Urine
• Personalizing Anticoagulation: Determination of Warfarin Dosing
• Microcytic Anemia Refractory to Oral Iron Supplementation
• ITP is Also a Platelet Production Problem
• A 26-Year-Old Man With History of Fatigue, Fevers, and Gingival Bleeding
• Finding the Best Prognostic Outcome in a Patient With AML
• Bcl-6 and Its Relationship to Diffuse Large B-Cell Lymphoma
• A 78-Year-Old Man With Elevated Leukocytes and Anemia
• Flow Cytometry Pattern in APL
• Identifying One of the 5q- Syndrome Genes
• Do You Know JAK?

Table of Contents

Explore the latest case studies  and articles  from  Hematopoiesis .

• Announcing Hematopoiesis, Our New ASH Trainee Council Newsletter by Trainees and for Trainees
• A Primer on Advocacy for the Hematology Trainee
• Blood Smear: The Fifth Vital Sign in Hematology
• Chimeric Antigen Receptor T-cell Therapy: What Fellows Need to Know
• The Blood Sisters Project
• Case Study: A 73-Year-Old Man With Extensive Bruising
• Case Study: A 2.5-Year-Old Girl With Fever and Pancytopenia

The Biology Corner

Biology Teaching Resources

Blood Case Studies for Anatomy (Hematology)

I found this assignment online and re-created it to work for remote-learning, so that it is now in slide format. This format will also work when students are back to in-person learning. I plant to print the slides in color and then place them into dry-erase sleeves so that students can write on them with expo markers and then erase for the next class. This saves on color printing costs and paper.

Another thing that is preferable with in-person learning is the ability for students to work together and communicate what they know. Each group can get a single case (slide) and then we can share the images on the projector. They can point out to the class where the data is highlighted to indicate an abnormal values.

If using this as a remote assignment, I don’t think it would be too much to ask students to complete all of the slides. (Note: if you assign this on LMS, you will need to make a copy and remove the note on the slide that has the answer.)

Ideally, students will have already learned about various conditions, like sickle cell disease and anemia. I have Google slides and guided notes for these units. The remote version, Interactive Slides: Blood also explains the different types of blood cells and their functions.

Each slide shows a CBC (complete blood count) with values for each type of blood cell in the sample. The normal range is shown next to the patient values, so students can easily compare the two. The image of the blood slide does not reveal as many clues as the CBC panel, and is mainly there as a reference.

There are five cases, each showing a particular condition with the CBC counts. Students highlight any abnormalities in the patient’s blood. For example, Teddy has swollen lymph nodes and a high lymphocyte count. From the list of possibilities, the best fit for his disorder is mononucleosis. Each slide has the answer listed under speaker notes. If you are assigning the slides over LMS, make a copy that does not include the answers.

Shannan Muskopf

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Case Studies in Hematology and Coagulation

• Product Description

This compendium of 200 case studies is the result of a unique collaboration of leading hematologists, hematopathologists, and oncologists. It serves as both a case-based guide to the diagnosis and management of patients suffering from hematologic conditions and a valuable teaching tool.

The editors have compiled an invaluable collection of cases covering common and rare entities—from anemias and acute leukemias to plasma cell, platelet and coagulation disorders. Cases are presented in an easy-to-follow format, grouped by related conditions. The final two sections present 27 self-study challenge cases that include answers (with images) provided by the authors of each case.

A broad range of topics in hematology and coagulation are covered in this CaseSet, including:

• Myeloproliferative Disorders
• Myelodysplastic Syndromes
• Lymphoproliferative Disorders
• Lymphomas and Their Mimicks
• Plasma Cell Disorders
• Platelet Disorders
• Hematologic Infectious Diseases
• Other Hematologic Disorders
• Bleeding Disorders
• Thrombophilias
• Other Hemostasis Disorders

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9. Hematology Questions and Answers

• Published: August 2013
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Chapter 9 presents multiple-choice, board review questions on hematology including anemia, myeloid malignancies, coagulation disorders, and lymphoid malignancies. Full explanations are provided with the correct answers.

Multiple Choice (choose the best answer)

Anemias and Myeloid Malignancies

1. A 67-year-old man is evaluated for exertional dyspnea. He recalls that 3 years ago he was told that he had anemia. In reviewing his records, you note that at that time his hemoglobin level was 9.5 g/dL and his hematocrit was 33% with an increased mean corpuscular volume (MCV); the remainder of his complete blood cell count was normal. On physical examination, he had conjunctival pallor, normal heart and lung findings, no lymphadenopathy, no hepatomegaly or splenomegaly, and no petechiae or ecchymoses. Diagnostic testing results are shown in Table 9.Q1 .

Which of the following is the most likely explanation for these findings?

Acute myeloid leukemia (AML)

Vitamin B 12 deficiency

Hemolytic anemia

Myelodysplastic syndrome (MDS)

Primary myelofibrosis

2. A 45-year-old woman is admitted to the surgical service with severe arterial insufficiency of the right second toe. She has no prior medical history and takes no medications. Physical examination findings are normal except for mild splenomegaly and signs of early gangrene in the right second toe. All pulses are full and equal throughout. Diagnostic testing results are shown in Table 9.Q2 .

Which of the following is the most likely diagnosis?

Essential thrombocythemia

Philadelphia chromosome–negative chronic myeloid leukemia (CML)

Primary myelofibrosis (PMF)

3. A 22-year-old man is admitted to the hospital for an elective cholecystectomy. You are asked to see him because he had anemia on preoperative testing. He tells you that he has always been told by his physicians that he has mild anemia; his medical history is otherwise unremarkable. His vital signs are normal. His conjunctivae are mildly icteric, and the spleen is palpable in the left upper quadrant. Findings on the remainder of the physical examination are normal. Diagnostic testing results are shown in Table 9.Q3 .

Which of the following tests would most likely help confirm the diagnosis?

Hemoglobin electrophoresis

Osmotic fragility test

Direct and indirect antiglobulin (Coombs) tests

Bone marrow aspiration and biopsy

4. A 28-year-old black man with sickle cell disease presents to the emergency department with abdominal pain, chest pain, and shortness of breath. His dyspnea evolved over 36 hours after a visit with his niece and nephew. His history is significant for approximately 2 emergency department visits or hospital admissions per year for painful crises. Three years ago, he spent 4 weeks in the hospital after an episode of acute chest syndrome. He has been taking hydroxyurea but only intermittently because of financial concerns. His pulse is 116 beats per minute and regular, his blood pressure is 138/76 mm Hg, his respiratory rate is 18 breaths per minute, and his temperature is 38.3°C. Pulse oximetry shows 91% oxygen saturation with room air and 93% with 4 L of oxygen by nasal cannula. His lungs have scattered inspiratory crackles in the right midlung field. His spleen is not palpable. The remainder of the physical examination findings are normal. Diagnostic testing results are shown in Table 9.Q4 .

A chest radiograph shows a right middle and upper lobe air space infiltrate. The patient is given supplemental oxygen, adequate pain control, and intravenous antibiotics. Which of the following should you now order?

Hydroxyurea

Erythrocyte exchange transfusion

Plasma exchange

Anticoagulation with unfractionated heparin

Aggressive intravenous fluid hydration

5. A 70-year-old man presents with weakness of his right arm and leg. His symptoms began yesterday and are now resolved. He also reports a 6-month history of recurrent headaches and fatigue. He is a nonsmoker. His medical history is significant for high blood pressure. His blood pressure is 167/88 mm Hg, his oxygen saturation is 93% on room air, his face is plethoric, and a right carotid bruit is heard. Other findings on physical examination are normal. Diagnostic testing results are shown in Table 9.Q5 .

Carotid ultrasonography shows a 30% stenotic lesion in the right carotid. The patient is hospitalized and begins antiplatelet therapy. Which of the following should you order next?

JAK2 V617F mutation testing

Fluorescence in situ hybridization (FISH) for BCR-ABL testing

Arterial blood gas analysis

6. A 42-year-old woman with a history of systemic lupus erythematosus (SLE) presents with fatigue. She has been receiving anti–tumor necrosis factor therapy and has been managing the SLE well. However, she has recently experienced worsening fatigue. Her vital signs are normal. Her face and conjunctivae are jaundiced, and she has a fading butterfly rash on her face. The spleen is palpable on deep inspiration. Diagnostic testing results are shown in Table 9.Q6 , and the peripheral blood film is shown in Figure 9.Q6 .

Which of the following is the best interpretation of these data?

The hemolysis is predominantly intravascular.

The bone marrow is not responding to the anemia.

Direct Coombs testing results should be positive.

Urine hemoglobin testing results should be positive.

7. A 58-year-old woman with active rheumatoid arthritis presents with fatigue and joint pain. She received the diagnosis of rheumatoid arthritis 5 years earlier and has been taking prednisone 10 mg daily and methotrexate with folate weekly. She has had chronic fatigue and anemia. Her vital signs are normal. Her conjunctivae are pale, and she has active synovitis affecting both knees, her wrists, and elbows, with rheumatoid nodules on the extensor surface of her right forearm. The remainder of the physical examination findings are normal. Diagnostic testing results are shown in Table 9.Q7 .

Which of the following laboratory findings are consistent with this condition?

Elevated hepcidin, elevated ferritin, elevated total iron-binding capacity (TIBC), elevated serum iron

Elevated hepcidin, elevated ferritin, decreased TIBC, elevated serum iron

Decreased hepcidin, elevated ferritin, decreased TIBC, elevated serum iron

Elevated hepcidin, elevated ferritin, decreased TIBC, normal serum iron

Decreased hepcidin, elevated ferritin, elevated TIBC, normal serum iron

Coagulation

8. A 62-year-old man underwent right total knee replacement 8 days ago. Swelling has developed in his right lower extremity, and Doppler ultrasonography confirms the presence of a right superficial femoral vein thrombosis. His current medications include oxycodone and subcutaneous unfractionated heparin. Results of preoperative tests, including a complete blood cell count and liver and kidney function, were normal. Other laboratory data include the following: hemoglobin 12.2 g/dL, leukocyte count 8.5×10 9 /L, and platelet count 60×10 9 /L. In addition to stopping the use of subcutaneous heparin, what is the next most appropriate step in management of this patient?

Start low-molecular-weight heparin therapy.

Start intravenous therapeutic doses of heparin.

Start direct thrombin inhibitor therapy.

Start aspirin therapy.

9. A 45-year-old man presents with deep vein thrombosis of the right femoral vein. Three months ago, he received a diagnosis of systemic lupus erythematosus (SLE). In addition to confirming SLE, laboratory testing also documented the presence of a lupus anticoagulant (LAC). There is no family history of venous thrombosis. Current medications include hydroxychloroquine. Laboratory testing shows normal results for a complete blood cell count and for tests of liver and kidney function. Special coagulation testing confirms the persistence of an LAC. What is the most reasonable duration of warfarin anticoagulation for this patient?

10. A 20-year-old white woman has been admitted to the hospital with pulmonary embolism. She has no chronic illnesses and is receiving no medications except for combination estrogen-progesterone birth control pills that she started using approximately 1 year earlier. Results were normal for a complete blood cell count, baseline prothrombin time, activated partial thromboplastin time (aPTT), and tests of kidney and liver function. The patient is currently receiving therapeutic doses of intravenous unfractionated heparin, and her aPTT is therapeutic at 72 seconds. A panel of thrombophilia tests has been performed. Which of the following statements about her thrombophilia test results is correct?

DNA-based testing for factor V Leiden and prothrombin G20210A mutations are reliable.

Low antithrombin confirms a hereditary deficiency state.

A positive result on lupus anticoagulant (LAC) testing confirms antiphospholipid antibody syndrome.

Low protein S confirms the presence of a hereditary deficiency state.

11. A 62-year-old man with chronic atrial fibrillation has been treated with warfarin. He has no other chronic illnesses and is receiving no other medications long-term except for lipid-lowering agents. Results of his complete blood cell count and tests of renal and kidney function are normal. He checks his prothrombin time monthly and has kept the international normalized ratio (INR) within the therapeutic range (2–3) for the duration of his therapy with warfarin. He has heard about recent US Food and Drug Administration (FDA) approval of dabigatran, which requires no monitoring, and he would like a prescription for this new drug. Which of the following statements is true about the use of dabigatran in atrial fibrillation compared with the well-managed use of warfarin?

Switching to dabigatran would result in superior outcomes.

Switching to dabigatran would result in inferior outcomes.

Switching to dabigatran would provide no significant benefit.

Dabigatran is FDA approved for postoperative thromboprophylaxis for knee and hip replacement surgery.

Dabigatran is FDA approved as an anticoagulant for patients who have received a mechanical heart valve.

12. A 22-year-old woman is brought to the emergency department after having 1 witnessed tonic-clonic seizure. She had appeared confused for the preceding few hours. On examination, she is febrile and appears slightly confused; otherwise, neurologic and physical examination findings are normal. Laboratory testing results are shown in Table 9.Q12 , and the peripheral blood smear is shown in Figure 9.Q12 .

What is the most appropriate next step in management?

Red blood cell transfusion

Platelet transfusion

Gamma globulin administration

13. A 72-year-old man with chronic atrial fibrillation has been receiving dabigatran 75 mg twice daily for the past 6 months. He has not had any thrombotic or hemorrhagic complications. He has a history of colon polyps, for which he needs to undergo a colonoscopy with possible polypectomy. Apart from an irregular pulse, his physical examination findings are normal. Results were normal for a complete blood cell count and tests of renal and liver function. The calculated creatinine clearance is 28 mL/min. For how long should dabigatran use be discontinued before the colonoscopy?

No need to discontinue

Lymphoid Malignancies

14. At her annual physical examination, an asymptomatic 68-year-old woman has lymphocytosis (32×10 9 /L) with a normal hemoglobin level and platelet count. On examination, she has 1-cm lymphadenopathy in the cervical region and no palpable liver or spleen enlargement. A peripheral blood smear shows identically appearing mature lymphocytes with smudge cells. Flow cytometry of the peripheral blood lymphocytes shows a monoclonal B population with dim expression of λ light chain and CD20 that is positive for expression of CD5, CD19, and CD23. Which of the following is the best next step in her management?

Combination chemoimmunotherapy

Chlorambucil therapy

Allogeneic peripheral blood stem cell transplant

Combination monoclonal antibody therapy

Active monitoring for disease progression and complications

15. Ten years ago, a previously healthy 20-year-old woman presented to her physician with a 2-month history of pruritis, drenching night sweats, unintentional weight loss, and nonproductive cough. On examination, she had 2-cm cervical lymphadenopathy. A computed tomographic scan showed a 12-cm-diameter anterior mediastinal mass. An excisional biopsy of a cervical lymph node showed nodular sclerosing Hodgkin lymphoma. After she was treated with ABVD (doxorubicin [ A driamycin], b leomycin, v inblastine, and d acarbazine) combination chemotherapy followed by involved field radiotherapy, the disease was in complete remission. Now you see her for the first time for an annual physical examination. The disease remains in complete remission. Compared to her peers, this patient is at increased risk of which of the following conditions?

Breast cancer

Coronary artery disease

Hypothyroidism

Skin cancer

All of the above

16. An 80-year-old man is admitted to the hospital after falling on an icy sidewalk and fracturing his hip. He undergoes open reduction and internal fixation of the fracture. At surgery, there does not appear to be any bone disease at the fracture site. The patient was previously asymptomatic. Physical examination findings are otherwise unremarkable. Serum protein electrophoresis and immunofixation show an IgM κ monoclonal protein (0.3 g/dL). The complete blood cell count and serum creatinine levels are normal. Skeletal survey shows no additional bone defects. Which of the following statements is true for this patient?

He has multiple myeloma and requires treatment.

He has a lower risk of a clinically significant lymphocytic or plasma cell malignancy than patients with an IgG monoclonal protein.

He requires a radioisotope bone scan to evaluate his bone integrity.

He requires regular follow-up and serial measurements of his monoclonal protein level.

He has a 10% annual risk of multiple myeloma.

17. A 75-year-old African American man was seen last week by his primary care physician for mild dyspnea. He has also noted intermittent peripheral edema. During the evaluation, an electrocardiogram showed low-voltage QRS complexes in the limb leads. The troponin T level was elevated (0.07 ng/mL). This finding suggested the need for a coronary angiogram, which showed no significant coronary artery disease. An echocardiogram showed diffuse left ventricular thickening with a granular texture to the myocardium and a septal thickness of 2.5 cm (normal <1.1 cm). The complete blood cell count results were normal. Serum and urine protein electrophoresis and immunofixation were unremarkable. Serum free light chain levels were not increased. What is the most likely diagnosis?

AA amyloidosis

Light chain–related amyloidosis

Hypertrophic obstructive cardiomyopathy

Amyloidosis due to transthyretin deposition

Amyloidosis due to β 2 -microglobulin deposition

18. A 55-year-old man presented to his primary care physician for evaluation of fatigue. He was previously healthy with the exception of chronic musculoskeletal low back pain, for which he occasionally takes nonsteroidal anti-inflammatory drugs. On examination, he is pale. Complete blood cell count results are as follows: hemoglobin 8.3 g/dL, mean corpuscular volume 73 fL, leukocyte count 6.9×10 9 /L, and platelet count 398×10 9 /L. Results of the fecal occult blood test are positive. During upper and lower endoscopy, a 1.2×2.5-cm ulcerative lesion is noted in the lesser curvature of the stomach. The lesion is biopsied and identified as a MALT lymphoma. Which of the following is characteristic of MALT lymphoma?

Most cases are treated with anthracycline-based chemotherapy.

It is caused by chronic stimulation with Chlamydophila psittaci .

Radiotherapy is necessary in most cases.

It frequently undergoes transformation to a large-cell lymphoma.

The combination of amoxicillin, omeprazole, and clarithromycin is the most appropriate first-line treatment.

19. A 73-year-old woman presented to the emergency department with new-onset back pain, confusion, and constipation over the past week. Her past medical history is significant only for hypertension. On examination, she is slightly pale with slow cognition and point tenderness over the lumbar spine. Plain films of the lumbar spine show osteolytic lesions in L2, L3, and L5. Laboratory values are as follows: hemoglobin 9.3 g/dL, leukocyte count 4.6×10 9 /L with a normal differential count, platelet count 230×10 9 /L, creatinine 1.6 mg/dL, total calcium 13.1 mg/dL, albumin 3.6 g/dL, and total protein 9.1 g/dL. What is the most likely diagnosis?

Metastatic breast cancer

Hydrochlorothiazide use

Multiple myeloma

Primary hyperparathyroidism

Milk alkali syndrome

20. A 48-year-old man presents to the emergency department with a 6-week history of progressively worsening abdominal pain and night sweats. Physical examination findings were significant for palpable bilateral 2-cm axillary lymph nodes and diffuse abdominal tenderness with no rebound or guarding. Computed tomography of the abdomen and pelvis showed retroperitoneal and mesenteric lymphadenopathy. Excisional biopsy of an axillary node was positive for diffuse, large B-cell lymphoma. Positron emission tomography showed fluorodeoxyglucose-avidity in the axillary, mesenteric, and retroperitoneal lymph nodes. Results of the bone marrow examination were normal. Which of the following is the best next step?

Combination therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)

Observation

Combination therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)

Autologous stem cell transplant

Involved field radiotherapy

1. Answer d.

MDS most commonly manifests as isolated macrocytic anemia. MDS can evolve to include pancytopenia over several years; the typical peripheral smear findings include a dimorphic erythrocyte population (microcytes and oval macrocytes) with an overall prominent macrocytosis and an MCV around 110 fL. The chronicity of MDS—in particular, anemia preceding the diagnosis of pancytopenia by several years—is in contrast to the typically acute manifestation of AML, which is therefore an unlikely possibility in this patient. Primary myelofibrosis, a myeloproliferative neoplasm, causes fibrosis in the bone marrow, resulting in extramedullary hematopoiesis and significant splenomegaly, and typically does not cause a macrocytic anemia. Vitamin B 12 deficiency can cause a megaloblastic anemia and manifest with slowly evolving macrocytic anemia and eventually pancytopenia, but the peripheral smear would not show a dimorphic erythrocyte population. (See Tefferi and Vardiman in the “Suggested Reading” list.)

2. Answer a.

Extreme thrombocytosis may be reactive and occur with severe iron deficiency or inflammatory states (with elevated erythrocyte sedimentation rates) or after splenectomy; patients are typically asymptomatic. Clonal thrombocytosis is related to a myeloproliferative neoplasm, which usually causes splenomegaly. Typical bone marrow findings include a hypercellular bone marrow with increased atypical megakaryocytes in clusters. Essential thrombocythemia may cause extreme thrombocytosis (platelet count >1,000×10 9 /L); however, it can also occur less commonly with polycythemia rubra vera (typically with erythrocytosis), the cellular phase of PMF, or rarely CML. The normal karyotype makes CML much less likely since it typically manifests with the Philadelphia chromosome t(9;22). Increased reticulin fibrosis would have been seen on the bone marrow biopsy if the patient had PMF. (See Tefferi in the “Suggested Reading” list.)

3. Answer b.

When a patient presents with premature gallstones, one should consider whether they may be due to pigment gallstones from chronic hemolysis causing indirect hyperbilirubinemia. The presence of microspherocytes is consistent with hereditary spherocytosis, and the diagnostic test is an osmotic fragility test, which identifies a congenital membrane defect. Typically, acquired warm autoimmune hemolytic anemia, which produces positive Coombs test results, can cause spherocytes as well; however, the history of lifelong anemia makes this diagnosis unlikely. A hemoglobin electrophoresis would help in diagnosing thalassemia or a hemoglobinopathy; however, these conditions do not manifest with microspherocytes on the peripheral blood film. There is no indication for a bone marrow biopsy since the reticulocyte response is appropriate and no other cytopenias are apparent. (See Gallagher in the “Suggested Reading” list.)

4. Answer b.

The patient has acute chest syndrome, a sickle cell anemia complication that is an indication for urgent red cell (not plasma) exchange transfusion to decrease the hemoglobin S level to less than 30% to 35%. Gentle fluid resuscitation is appropriate (along with oxygen support and antibiotics, since about one-third of acute chest syndrome events are initiated by or associated with bacterial pneumonia). Aggressive fluid resuscitation, leading to overhydration, might cause pulmonary edema and worsen the oxygenation. Pulmonary embolism is possible, but full anticoagulation is not warranted until embolism is documented. Use of hydroxyurea might have prevented this crisis, but it is of no value for the acute condition. (See Vij and Machado in the “Suggested Reading” list.)

5. Answer a.

Polycythemia may be secondary, as with erythropoietin- mediated causes such as chronic hypoxemia, living at high altitude, and high oxygen affinity hemoglobinopathies. Polycythemia vera is a myeloproliferative neoplasm that can manifest with arterial thrombosis secondary to hyperviscosity from the increased concentration of erythrocytes. The low erythropoietin rules out erythropoietin-mediated causes, leaving the presumptive diagnosis of polycythemia vera. With JAK2 V617F mutation testing of peripheral blood, results are positive for approximately 90% of patients who have polycythemia vera. FISH for BCR-ABL testing would screen for chronic myeloid leukemia, which does not manifest with polycythemia. Although bone marrow aspiration and biopsy would be helpful, it is not immediately necessary and could be considered later. (See Patnaik and Tefferi in the “Suggested Reading” list.)

6. Answer c.

Hematologic complications of SLE include anemia of chronic disease, pure red cell aplasia, and warm autoimmune hemolytic anemia (WAIHA). The presentation and laboratory data suggest hemolysis, and the blood smear shows spherocytes. These findings are consistent with WAIHA, which causes extravascular hemolysis. The reticulocytosis suggests that the bone marrow response is adequate. In intravascular hemolysis, the urine is positive for hemoglobin. (See Packman in the “Suggested Reading” list.)

7. Answer d.

Rheumatoid arthritis is a chronic inflammatory disorder that may lead to anemia of chronic disease. Anemia of chronic disease results from the effect of elevated cytokines on hematopoiesis, including upregulation of hepcidin, leading to increased ferritin from iron malutilization and downregulation of ferroportin, the main iron exporting system. Transferrin is also downregulated, leading to decreased TIBC and normal to decreased serum iron levels. (See Weiss and Goodnough in the “Suggested Reading” list.)

8. Answer c.

The timing and degree of thrombocytopenia are consistent with immune-mediated heparin-induced thrombocytopenia type II. Unfractioned heparin and low-molecular-weight heparin are contraindicated. Aspirin would not be the sole management agent for established thrombosis. The most appropriate step is to start a direct thrombin inhibitor.

9. Answer d.

Presentation with a vascular thrombosis and persistence of a LAC for 12 weeks or more satisfies the criteria for an antiphospholipid syndrome. This patient has a high risk for recurrent venous thrombosis on discontinuing anticoagulation; thus, long-term warfarin is recommended with periodic reassessment for safety.

10. Answer a.

DNA-based testing is reliable for patients receiving heparin or warfarin and for patients who have acute thrombosis. However, acute thrombosis and heparin can cause lower antithrombin activity results, which should be verified at another time, when heparin and acute thrombosis are not factors. A single positive test result for LAC does not confirm antiphospholipid syndrome; follow-up testing at 12-week intervals is required to demonstrate persistence of LAC. Acute thrombosis and estrogen use can lower protein S levels; thus, abnormally low results require follow-up confirmation.

11. Answer c.

Among patients randomly assigned to receive dabigatran, overall outcomes were noninferior when compared with the well-managed use of warfarin, thus providing no significant advantages. The group of patients that derived the most benefit from dabigatran was the group with INRs outside the recommended therapeutic range. Dabigatran is FDA approved only to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

12. Answer d.

Plasma exchange is the treatment of choice for thrombotic thrombocytopenic purpura (TTP). Although red blood cell transfusion may be indicated, it does not address the underlying pathogenesis of TTP. Platelets are thought to be contraindicated in TTP because of the theoretical possibility of worsening the TTP. Gamma globulin is ineffective in increasing the platelet count in TTP.

13. Answer d.

Dabigatran is cleared through the kidneys. It has a prolonged half-life in patients who have a creatinine clearance less than 30 mL/min compared with patients who have a creatinine clearance greater than 30 mL/min.

14. Answer e.

Chronic lymphocytic leukemia (CLL) is a clonal lymphoproliferative disorder of mature lymphocytes. The clinical diagnosis requires a B-lymphocyte count of more than 5×10 9 /L. Peripheral blood smears typically show smudge cells, which are lymphocytes that have broken during processing of the slide. The clinical course of CLL is chronic in most patients. For those with early-stage disease, standard practice is to withhold treatment until the disease is active or progressive. However, patients need to be monitored for disease progression, autoimmune complications, infections, and second cancers.

15. Answer e.

Hodgkin lymphoma therapy is curative in about 80% of cases. However, there are late complications of therapy, particularly in those treated before modern chemotherapy and radiotherapy. At 15 years, the risk of death from other causes surpasses that of risk of death from Hodgkin lymphoma. Patients are at higher risk of secondary malignancies, cardiovascular disease, thyroid disorders, and infertility than the general population. Many of these conditions can be attributed to chemotherapy and radiotherapy.

16. Answer d.

This patient has monoclonal gammopathy of undetermined significance (MGUS), the most common dysproteinemia. In MGUS, the M protein level is typically less than 3 g/dL, the bone marrow has less than 10% plasma cells, and the hemoglobin, creatinine, calcium, and bone radiographs are normal. The risk of progression to a lymphocytic or plasma cell malignancy is about 1% per year. Patients with an IgM or IgA monoclonal protein are at higher risk of progression than those with an IgG protein. Patients with MGUS need to be observed.

17. Answer d.

The patient has senile cardiac amyloidosis. This syndrome is usually isolated to the heart with few clinically significant deposits elsewhere, and the echocardiographic findings are often out of proportion to the degree of symptoms. Transthyretin is the protein causing the amyloid deposits; most patients have wild-type transthyretin.

18. Answer e.

With combination antibiotic therapy, 70% of gastric MALT lymphomas are cured. In cases refractory to antibiotics, tumors may carry the t(11;18) translocation, and involved field radiotherapy is effective. Combination chemotherapy is reserved for advanced disease. The majority of cases are associated with Helicobacter pylori infection.

19. Answer c.

This patient has multiple myeloma with evidence of end-organ damage from the plasma cell proliferative disorder (hypercalcemia, renal failure, anemia, and osteolytic bone lesions). The other answer choices are possible causes of hypercalcemia, but only multiple myeloma accounts for all the presenting symptoms, including the elevated level of total protein.

20. Answer a.

This patient has advanced-stage, diffuse, large B-cell lymphoma, and R-CHOP chemotherapy is the standard of care. Rituximab is an anti-CD20 monoclonal antibody that improves overall survival when added to CHOP chemotherapy for aggressive B-cell lymphomas. For patients whose disease relapses or is refractory, autologous stem cell transplant is the standard therapy. Radiotherapy can be used in combination with chemotherapy in early-stage (I-IIA) nonbulky disease but is not standard therapy for advanced disease.

Suggested Reading

Gallagher PG . Red cell membrane disorders. Hematology Am Soc Hematol Educ Program.   2005 :13–8.

Packman CH . Hemolytic anemia due to warm autoantibodies.   Blood Rev.   2008 Jan;22(1):17–31. Epub 2007 Sep 27.

Google Scholar

Patnaik MM , Tefferi A . The complete evaluation of erythrocytosis: congenital and acquired.   Leukemia.   2009 May;23(5):834–44. Epub 2009 Mar 19.

Tefferi A . Annual clinical updates in hematological malignancies : a continuing medical education series: polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2011 Mar;86(3):292–301.

Tefferi A , Vardiman JW . Myelodysplastic syndromes.   N Engl J Med.   2009 Nov 5;361(19):1872–85.

Vij R , Machado RF . Pulmonary complications of hemoglobinopathies.   Chest.   2010 Oct;138(4):973–83.

Weiss G , Goodnough LT . Anemia of chronic disease.   N Engl J Med.   2005 Mar 10;352(10):1011–23.

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Lablogatory

A blog for medical laboratory professionals

Hematology Case Study: A 20 Year Old with Anemia

Case History

A 20 year old Black male with a known history of HbS trait went to the primary care office for a pre-surgical evaluation for elective laparoscopic cholecystectomy for symptomatic cholelithiasis. All physical exam findings were negative. The patient had blood work completed and was found to have mild anemia with microcytosis. On previous imaging, the spleen was noted to be slightly enlarged. Further workup included a peripheral blood smear, finding target cells, microspherocytes, folded cells, and rod-shaped Hb C crystals (see image below). No sickled RBCs were noted.

Hemoglobin C disease is an intrinsic red cell disorder caused by Hemoglobin C (Hb C). Hb C is a variant of normal Hemoglobin A (Hb A) that results from a missense mutation in the β-globin protein, replacing the glutamic acid at position 6 with a lysine molecule. The disease can be either in the homozygous state (Hb CC) or in the heterozygous states (Hb AC or Hb SC). The origin of this mutation was traced back to West Africa and is found to confer protection against severe manifestations of malaria. In the United States, the Hb C allele is prevalent in about 1-2% of the African American population. There is an equal incidence between gender, and the incidence of the homozygous disease (i.e., Hb CC) is only 0.02%. Nevertheless, these statistics may be under-representative, since the disease is generally asymptomatic.

Heterozygous individuals with Hb AC usually show no symptoms, while homozygous individuals with Hb CC can have mild hemolytic anemia, jaundice, and splenomegaly. When Hb C is combined with other hemoglobinopathies, such as Hemoglobin S (Hb S), more serious complications can result. Hb S is similar to HbC in that it arises from a missense mutation; ie, a valine is substituted for the glutamic acid at the 6th position on the β-globin protein. As a result of this mutation, HbS abnormally polymerizes when in the presence of low oxygen tension, leaving the red blood cells (RBCs) rigid and irregularly shaped. Sickle cell disease (SCD) typically is a result of homozygous Hb S mutations (i.e., Hb SS), but the disease can also come from Hb SC.

All clinical features of Hb SS can be seen in Hb SC, including painful vaso-occlusive crises, chronic hemolytic anemia, stroke, acute chest syndrome, etc. Nevertheless, Hb SC is generally a milder disease. The complications from HbSC disease are less severe and less frequent when compared to Hb SS. Fortunately, unlike those with Hb SS disease, patients with Hb SC disease do not experience autosplenectomy, but they can develop splenomegaly. There are two complications that occur in HbSC disease occur more frequently than in HbSS disease, and they include proliferative sickle cell retinopathy and avascular necrosis of the femoral head (the latter case presents especially in peripartum women). Therefore, patients with HbSC disease should follow up with ophthalmology and obstetrics to monitor these complications. Furthermore, patients with Hb SC disease can vary in the severity of symptoms and the resulting complications. For example, some patients may develop a severe anemia and require blood transfusions; whereas, other patients are minimally affected by the disease. Overall, patients with Hb SC disease tend to have a better life expectancy compared to those with Hb SS disease. Patients with Hb SS disease have an average life expectancy of 40 years, while those with Hb SC disease are expected to live into their 60s and 70s. In contrast to Hb SS and Hb SC disease, Hb CC disease does not have an increase in mortality. As mentioned earlier, Hb CC disease results only in mild anemia, asymptomatic splenomegaly, and largely absent clinical symptoms.

Pathologic features of Hb SC and Hb CC diseases can be seen on a peripheral blood smear (PBS). Hb CC disease does not show sickled RBCs, while Hb SC can show sickled RBCs though very rarely. More importantly, Hb C is prone to polymerize into characteristic crystals. Depending on the zygosity of the individual, the crystals take on a defining shape. In heterozygous individuals (Hb SC), the crystals are found as irregular, amorphous, or bent appearing, and the RBCs can take on a “spiked and hooked” appearance. In homozygous individuals (Hb CC), the crystals are elongate, straight, and uniformly dense (as seen in the case above). In addition to crystals, the PBS shows numerous target cells, scattered folded cells, and microspherocytes.

Ancillary studies for diagnosis of these diseases include Hb variant analysis, such as electrophoresis and high-pressure liquid chromatography. Cellulose acetate (alkaline) electrophoresis is a standard method used to separate Hb A, Hb A 2 , Hb F, Hb C, Hb S, and other variants according to charge. Some hemoglobin variants comigrate using this described method, so citrate agar (acid) electrophoresis can be used additionally to distinguish between these variants. In Hb CC disease, analysis shows nearly all Hb C with small amounts of Hb F (i.e., fetal hemoglobin) and HbA 2 (i.e., a normal variant of Hb A, in which the hemoglobin molecule is made up of 2 α chains and 2 δ chains). In Hb SC disease, analysis demonstrates almost equal amounts of Hb S and Hb C.

• Aster JC, Pozdnyakova O, Kutok JL. Hematopathology: A Volume in the High Yield Pathology Series. Philadelphia, PA: Saunders, an imprint of Elsevier Inc.; 2013.
• Gao J, Monaghan SA. Hematopathology. Chapter 1: Red Blood Cell/Hemoglobin Disorders. 3rd edition. Philadelphia, PA: Elsevier; 2018.
• Karna B, Jha SK, Al Zaabi E. Hemoglobin C Disease. 2020 Jun 9. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. PMID: 32644469.
• Mitton BA. Hemoglobin C Disease. Medscape, 9 Nov. 2019, emedicine.medscape.com/article/200853-overview.
• Saunthararajah Y, Vichinsky EP. Hematology: Basic Principles and Practice. Chapter 42: Sickle Cell Disease: Clinical Features and Management. Philadelphia, PA: Elsevier; 2018.

-Amy Brady is a 4th-year medical student at the Philadelphia College of Osteopathic Medicine. She is currently applying to AP/CP pathology residency programs. Follow her on Twitter @amybrady517.

-Kamran Mirza, MD PhD is an Associate Professor of Pathology and Laboratory Medicine and Medical Education, and the Vice-Chair of Education in the Department of Pathology at Loyola University Chicago Stritch School of Medicine. Follow him on Twitter @KMirza.

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• Open access
• Published: 22 April 2024

The influence of maternal prepregnancy weight and gestational weight gain on the umbilical cord blood metabolome: a case–control study

• Xianxian Yuan   ORCID: orcid.org/0000-0001-8762-8471 1 ,
• Yuru Ma 1 ,
• Jia Wang 2 ,
• Yan Zhao 1 ,
• Wei Zheng 1 ,
• Ruihua Yang 1 ,
• Lirui Zhang 1 ,
• Xin Yan 1 &
• Guanghui Li   ORCID: orcid.org/0000-0003-2290-1515 1  

BMC Pregnancy and Childbirth volume  24 , Article number:  297 ( 2024 ) Cite this article

63 Accesses

Metrics details

Maternal overweight/obesity and excessive gestational weight gain (GWG) are frequently reported to be risk factors for obesity and other metabolic disorders in offspring. Cord blood metabolites provide information on fetal nutritional and metabolic health and could provide an early window of detection of potential health issues among newborns. The aim of the study was to explore the impact of maternal prepregnancy overweight/obesity and excessive GWG on cord blood metabolic profiles.

A case control study including 33 pairs of mothers with prepregnancy overweight/obesity and their neonates, 30 pairs of mothers with excessive GWG and their neonates, and 32 control mother-neonate pairs. Untargeted metabolomic profiling of umbilical cord blood samples were performed using UHPLC‒MS/MS.

Forty-six metabolites exhibited a significant increase and 60 metabolites exhibited a significant reduction in umbilical cord blood from overweight and obese mothers compared with mothers with normal body weight. Steroid hormone biosynthesis and neuroactive ligand‒receptor interactions were the two top-ranking pathways enriched with these metabolites ( P  = 0.01 and 0.03, respectively). Compared with mothers with normal GWG, in mothers with excessive GWG, the levels of 63 metabolites were increased and those of 46 metabolites were decreased in umbilical cord blood. Biosynthesis of unsaturated fatty acids was the most altered pathway enriched with these metabolites ( P  < 0.01).

Conclusions

Prepregnancy overweight and obesity affected the fetal steroid hormone biosynthesis pathway, while excessive GWG affected fetal fatty acid metabolism. This emphasizes the importance of preconception weight loss and maintaining an appropriate GWG, which are beneficial for the long-term metabolic health of offspring.

Peer Review reports

The obesity epidemic is an important public health problem in developed and developing countries [ 1 ] and is associated with the emergence of chronic noncommunicable diseases, including type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), and cancer [ 2 , 3 , 4 ]. Maternal obesity is the most common metabolic disturbance in pregnancy, and the prevalence of obesity among women of childbearing age is 7.1% ~ 31.9% in some countries [ 5 ]. In China, the prevalence of overweight and obesity has also increased rapidly in the past four decades. Based on Chinese criteria, the latest national prevalence estimates for 2015–2019 were 34.3% for overweight and 16.4% for obesity in adults (≥ 18 years of age) [ 6 ].

Increasing evidence implicates overnutrition in utero as a major determinant of the health of offspring during childhood and adulthood, which is compatible with the developmental origins of health and disease (DOHaD) framework [ 7 ]. Maternal obesity and excessive gestational weight gain (GWG) are important risk factors for several adverse maternal outcomes, including gestational diabetes and hypertensive disorders, fetal death, and preterm birth [ 8 , 9 , 10 ]. More importantly, they have negative implications for offspring, both perinatally and later in life. Evidence from cohort studies focusing on offspring development confirms the relationship between maternal obesity/excessive GWG and offspring obesity programming [ 11 , 12 , 13 ]. Currently, there is no unified mechanism to explain the adverse outcomes associated with maternal obesity and excessive GWG, which may be the independent and interactive effects of the obese maternal phenotype itself and the diet associated with this phenotype. In addition to genetic and environmental factors, metabolic programming may also lead to the intergenerational transmission of obesity through epigenetic mechanisms.

Metabolomics, which reflects the metabolic phenotype of human subjects and animals, is the profiling of metabolites in biofluids, cells and tissues using high-throughput platforms, such as mass spectrometry. It has unique potential in identifying biomarkers for predicting occurrence, severity, and progression of diseases, as well as exploring underlying mechanistic abnormalities [ 14 , 15 ]. Umbilical cord metabolites can provide information about fetal nutritional and metabolic health, and may provide an early window for detection of potential health issues in newborns [ 16 ]. Previous studies have reported differences in umbilical cord metabolite profiles associated with maternal obesity [ 17 , 18 ]. However, the results were inconsistent due to differences in sample sizes, ethnicity and region, and mass spectrometry. In addition, most studies have not considered the difference in the effects of prepregnancy body mass index (BMI) and GWG on cord blood metabolites.

To investigate the relationship between early metabolic programming and the increased incidence of metabolic diseases in offspring, we studied the associations between elevated prepregnancy BMI/excessive GWG and umbilical cord metabolic profiles. Another purpose of this study was to explore whether there were differences in the effects of prepregnancy overweight/obesity and excessive GWG on cord blood metabolites.

Study population

This was a hospital-based, case control study that included singleton pregnant women who received prenatal care and delivered vaginally at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, from January 2022 to March 2022. We selected 33 pregnant women with a prepregnancy BMI ≥ 24.0 kg/m 2 regardless of their gestational weight gain as the overweight/obese group, 30 pregnant women with a prepregnancy BMI of 18.5–23.9 kg/m 2 and a GWG > 14.0 kg as the excessive GWG group, and 32 pregnant women with a BMI of 18.5–23.9 kg/m 2 and a GWG of 8.0–14.0 kg as the control group. The ages of the three groups were matched (± 1.0 years), and the prepregnancy BMIs of the excessive GWG and control groups were matched (± 1.0 kg/m 2 ).

The inclusion criteria were women with singleton pregnancies, those aged between 20 and 45 years, those with full-term delivery (gestational age ≥ 37 weeks), those with a prepregnancy BMI ≥ 18.5 kg/m 2 , those without prepregnancy diabetes mellitus (DM) or hypertension, and those without gestational diabetes mellitus (GDM). The exclusion criteria were women with multiple pregnancies, those less than 20 years or more than 45 years old, those with a prepregnancy BMI < 18.5 kg/m 2 , those with prepregnancy DM, hypertension or GDM, and those without cord blood samples.

We classified pregnant women into BMI categories based on Chinese guidelines [ 19 ]: normal weight (prepregnancy BMI 18.5–23.9 kg/m 2 ), overweight (prepregnancy BMI 24.0–27.9 kg/m 2 ), and obese (prepregnancy BMI ≥ 28.0 kg/m 2 ). GWG guideline concordance was defined by the 2021 Chinese Nutrition Society recommendations according to prepregnancy BMI. The upper limits of GWG for normal weight, overweight, and obesity were 14.0 kg, 11.0 kg, and 9.0 kg, respectively.

Ethical approval and written informed consent were obtained from all participants. The study has been performed according to the Declaration of Helsinki, and the procedures have been approved by the ethics committees of Beijing Obstetrics and Gynecology Hospital, Capital Medical University (2021-KY-037).

Sample and data collection

Maternal and neonatal clinical data were collected from the electronic medical records system of Beijing Obstetrics and Gynecology Hospital. Maternal clinical characteristics included age, height, prepregnancy and predelivery weight, education level, smoking and drinking status during pregnancy, parity, conception method, comorbidities and complications of pregnancy, family history of DM and hypertension, gestational age, mode of delivery, and biochemical results during pregnancy. Prepregnancy BMI was calculated as prepregnancy weight in kilograms divided by the square of height in meters. GWG was determined by subtracting the prepregnancy weight in kilograms from the predelivery weight in kilograms. GDM was defined using the IAPDSG’s diagnostic criteria at 24 to 28 +6  weeks gestation and the fasting glucose and 1- and 2-h glucose concentrations at the time of the oral glucose tolerance test (OGTT). Neonatal clinical characteristics included sex, birth weight and length. Macrosomia was defined as a birth weight of 4,000 g or more [ 20 ]. Low birth weight (LBW) was defined as a birth weight less than 2,500 g [ 21 ].

Umbilical cord blood samples were obtained by trained midwives after clamping the cord at delivery. Whole blood samples were collected in EDTA tubes, refrigerated for < 24 h, and centrifuged at 2,000 r.p.m. at 4 ℃ for 10 min. Plasma aliquots were stored at -80 ℃ until shipment on dry ice to Novogene, Inc. (Beijing, China) for untargeted metabolomic analysis.

Untargeted metabolomic analyses

Ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC‒MS/MS) analyses were performed using a Vanquish UHPLC system (Thermo Fisher, Germany) coupled with an Orbitrap Q Exactive™ HF mass spectrometer (Thermo Fisher, Germany) at Novogene Co., Ltd. (Beijing, China). Detailed descriptions of the sample preparation, mass spectrometry and automated metabolite identification procedures are described in the Supplementary materials .

Statistical analysis

Clinical data statistical analysis.

Quantitative data are shown as the mean ± standard deviation (SD) or median (interquartile range), and categorical data are presented as percentages. The Mann‒Whitney U test, chi-square test, and general linear repeated-measures model were used to assess the differences between the control and study groups when appropriate. A P value < 0.05 was considered statistically significant. All analyses were performed using Statistical Package of Social Sciences version 25.0 (SPSS 25.0) for Windows (SPSS Inc).

Umbilical cord metabolome statistical analysis

These metabolites were annotated using the Human Metabolome Database (HMDB) ( https://hmdb.ca/metabolites ), LIPIDMaps database ( http://www.lipidmaps.org/ ), and Kyoto Encylopaedia of Genes and Genomes (KEGG) database ( https://www.genome.jp/kegg/pathway.html ). Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) were performed at metaX. We applied univariate analysis ( T test) to calculate the statistical significance ( P value). Metabolites with a variable importance for the projection (VIP) > 1, a P value < 0.05 and a fold change (FC) ≥ 2 or FC ≤ 0.5 were considered to be differential metabolites. A false discovery rate (FDR) control was implemented to correct for multiple comparisons. The q -value in the FDR control was defined as the FDR analog of the P -value. In this study, the q -value was set at 0.2. For clustering heatmaps, the data were normalized using z scores of the intensity areas of differential metabolites and were plotted by the Pheatmap package in R language.

The correlations among differential metabolites were analyzed by cor () in R language (method = Pearson). Statistically significant correlations among differential metabolites were calculated by cor.mtest () in R language. A P value < 0.05 was considered statistically significant, and correlation plots were plotted by the corrplot package in R language. The functions of these metabolites and metabolic pathways were studied using the KEGG database. The metabolic pathway enrichment analysis of differential metabolites was performed when the ratio was satisfied by x/n > y/N, and the metabolic pathway was considered significantly enriched when P  < 0.05.

Demographic characteristics of study participants

The demographic and clinical characteristics of the three population groups enrolled in the study are summarized in Table  1 . Mothers had no significant difference regarding their ages or gestational ages. Compared to the mothers in the excessive GWG and control groups, those in the prepregnancy overweight/obesity group had a significantly higher prepregnancy BMI (25.6 (24.5, 27.2) kg/m 2 ). However, there was no significant difference in prepregnancy BMI between mothers in the excessive GWG group (20.3 ± 1.2 kg/m 2 ) and mothers in the control group (20.6 ± 1.5 kg/m 2 ). Mothers in the excessive GWG group had the highest GWG (17.0 (15.5, 19.1) kg) among the three groups. The mean GWG of the mothers in the prepregnancy overweight/obesity group was 12.9 ± 3.8 kg, which was similar to that of the control group (11.8 ± 1.5 kg). It was noteworthy that among the 33 prepregnancy overweight/obese pregnant women, 20 of them had appropriate GWG, 1 had insufficient GWG, and 12 had excessive GWG. The proportion of mothers who underwent invitro fertilization and embryo transfer (IVF-ET) in the prepregnancy overweight/obesity group (15.2%) was significantly higher than that in the excessive GWG and control groups. There were no statistically significant differences in the proportions of pregnancy outcomes among the three groups, including preeclampsia, premature rupture of membranes, postpartum hemorrhage, macrosomia, and LBW. The babies in the three groups showed no significant difference regarding their birth weights or lengths.

The biochemical parameters of the mothers during pregnancy are shown in Table  2 . The levels of triglyceride (TG) and uric acid (UA) of mothers in the prepregnancy overweight/obesity group were significantly higher than those of the mothers in the excessive GWG and control groups in the first trimester. However, there was no significant difference in the blood glucose and lipid levels in the second and third trimesters of pregnancy among the three groups.

PCA and PLS-DA analysis of cord blood metabolites

Functional and taxonomic annotations of the identified metabolites included the HMDB classification annotations, LIPID MAPS classification annotations, and KEGG pathway annotations. Those cord blood metabolites included lipids and lipid-like molecules, organic acids and their derivatives, and organoheterocyclic compounds, which were mainly involved in metabolism. To better understand the structure of the cord blood metabolome in cases versus controls, we used unsupervised PCA to identify metabolites contributing the most to observed differences in the dataset. PCA did not clearly separate the three groups. We next used PLS-DA to identify metabolites that were predictive of case versus control status. PLS-DA clearly distinguished the cases from the controls (Fig.  1 ), the prepregnancy overweight/obesity group vs. the control group (R2Y = 0.82, Q2Y = 0.37; R2Y = 0.77, Q2Y = 0.13, respectively) (Fig.  1 A), and the excessive GWG group vs. the control group (R2Y = 0.76, Q2Y = 0.16; R2Y = 0.81, Q2Y = 0.41) (Fig.  1 B).

PLS-DA of identified cord blood metabolites. A the prepregnancy overweight/obesity group vs. the control group; B the excessive GWG group vs. the control group. (a) PLS-DA score. The horizontal coordinates are the score of the sample on the first principal component; the longitudinal coordinates are the score of the sample on the second principal component; R2Y represents the interpretation rate of the model, and Q2Y is used to evaluate the predictive ability of the PLS-DA model, and when R2Y is greater than Q2Y, it means that the model is well established. (b) PLS-DA valid. Horizontal coordinates represent the correlation between randomly grouped Y and the original group Y, and vertical coordinates represent the scores of R2 and Q2. (1) POS, positive metabolites; (2) NEG, negative metabolites

Maternal prepregnancy overweight/obesity

Screening differential metabolites according to a PLS-DA VIP > 1.0, a FC > 1.2 or < 0.833 and a P value < 0.05, a total of 106 cord blood metabolites (77 positive metabolites and 29 negative metabolites) differed between the prepregnancy overweight/obesity group and the control group. Compared with those in the control group, the levels of 46 metabolites (19 positive metabolites and 27 negative metabolites) were increased in the prepregnancy overweight/obesity group, among which octopamine was the metabolite with the largest increase, followed by (2S)-4-Oxo-2-phenyl-3,4-dihydro-2H-chromen-7-yl beta-D-glucopyranoside, N-tetradecanamide, stearamide, and methanandamide (Fig.  2 A). Compared with the control group, in the prepregnancy overweight/obesity group, there were 60 metabolites (58 positive metabolites and 2 negative metabolites) with reduced concentrations, among which senecionine was the metabolite with the largest decrease, followed by 3-(methylsulfonyl)-2H-chromen-2-one, methyl EudesMate, cuminaldehyde, and 2-(tert-butyl)-1,3-thiazolane-4-carboxylic acid (Fig.  2 A).

Stem plots of differential cord blood metabolites. A the prepregnancy overweight/obesity group vs. the control group; B the excessive GWG group vs. the control group. (1) positive metabolites; (2) negative metabolites. Notes: The color of the dot in the stem plots represents the upward and lower adjustment, the blue represents downward, and the red represents upward. The length of the rod represents the size of log2 (FC), and the size of the dot represents the size of the VIP value

A hierarchical analysis of the two groups of differential metabolites obtained was carried out, and the difference in metabolic expression patterns between the two groups and within the same comparison was obtained, which is shown in Fig.  3 . KEGG pathway analysis of differential cord blood metabolites associated with the prepregnancy overweight/obesity group versus the control group is shown in Table  3 and Fig.  4 A. The metabolite enrichment analysis revealed that steroid hormone biosynthesis ( P value = 0.01) and neuroactive ligand‒receptor interactions ( P value = 0.03) were the two pathways that were most altered between the prepregnancy overweight/obesity group and the control group. 19 metabolites were distributed in the pathway of steroid hormone biosynthesis, and 4 metabolites were distributed in the pathway of neuroactive ligand‒receptor interactions. In the steroid hormone biosynthesis pathway, the levels of corticosterone, 11-deoxycortisol, cortisol, testosterone, and 7α-hydroxytestosterone were decreased in the prepregnancy overweight/obesity group relative to those in the control group. In the neuroactive ligand‒receptor interaction pathway, the level of cortisol was decreased and the levels of trace amines were increased in the prepregnancy overweight/obesity group relative to the control group.

Clustering heat maps of differential cord blood metabolites of the three groups. A positive metabolites; B negative metabolites. Notes: Longitudinal clustering of samples and trans-verse clustering of metabolites. The shorter the clustering branches, the higher the similarity. Through horizontal comparison, we can see the relationship between groups of metabolite content clustering

KEGG enrichment scatterplots (a) and net (b) of differential cord blood metabolites. A the prepregnancy overweight/obesity group vs. the control group; B the excessive GWG group vs. the control group. (1) positive metabolites; (2) negative metabolites. Notes: (a) The horizontal co-ordinates in the figure are x/y (the number of differential metabolites in the corresponding metabolic pathway/the total number of total metabolites identified in this pathway). The value represents the enrichment degree of differential metabolites in the pathway. The color of the point rep-resents the P -value of the hypergeometric test, and the size of the point represents the number of differential metabolites in the corresponding pathway. (b) The red dot represents a metabolic pathway, the yellow dot represents a substance-related regulatory enzyme information, the green dot represents the background substance of a metabolic pathway, the purple dot represents the molecular module information of a class of substances, the blue dot represents a substance chemical reaction, and the green square represents the differential substance obtained by this comparison

Maternal excessive GWG

A total of 109 cord blood metabolites (52 positive metabolites and 57 negative metabolites) differed between the excessive GWG group and the control group. Compared with the control group, in the excessive GWG group, there were 63 metabolites (15 positive metabolites and 48 negative metabolites) with increased concentrations, among which 2-thio-acetyl MAGE was the metabolite with the largest increase, followed by PC (7:0/8:0), lysopc 16:2 (2 N isomer), MGMG (18:2), and thromboxane B2 (Fig.  2 B). Compared with the levels in the control group, the levels of 46 metabolites (37 positive metabolites and 9 negative metabolites) in the excessive GWG group were reduced, among which hippuric acid had the largest decrease, followed by 8-hydroxyquinoline, gamithromycin, 2-phenylglycine, and cefmetazole (Fig.  2 B).

A hierarchical analysis of differential metabolites obtained in the two groups was carried out, and the difference in metabolic expression patterns between the two groups and within the same comparison was obtained, which is shown in Fig.  3 . KEGG pathway analysis of the cord blood metabolites associated with the excessive GWG group versus the control group is shown in Table  4 and Fig.  4 B. The metabolite enrichment analysis revealed that biosynthesis of unsaturated fatty acids was the most altered pathway between the excessive GWG and control groups ( P value < 0.01). There were 13 metabolites distributed in the enriched pathway. The levels of docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), arachidonic acid, adrenic acid, palmitic acid, stearic acid, behenic acid, lignoceric acid, and erucic acid were increased in the excessive GWG group relative to those in the control group.

Our present study found that both maternal prepregnancy overweight/obesity and excessive GWG could affect umbilical cord blood metabolites, and they had different effects on these metabolites. Regardless of their gestational weight gain, the umbilical cord blood of prepregnancy overweight and obese mothers had 46 metabolites increased and 60 metabolites decreased compared with the umbilical cord blood of mothers with normal body weight and appropriate GWG. Steroid hormone biosynthesis and neuroactive ligand‒receptor interactions were the two top-ranking pathways enriched with these metabolites. Compared with mothers with normal prepregnancy BMI and appropriate GWG, in mothers with normal prepregnancy BMI but excessive GWG, the levels of 63 metabolites were increased and those of 46 metabolites were decreased in umbilical cord blood. Biosynthesis of unsaturated fatty acids was the most altered pathway enriched with these metabolites.

There were many differential metabolites in the cord blood between the prepregnancy overweight/obesity group and the control group and between the excessive GWG group and the control group. However, the roles of most of these differential metabolites are unknown. The levels of stearamide and methanandamide were increased in the prepregnancy overweight/obesity group. Stearamide, also known as octadecanamide or kemamide S, belongs to the class of organic compounds known as carboximidic acids. Stearamide, which is increased in the serum of patients with hepatic cirrhosis and sepsis, may be associated with the systemic inflammatory state [ 22 , 23 ]. Methanandamide is a stable analog of anandamide that participates in energy balance mainly by activating cannabinoid receptors. Methanandamide dose-dependently inhibits and excites tension-sensitive gastric vagal afferents (GVAs), which play a role in appetite regulation [ 24 ]. In mice fed a high-fat diet, only an inhibitory effect of methanandamide was observed, and GVA responses to tension were dampened [ 24 , 25 ]. These changes may contribute to the development and/or maintenance of obesity. Moreover, methanandamide can produce dose-related hypothermia and attenuate cocaine-induced hyperthermia by a cannabinoid 1-dopamine D2 receptor mechanism [ 26 ].

Metabolomic pathway analysis of the cord blood metabolite features in the prepregnancy overweight and obesity group identified two filtered significant pathways: steroid hormone biosynthesis and neuroactive ligand‒receptor interaction pathways. In the steroid hormone biosynthesis pathway, the levels of several glucocorticoids (including corticosterone, 11-deoxycortisol, cortisol, testosterone, and 7α-hydroxytestosterone) were decreased in the prepregnancy overweight/obesity group. In addition to the physiological role of glucocorticoids in the healthy neuroendocrine development and maturation of fetuses and babies, glucocorticoids are essential to human health by regulating different physiological events in mature organs and tissues, such as glucose metabolism, lipid biosynthesis and distribution, food intake, thermogenesis, and mood and learning patterns [ 27 ]. Glucocorticoids have been considered as a link between adverse early-life conditions and the development of metabolic disorders in later life [ 28 , 29 , 30 ]. However, there is still much controversy regarding the role of maternal obesity in the fetal–steroid hormone biosynthesis pathway. Studies of maternal obesity animal models showed that corticosterone and cortisol levels were increased in the offspring of obese mothers [ 31 , 32 ]. A study reported by Satu M Kumpulainen et al. showed that young adults born to mothers with higher early pregnancy BMIs show lower average levels of diurnal cortisol, especially in the morning [ 33 ]. Laura I. Stirrat et al. found that increased maternal BMI was associated with lower maternal cortisol, corticosterone, and 11-dehydrocorticosterone levels. However, there were no associations between maternal BMI and glucocorticoid levels in the cord blood [ 34 ]. The differences in the study protocols of these previous studies may explain the mixed findings, such as cortisol measured from peripheral blood, cord blood or saliva; variation in measurement time points; the number of samples. Although the effect of maternal obesity on fetal steroid hormone levels is controversial, dysregulation of glucocorticoids may be a plausible mechanism by which maternal obesity can increase the risk of metabolic disorders and mental health disorders in offspring.

The effect of excessive GWG on umbilical cord blood metabolites is different from that of maternal overweight and obesity. Compared with the control group, in the excessive GWG group, the level of thromboxane B2 was increased and the level of hippuric acid was decreased. Thromboxane B2, which is important in the platelet release reaction, is a stable, physiologically active compound formed in vivo from prostaglandin endoperoxides. Hippuric acid is an acyl glycine formed from the conjugation of benzoic acid with glycine. Several studies have confirmed that both thromboxane B2 and hippuric acid levels are associated with diet. Dietary fatty acids affect platelet thromboxane production [ 35 , 36 , 37 ]. In our study, several fatty acids (e.g., palmitic acid, stearic acid, behenic acid, and lignoceric acid) in the excessive GWG group were also increased, which may have led to the increase in thromboxane B2 levels. Hippuric acid can be detected after the consumption of whole grains and anthocyanin-rich bilberries [ 38 , 39 ]. A healthy diet intervention increased the signals for hippuric acid to incorporate polyunsaturated fatty acids [ 38 ], and the low level of hippuric acid was associated with lower fruit-vegetable intakes [ 39 ]. Maternal overnutrition and unhealthy dietary patterns are the main reasons for excessive GWG [ 40 , 41 ]. Therefore, we speculated that the differences in thromboxane B2 and hippuric acid between the excessive GWG and control groups were associated with maternal diet during pregnancy. The effect of these differential metabolites on the long-term metabolic health of offspring after birth needs further study.

Metabolomic pathway analysis of the cord blood metabolite features in the excessive GWG group identified that biosynthesis of unsaturated fatty acids was the filtered significant pathway. The levels of several fatty acids in this pathway were increased in the excessive GWG group, including long-chain saturated fatty acids (e.g., palmitic acid (C 16:0), stearic acid (C 18:0), behenic acid (C 22:0), and lignoceric acid (C 23:0)), monounsaturated fatty acids (erucic acid), and polyunsaturated fatty acids (e.g., DPA, DHA, arachidonic acid, and adrenic acid). Because perinatal fatty acid status can be influenced by maternal dietary modifications or supplementation [ 42 ], we speculated that maternal diet during pregnancy caused the difference in umbilical cord blood fatty acids between the excessive GWG and control groups. A large body of evidence from mechanistic studies supports the potential of fatty acids to influence later obesity. However, the possible mechanisms and observed relationships are complex and related to the types and patterns of fatty acids [ 43 , 44 ]. Maternal dietary fatty acids have been found to induce hypothalamic inflammation, cause epigenetic changes, and alter the mechanisms of energy control in offspring [ 43 ]. Evidence from cell culture and rodent studies showed that polyunsaturated fatty acids might serve several complex roles in fetuses, including the stimulation and/or inhibition regulation of adipocyte differentiation [ 44 ]. The questions of whether lower n-6 long-chain polyunsaturated fatty acid levels or higher n-3 long-chain polyunsaturated fatty acid levels are of more relevance and whether the long-term effects differ with different offspring ages remain [ 44 ]. Although there is a biologically plausible case for the relevance of perinatal fatty acid status in later obesity risk, available data in humans suggest that the influence of achievable modification of perinatal n-3/n-6 status is not sufficient to influence offspring obesity risk in the general population [ 45 ]. Further studies seem justified to clarify the reasons.

The advantage of our present study is that we simultaneously analyzed the effects of prepregnancy overweight/obesity and excessive GWG on cord blood metabolites and explored their differences. In addition, to exclude the effect of hyperglycemia on cord blood metabolites, both women with prepregnancy diabetes mellitus and gestational diabetes mellitus were excluded from our study. The limitation of our study is that it was a single-center study with a small sample, especially in the prepregnancy overweight/obesity group. In the future, we can expand the sample size and conduct a subgroup analysis of the prepregnancy overweight/obesity group and analyze the differences in the effects of different degrees of obesity on cord blood metabolites. The prepregnancy overweight/obesity group can be further divided into an appropriate GWG group and an excessive GWG group, and the differences in the effects of these two groups on umbilical cord blood metabolites can be analyzed. Moreover, the dietary pattern of the pregnant woman could affect the production of cord blood metabolites. We did not investigate the dietary patterns of the mothers in this study, which is another limitation of this study. In future studies, we should investigate maternal dietary patterns as a very important confounding variable.

In conclusion, our present study confirmed that both prepregnancy overweight/obesity and excessive GWG could affect umbilical cord blood metabolites, and they had different effects on these metabolites. Prepregnancy overweight and obesity affected the fetal steroid hormone biosynthesis pathway, while normal prepregnancy body weight but excessive GWG affected fetal fatty acid metabolism. This emphasizes the importance of preconception weight loss and maintaining an appropriate GWG, which are beneficial for the long-term metabolic health of offspring.

Availability of data and materials

Data sets generated during the current study are not publicly available but will be available from the corresponding author at a reasonable request. Responses to the request for the raw data will be judged by a committee including XXY and GHL.

Abbreviations

Excessive gestational weight gain

Ultrahigh-performance liquid chromatography tandem mass spectrometry

Type 2 diabetes mellitus

Nonalcoholic fatty liver disease

The developmental origins of health and disease

Body mass index

Diabetes mellitus

Gestational diabetes mellitus

Oral glucose tolerance test

Low birth weight

Standard deviation

The Human Metabolome Database

Kyoto Encylopaedia of Genes and Genomes

Principal component analysis

Partial least-squares discriminant analysis

Importance for the projection

Fold change

Invitro fertilization and embryo transfer

Triglyceride

Docosapentaenoic acid

Docosahexaenoic acid

Gastric vagal afferents

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Acknowledgements

The authors thank the study participants for their involvement and research assistants for their help conducting the study.

This research was funded by the Beijing Natural Science Foundation, grant number 7214231.

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Xianxian Yuan, Yuru Ma, Yan Zhao, Wei Zheng, Ruihua Yang, Lirui Zhang, Xin Yan & Guanghui Li

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XXY designed the study. XXY, WZ, LRZ and XY analyzed the data. YRM, JW, YZ and RHY took part in data collection and management. XXY wrote the manuscript. XXY and GHL reviewed the manuscript and contributed to manuscript revision. All authors contributed to the article and approved the submitted version. All authors reviewed the manuscript.

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Yuan, X., Ma, Y., Wang, J. et al. The influence of maternal prepregnancy weight and gestational weight gain on the umbilical cord blood metabolome: a case–control study. BMC Pregnancy Childbirth 24 , 297 (2024). https://doi.org/10.1186/s12884-024-06507-x

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Artificial intelligence and medical education: application in classroom instruction and student assessment using a pharmacology & therapeutics case study

• Kannan Sridharan 1 &
• Reginald P. Sequeira 1  

BMC Medical Education volume  24 , Article number:  431 ( 2024 ) Cite this article

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Artificial intelligence (AI) tools are designed to create or generate content from their trained parameters using an online conversational interface. AI has opened new avenues in redefining the role boundaries of teachers and learners and has the potential to impact the teaching-learning process.

In this descriptive proof-of- concept cross-sectional study we have explored the application of three generative AI tools on drug treatment of hypertension theme to generate: (1) specific learning outcomes (SLOs); (2) test items (MCQs- A type and case cluster; SAQs; OSPE); (3) test standard-setting parameters for medical students.

Analysis of AI-generated output showed profound homology but divergence in quality and responsiveness to refining search queries. The SLOs identified key domains of antihypertensive pharmacology and therapeutics relevant to stages of the medical program, stated with appropriate action verbs as per Bloom’s taxonomy. Test items often had clinical vignettes aligned with the key domain stated in search queries. Some test items related to A-type MCQs had construction defects, multiple correct answers, and dubious appropriateness to the learner’s stage. ChatGPT generated explanations for test items, this enhancing usefulness to support self-study by learners. Integrated case-cluster items had focused clinical case description vignettes, integration across disciplines, and targeted higher levels of competencies. The response of AI tools on standard-setting varied. Individual questions for each SAQ clinical scenario were mostly open-ended. The AI-generated OSPE test items were appropriate for the learner’s stage and identified relevant pharmacotherapeutic issues. The model answers supplied for both SAQs and OSPEs can aid course instructors in planning classroom lessons, identifying suitable instructional methods, establishing rubrics for grading, and for learners as a study guide. Key lessons learnt for improving AI-generated test item quality are outlined.

Conclusions

AI tools are useful adjuncts to plan instructional methods, identify themes for test blueprinting, generate test items, and guide test standard-setting appropriate to learners’ stage in the medical program. However, experts need to review the content validity of AI-generated output. We expect AIs to influence the medical education landscape to empower learners, and to align competencies with curriculum implementation. AI literacy is an essential competency for health professionals.

Peer Review reports

Artificial intelligence (AI) has great potential to revolutionize the field of medical education from curricular conception to assessment [ 1 ]. AIs used in medical education are mostly generative AI large language models that were developed and validated based on billions to trillions of parameters [ 2 ]. AIs hold promise in the incorporation of history-taking, assessment, diagnosis, and management of various disorders [ 3 ]. While applications of AIs in undergraduate medical training are being explored, huge ethical challenges remain in terms of data collection, maintaining anonymity, consent, and ownership of the provided data [ 4 ]. AIs hold a promising role amongst learners because they can deliver a personalized learning experience by tracking their progress and providing real-time feedback, thereby enhancing their understanding in the areas they are finding difficult [ 5 ]. Consequently, a recent survey has shown that medical students have expressed their interest in acquiring competencies related to the use of AIs in healthcare during their undergraduate medical training [ 6 ].

Pharmacology and Therapeutics (P & T) is a core discipline embedded in the undergraduate medical curriculum, mostly in the pre-clerkship phase. However, the application of therapeutic principles forms one of the key learning objectives during the clerkship phase of the undergraduate medical career. Student assessment in pharmacology & therapeutics (P&T) is with test items such as multiple-choice questions (MCQs), integrated case cluster questions, short answer questions (SAQs), and objective structured practical examination (OSPE) in the undergraduate medical curriculum. It has been argued that AIs possess the ability to communicate an idea more creatively than humans [ 7 ]. It is imperative that with access to billions of trillions of datasets the AI platforms hold promise in playing a crucial role in the conception of various test items related to any of the disciplines in the undergraduate medical curriculum. Additionally, AIs provide an optimized curriculum for a program/course/topic addressing multidimensional problems [ 8 ], although robust evidence for this claim is lacking.

The existing literature has evaluated the knowledge, attitude, and perceptions of adopting AI in medical education. Integration of AIs in medical education is the need of the hour in all health professional education. However, the academic medical fraternity facing challenges in the incorporation of AIs in the medical curriculum due to factors such as inadequate grounding in data analytics, lack of high-quality firm evidence favoring the utility of AIs in medical education, and lack of funding [ 9 ]. Open-access AI platforms are available free to users without any restrictions. Hence, as a proof-of-concept, we chose to explore the utility of three AI platforms to identify specific learning objectives (SLOs) related to pharmacology discipline in the management of hypertension for medical students at different stages of their medical training.

Study design and ethics

The present study is observational, cross-sectional in design, conducted in the Department of Pharmacology & Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Kingdom of Bahrain, between April and August 2023. Ethical Committee approval was not sought given the nature of this study that neither had any interaction with humans, nor collection of any personal data was involved.

Study procedure

We conducted the present study in May-June 2023 with the Poe© chatbot interface created by Quora© that provides access to the following three AI platforms:

Sage Poe [ 10 ]: A generative AI search engine developed by Anthropic © that conceives a response based on the written input provided. Quora has renamed Sage Poe as Assistant © from July 2023 onwards.

Claude-Instant [ 11 ]: A retrieval-based AI search engine developed by Anthropic © that collates a response based on pre-written responses amongst the existing databases.

ChatGPT version 3.5 [ 12 ]: A generative architecture-based AI search engine developed by OpenAI © trained on large and diverse datasets.

We queried the chatbots to generate SLOs, A-type MCQs, integrated case cluster MCQs, integrated SAQs, and OSPE test items in the domain of systemic hypertension related to the P&T discipline. Separate prompts were used to generate outputs for pre-clerkship (preclinical) phase students, and at the time of graduation (before starting residency programs). Additionally, we have also evaluated the ability of these AI platforms to estimate the proportion of students correctly answering these test items. We used the following queries for each of these objectives:

Specific learning objectives

Can you generate specific learning objectives in the pharmacology discipline relevant to undergraduate medical students during their pre-clerkship phase related to anti-hypertensive drugs?

Can you generate specific learning objectives in the pharmacology discipline relevant to undergraduate medical students at the time of graduation related to anti-hypertensive drugs?

A-type MCQs

In the initial query used for A-type of item, we specified the domains (such as the mechanism of action, pharmacokinetics, adverse reactions, and indications) so that a sample of test items generated without any theme-related clutter, shown below:

Write 20 single best answer MCQs with 5 choices related to anti-hypertensive drugs for undergraduate medical students during the pre-clerkship phase of which 5 MCQs should be related to mechanism of action, 5 MCQs related to pharmacokinetics, 5 MCQs related to adverse reactions, and 5 MCQs should be related to indications.

The MCQs generated with the above search query were not based on clinical vignettes. We queried again to generate MCQs using clinical vignettes specifically because most medical schools have adopted problem-based learning (PBL) in their medical curriculum.

Write 20 single best answer MCQs with 5 choices related to anti-hypertensive drugs for undergraduate medical students during the pre-clerkship phase using a clinical vignette for each MCQ of which 5 MCQs should be related to the mechanism of action, 5 MCQs related to pharmacokinetics, 5 MCQs related to adverse reactions, and 5 MCQs should be related to indications.

We attempted to explore whether AI platforms can provide useful guidance on standard-setting. Hence, we used the following search query.

Can you do a simulation with 100 undergraduate medical students to take the above questions and let me know what percentage of students got each MCQ correct?

Integrated case cluster MCQs

Write 20 integrated case cluster MCQs with 2 questions in each cluster with 5 choices for undergraduate medical students during the pre-clerkship phase integrating pharmacology and physiology related to systemic hypertension with a case vignette.

Write 20 integrated case cluster MCQs with 2 questions in each cluster with 5 choices for undergraduate medical students during the pre-clerkship phase integrating pharmacology and physiology related to systemic hypertension with a case vignette. Please do not include ‘none of the above’ as the choice. (This modified search query was used because test items with ‘None of the above’ option were generated with the previous search query).

Write 20 integrated case cluster MCQs with 2 questions in each cluster with 5 choices for undergraduate medical students at the time of graduation integrating pharmacology and physiology related to systemic hypertension with a case vignette.

Integrated short answer questions

Write a short answer question scenario with difficult questions based on the theme of a newly diagnosed hypertensive patient for undergraduate medical students with the main objectives related to the physiology of blood pressure regulation, risk factors for systemic hypertension, pathophysiology of systemic hypertension, pathological changes in the systemic blood vessels in hypertension, pharmacological management, and non-pharmacological treatment of systemic hypertension.

Write a short answer question scenario with moderately difficult questions based on the theme of a newly diagnosed hypertensive patient for undergraduate medical students with the main objectives related to the physiology of blood pressure regulation, risk factors for systemic hypertension, pathophysiology of systemic hypertension, pathological changes in the systemic blood vessels in hypertension, pharmacological management, and non-pharmacological treatment of systemic hypertension.

Write a short answer question scenario with questions based on the theme of a newly diagnosed hypertensive patient for undergraduate medical students at the time of graduation with the main objectives related to the physiology of blood pressure regulation, risk factors for systemic hypertension, pathophysiology of systemic hypertension, pathological changes in the systemic blood vessels in hypertension, pharmacological management, and non-pharmacological treatment of systemic hypertension.

Can you generate 5 OSPE pharmacology and therapeutics prescription writing exercises for the assessment of undergraduate medical students at the time of graduation related to anti-hypertensive drugs?

Can you generate 5 OSPE pharmacology and therapeutics prescription writing exercises containing appropriate instructions for the patients for the assessment of undergraduate medical students during their pre-clerkship phase related to anti-hypertensive drugs?

Can you generate 5 OSPE pharmacology and therapeutics prescription writing exercises containing appropriate instructions for the patients for the assessment of undergraduate medical students at the time of graduation related to anti-hypertensive drugs?

Both authors independently evaluated the AI-generated outputs, and a consensus was reached. We cross-checked the veracity of answers suggested by AIs as per the Joint National Commission Guidelines (JNC-8) and Goodman and Gilman’s The Pharmacological Basis of Therapeutics (2023), a reference textbook [ 13 , 14 ]. Errors in the A-type MCQs were categorized as item construction defects, multiple correct answers, and uncertain appropriateness to the learner’s level. Test items in the integrated case cluster MCQs, SAQs and OSPEs were evaluated with the Preliminary Conceptual Framework for Establishing Content Validity of AI-Generated Test Items based on the following domains: technical accuracy, comprehensiveness, education level, and lack of construction defects (Table  1 ). The responses were categorized as complete and deficient for each domain.

The pre-clerkship phase SLOs identified by Sage Poe, Claude-Instant, and ChatGPT are listed in the electronic supplementary materials 1 – 3 , respectively. In general, a broad homology in SLOs generated by the three AI platforms was observed. All AI platforms identified appropriate action verbs as per Bloom’s taxonomy to state the SLO; action verbs such as describe, explain, recognize, discuss, identify, recommend, and interpret are used to state the learning outcome. The specific, measurable, achievable, relevant, time-bound (SMART) SLOs generated by each AI platform slightly varied. All key domains of antihypertensive pharmacology to be achieved during the pre-clerkship (pre-clinical) years were relevant for graduating doctors. The SLOs addressed current JNC Treatment Guidelines recommended classes of antihypertensive drugs, the mechanism of action, pharmacokinetics, adverse effects, indications/contraindications, dosage adjustments, monitoring therapy, and principles of monotherapy and combination therapy.

The SLOs to be achieved by undergraduate medical students at the time of graduation identified by Sage Poe, Claude-Instant, and ChatGPT listed in electronic supplementary materials 4 – 6 , respectively. The identified SLOs emphasize the application of pharmacology knowledge within a clinical context, focusing on competencies needed to function independently in early residency stages. These SLOs go beyond knowledge recall and mechanisms of action to encompass competencies related to clinical problem-solving, rational prescribing, and holistic patient management. The SLOs generated require higher cognitive ability of the learner: action verbs such as demonstrate, apply, evaluate, analyze, develop, justify, recommend, interpret, manage, adjust, educate, refer, design, initiate & titrate were frequently used.

The MCQs for the pre-clerkship phase identified by Sage Poe, Claude-Instant, and ChatGPT listed in the electronic supplementary materials 7 – 9 , respectively, and those identified with the search query based on the clinical vignette in electronic supplementary materials ( 10 – 12 ).

All MCQs generated by the AIs in each of the four domains specified [mechanism of action (MOA); pharmacokinetics; adverse drug reactions (ADRs), and indications for antihypertensive drugs] are quality test items with potential content validity. The test items on MOA generated by Sage Poe included themes such as renin-angiotensin-aldosterone (RAAS) system, beta-adrenergic blockers (BB), calcium channel blockers (CCB), potassium channel openers, and centrally acting antihypertensives; on pharmacokinetics included high oral bioavailability/metabolism in liver [angiotensin receptor blocker (ARB)-losartan], long half-life and renal elimination [angiotensin converting enzyme inhibitors (ACEI)-lisinopril], metabolism by both liver and kidney (beta-blocker (BB)-metoprolol], rapid onset- short duration of action (direct vasodilator-hydralazine), and long-acting transdermal drug delivery (centrally acting-clonidine). Regarding the ADR theme, dry cough, angioedema, and hyperkalemia by ACEIs in susceptible patients, reflex tachycardia by CCB/amlodipine, and orthostatic hypotension by CCB/verapamil addressed. Clinical indications included the drug of choice for hypertensive patients with concomitant comorbidity such as diabetics (ACEI-lisinopril), heart failure and low ejection fraction (BB-carvedilol), hypertensive urgency/emergency (alpha cum beta receptor blocker-labetalol), stroke in patients with history recurrent stroke or transient ischemic attack (ARB-losartan), and preeclampsia (methyldopa).

Almost similar themes under each domain were identified by the Claude-Instant AI platform with few notable exceptions: hydrochlorothiazide (instead of clonidine) in MOA and pharmacokinetics domains, respectively; under the ADR domain ankle edema/ amlodipine, sexual dysfunction and fatigue in male due to alpha-1 receptor blocker; under clinical indications the best initial monotherapy for clinical scenarios such as a 55-year old male with Stage-2 hypertension; a 75-year-old man Stage 1 hypertension; a 35-year-old man with Stage I hypertension working on night shifts; and a 40-year-old man with stage 1 hypertension and hyperlipidemia.

As with Claude-Instant AI, ChatGPT-generated test items on MOA were mostly similar. However, under the pharmacokinetic domain, immediate- and extended-release metoprolol, the effect of food to enhance the oral bioavailability of ramipril, and the highest oral bioavailability of amlodipine compared to other commonly used antihypertensives were the themes identified. Whereas the other ADR themes remained similar, constipation due to verapamil was a new theme addressed. Notably, in this test item, amlodipine was an option that increased the difficulty of this test item because amlodipine therapy is also associated with constipation, albeit to a lesser extent, compared to verapamil. In the clinical indication domain, the case description asking “most commonly used in the treatment of hypertension and heart failure” is controversial because the options listed included losartan, ramipril, and hydrochlorothiazide but the suggested correct answer was ramipril. This is a good example to stress the importance of vetting the AI-generated MCQ by experts for content validity and to assure robust psychometrics. The MCQ on the most used drug in the treatment of “hypertension and diabetic nephropathy” is more explicit as opposed to “hypertension and diabetes” by Claude-Instant because the therapeutic concept of reducing or delaying nephropathy must be distinguished from prevention of nephropathy, although either an ACEI or ARB is the drug of choice for both indications.

It is important to align student assessment to the curriculum; in the PBL curriculum, MCQs with a clinical vignette are preferred. The modification of the query specifying the search to generate MCQs with a clinical vignette on domains specified previously gave appropriate output by all three AI platforms evaluated (Sage Poe; Claude- Instant; Chat GPT). The scenarios generated had a good clinical fidelity and educational fit for the pre-clerkship student perspective.

The errors observed with AI outputs on the A-type MCQs are summarized in Table  2 . No significant pattern was observed except that Claude-Instant© generated test items in a stereotyped format such as the same choices for all test items related to pharmacokinetics and indications, and all the test items in the ADR domain are linked to the mechanisms of action of drugs. This illustrates the importance of reviewing AI-generated test items by content experts for content validity to ensure alignment with evidence-based medicine and up-to-date treatment guidelines.

The test items generated by ChatGPT had the advantage of explanations supplied rendering these more useful for learners to support self-study. The following examples illustrate this assertion: “ A patient with hypertension is started on a medication that works by blocking beta-1 receptors in the heart (metoprolol)”. Metoprolol is a beta blocker that works by blocking beta-1 receptors in the heart, which reduces heart rate and cardiac output, resulting in a decrease in blood pressure. However, this explanation is incomplete because there is no mention of other less important mechanisms, of beta receptor blockers on renin release. Also, these MCQs were mostly recall type: Which of the following medications is known to have a significant first-pass effect? The explanation reads: propranolol is known to have a significant first pass-effect, meaning that a large portion of the drug is metabolized by the liver before it reaches systemic circulation. Losartan, amlodipine, ramipril, and hydrochlorothiazide do not have significant first-pass effect. However, it is also important to extend the explanation further by stating that the first-pass effect of propranolol does not lead to total loss of pharmacological activity because the metabolite hydroxy propranolol also has potent beta-blocking activity. Another MCQ test item had a construction defect: “A patient with hypertension is started on a medication that can cause photosensitivity. Which of the following medications is most likely responsible?” Options included: losartan, amlodipine, ramipril, hydrochlorothiazide, hydrochlorothiazide/triamterene. The explanation states that hydrochlorothiazide (HCTZ) can cause photosensitivity, which is increased sensitivity to sunlight that can cause skin rashes and sunburns. Losartan, amlodipine, ramipril, and HCTZ/triamterene are less likely to cause photosensitivity. However, it is irrational to claim that HCTZ/triamterene, one of the wrong options, is less likely to cause photosensitivity. The difficulty index of such test items is likely unacceptable in high-stake tests to make equitable psychometric decisions.

The responses from Sage Poe, Claude-Instant, and ChatGPT on guidance for standard-setting methods are listed in the electronic supplementary materials 13 – 15 . Sage Poe offered this information with the caveat that “the results of this simulation were purely hypothetical and do not reflect the actual performance of any real students”. The simulation estimates of examinees correctly answering test items ranged from 60 to 90% for the mechanism of action, 65–85% for pharmacokinetics, 60–80% for adverse reactions, and 75–90% for clinical indications of antihypertensives.

In contrast, Claude-Instant admitted that “Performing a full simulation with 100 medical students is beyond the scope of what I can do as an AI assistant. I can generate sample MCQ questions and answers, but I do not have access to a population of medical students to administer the questions. A true simulation that administers questions to real students and analyzes the results would require access to a database of medical students, a platform to deliver the questions, and code to analyze the responses. As an AI assistant, I lack these capabilities. While I cannot perform a full simulation, here are some considerations for administering MCQ questions to medical students: provide details on the purpose and instructions for the test to ensure students understand what is expected out of them; consider including some easier questions in addition to more challenging ones to boost students’ confidence and motivation; avoid ambiguous wording and ensure each question has only one unambiguously correct answer option; when analyzing results, look for questions factors that may have impacted performance, like unclear wording or answer options that are too similar. Focusing on weak questions can help improve future tests; compare performance across different student groups to identify areas where more teaching may be needed; provide detailed answer explanations and review sessions after the test to help students learn from any errors and reinforce correct concepts”. However, ChatGPT offered the simulation result estimates for the 20 MCQ on antihypertensive drugs: mechanism of action ranged from 67 to 92%, pharmacokinetics 63–86%, adverse effects 65–82%, and clinical indications 64–89%. Furthermore, it also stated that “Overall, the performance of the students was quite good, with most questions having a response rate of over 70%. However, there were some questions where the projected correct response rate was rather low, such as Question #5 (Mechanism of Action of Hydrochlorothiazide; see Electronic Supplementary Material 12 ) and Question 18 (Indications for Verapamil; see Electronic Supplementary Material 10 ). This may suggest areas where students need more focused education or review.”

We asked AI assistants to generate 20 integrated case cluster MCQs with 2 test items in each cluster with five options for undergraduate medical students in the pre-clerkship phase integrating pharmacology and physiology related to systemic hypertension with a case vignette and the responses by Sage Poe, Claude-Instant, and ChatGPT are listed in the electronic supplementary materials ( 16 – 18 ). In all instances, the test items generated had focused case descriptions in the form of a clinical vignette, and horizontal integration across the pathophysiology of hypertension and pharmacology of antihypertensive drugs. These test items mostly targeted the ‘knows (knowledge)’ or ‘knows how (competence)’ level on Miller’s pyramid and are suitable for assessing the clinical competence of pre-clerkship medical students, especially in an integrated PBL curriculum. Both the AI assistants generated excellent clinical vignettes and themes; however, most of the cluster MCQs by ChatGPT had “None of the above” as an option, which is often considered a test item construction flaw. Notwithstanding these limitations, case cluster integrated test items are valuable for learners to integrate their knowledge of different basic medical sciences and their application to clinical sciences. This integrated approach can be used for both instructional and student assessment purposes to make the course more meaningful. Indeed, one of the basic tenets of PBL is curriculum integration.

In the next query, we asked AI assistants to write integrated case cluster MCQs with 2 test items in each cluster with 5 options for undergraduate medical students at the time of graduation integrating pharmacology and physiology of hypertension with a case vignette. The responses are listed in the electronic supplementary materials 19 – 21 . Claude-Instant has provided only partial responses to both the queries. Overall, the information provided in case vignettes requires the learner to interpret the clinical information and make therapeutic decisions. Such test items are appropriate for assessing the minimum competency of medical school graduates to start internship or residency programs; these MCQs are generally comparable to test items used in USMLE Part 2. The evaluation of the integrated case cluster test items provided by all the AI platforms is summarized in Table  3 . In general, the AI outputs had at least one construction defect, and did not include all the core sub-topics to a sufficient degree.

When asked to simulate the above-generated test items to 100 undergraduate medical students at the time of graduation and provide a percentage of students who are likely to correctly answer each item, the AI assistant responded:

“ As an AI language model, I cannot simulate the responses of 100 undergraduate medical students likely to obtain the correct answer for each question. However, I can provide some general information about the difficulty level of each question based on the complexity of the concepts being tested and the level of integration between pharmacology and physiology ”.

AI assistant went on to clarify that questions that require knowledge of basic pharmacology principles, such as the mechanism of action of specific drugs, are likely to be easier for students to answer correctly. Test items that require an understanding of the physiological mechanisms underlying hypertension and correlating with symptoms are likely to be more challenging for students. The AI assistant sorted these test items into two categories accordingly. Overall, the difficulty level of the test item is based on the level of integration between pharmacology and pathophysiology. Test items that require an understanding of both pharmacological and physiological mechanisms are likely to be more challenging for students requiring a strong foundation in both pharmacology and physiology concepts to be able to correctly answer integrated case-cluster MCQs.

Short answer questions

The responses to a search query on generating SAQs appropriate to the pre-clerkship phase Sage Poe, Claude-Instant, and ChatGPT generated items are listed in the electronic supplementary materials 22 – 24 for difficult questions and 25–27 for moderately difficult questions.

It is apparent from these case vignette descriptions that the short answer question format varied. Accordingly, the scope for asking individual questions for each scenario is open-ended. In all instances, model answers are supplied which are helpful for the course instructor to plan classroom lessons, identify appropriate instructional methods, and establish rubrics for grading the answer scripts, and as a study guide for students.

We then wanted to see to what extent AI can differentiate the difficulty of the SAQ by replacing the search term “difficult” with “moderately difficult” in the above search prompt: the changes in the revised case scenarios are substantial. Perhaps the context of learning and practice (and the level of the student in the MD/medical program) may determine the difficulty level of SAQ generated. It is worth noting that on changing the search from cardiology to internal medicine rotation in Sage Poe the case description also changed. Thus, it is essential to select an appropriate AI assistant, perhaps by trial and error, to generate quality SAQs. Most of the individual questions tested stand-alone knowledge and did not require students to demonstrate integration.

The responses of Sage Poe, Claude-Instant, and ChatGPT for the search query to generate SAQs at the time of graduation are listed in the electronic supplementary materials 28 – 30 . It is interesting to note how AI assistants considered the stage of the learner while generating the SAQ. The response by Sage Poe is illustrative for comparison. “You are a newly graduated medical student who is working in a hospital” versus “You are a medical student in your pre-clerkship.”

Some questions were retained, deleted, or modified to align with competency appropriate to the context (Electronic Supplementary Materials 28 – 30 ). Overall, the test items at both levels from all AI platforms were technically accurate and thorough addressing the topics related to different disciplines (Table  3 ). The differences in learning objective transition are summarized in Table  4 . A comparison of learning objectives revealed that almost all objectives remained the same except for a few (Table  5 ).

A similar trend was apparent with test items generated by other AI assistants, such as ChatGPT. The contrasting differences in questions are illustrated by the vertical integration of basic sciences and clinical sciences (Table  6 ).

Taken together, these in-depth qualitative comparisons suggest that AI assistants such as Sage Poe and ChatGPT consider the learner’s stage of training in designing test items, learning outcomes, and answers expected from the examinee. It is critical to state the search query explicitly to generate quality output by AI assistants.

The OSPE test items generated by Claude-Instant and ChatGPT appropriate to the pre-clerkship phase (without mentioning “appropriate instructions for the patients”) are listed in the electronic supplementary materials 31 and 32 and with patient instructions on the electronic supplementary materials 33 and 34 . For reasons unknown, Sage Poe did not provide any response to this search query.

The five OSPE items generated were suitable to assess the prescription writing competency of pre-clerkship medical students. The clinical scenarios identified by the three AI platforms were comparable; these scenarios include patients with hypertension and impaired glucose tolerance in a 65-year-old male, hypertension with chronic kidney disease (CKD) in a 55-year-old woman, resistant hypertension with obstructive sleep apnea in a 45-year-old man, and gestational hypertension at 32 weeks in a 35-year-old (Claude-Instant AI). Incorporating appropriate instructions facilitates the learner’s ability to educate patients and maximize safe and effective therapy. The OSPE item required students to write a prescription with guidance to start conservatively, choose an appropriate antihypertensive drug class (drug) based on the patients’ profile, specifying drug name, dose, dosing frequency, drug quantity to be dispensed, patient name, date, refill, and caution as appropriate, in addition to prescribers’ name, signature, and license number. In contrast, ChatGPT identified clinical scenarios to include patients with hypertension and CKD, hypertension and bronchial asthma, gestational diabetes, hypertension and heart failure, and hypertension and gout (ChatGPT). Guidance for dosage titration, warnings to be aware, safety monitoring, and frequency of follow-up and dose adjustment. These test items are designed to assess learners’ knowledge of P & T of antihypertensives, as well as their ability to provide appropriate instructions to patients. These clinical scenarios for writing prescriptions assess students’ ability to choose an appropriate drug class, write prescriptions with proper labeling and dosing, reflect drug safety profiles, and risk factors, and make modifications to meet the requirements of special populations. The prescription is required to state the drug name, dose, dosing frequency, patient name, date, refills, and cautions or instructions as needed. A conservative starting dose, once or twice daily dosing frequency based on the drug, and instructions to titrate the dose slowly if required.

The responses from Claude-Instant and ChatGPT for the search query related to generating OSPE test items at the time of graduation are listed in electronic supplementary materials 35 and 36 . In contrast to the pre-clerkship phase, OSPEs generated for graduating doctors’ competence assessed more advanced drug therapy comprehension. For example, writing a prescription for:

(1) A 65-year- old male with resistant hypertension and CKD stage 3 to optimize antihypertensive regimen required the answer to include starting ACEI and diuretic, titrating the dosage over two weeks, considering adding spironolactone or substituting ACEI with an ARB, and need to closely monitor serum electrolytes and kidney function closely.

(2) A 55-year-old woman with hypertension and paroxysmal arrhythmia required the answer to include switching ACEI to ARB due to cough, adding a CCB or beta blocker for rate control needs, and adjusting the dosage slowly and monitoring for side effects.

(3) A 45-year-old man with masked hypertension and obstructive sleep apnea require adding a centrally acting antihypertensive at bedtime and increasing dosage as needed based on home blood pressure monitoring and refer to CPAP if not already using one.

(4) A 75-year-old woman with isolated systolic hypertension and autonomic dysfunction to require stopping diuretic and switching to an alpha blocker, upward dosage adjustment and combining with other antihypertensives as needed based on postural blood pressure changes and symptoms.

(5) A 35-year-old pregnant woman with preeclampsia at 29 weeks require doubling methyldopa dose and consider adding labetalol or nifedipine based on severity and educate on signs of worsening and to follow-up immediately for any concerning symptoms.

These case scenarios are designed to assess the ability of the learner to comprehend the complexity of antihypertensive regimens, make evidence-based regimen adjustments, prescribe multidrug combinations based on therapeutic response and tolerability, monitor complex patients for complications, and educate patients about warning signs and follow-up.

A similar output was provided by ChatGPT, with clinical scenarios such as prescribing for patients with hypertension and myocardial infarction; hypertension and chronic obstructive pulmonary airway disease (COPD); hypertension and a history of angina; hypertension and a history of stroke, and hypertension and advanced renal failure. In these cases, wherever appropriate, pharmacotherapeutic issues like taking ramipril after food to reduce side effects such as giddiness; selection of the most appropriate beta-blocker such as nebivolol in patients with COPD comorbidity; the importance of taking amlodipine at the same time every day with or without food; preference for telmisartan among other ARBs in stroke; choosing furosemide in patients with hypertension and edema and taking the medication with food to reduce the risk of gastrointestinal adverse effect are stressed.

The AI outputs on OSPE test times were observed to be technically accurate, thorough in addressing core sub-topics suitable for the learner’s level and did not have any construction defects (Table  3 ). Both AIs provided the model answers with explanatory notes. This facilitates the use of such OSPEs for self-assessment by learners for formative assessment purposes. The detailed instructions are helpful in creating optimized therapy regimens, and designing evidence-based regimens, to provide appropriate instructions to patients with complex medical histories. One can rely on multiple AI sources to identify, shortlist required case scenarios, and OSPE items, and seek guidance on expected model answers with explanations. The model answer guidance for antihypertensive drug classes is more appropriate (rather than a specific drug of a given class) from a teaching/learning perspective. We believe that these scenarios can be refined further by providing a focused case history along with relevant clinical and laboratory data to enhance clinical fidelity and bring a closer fit to the competency framework.

In the present study, AI tools have generated SLOs that comply with the current principles of medical education [ 15 ]. AI tools are valuable in constructing SLOs and so are especially useful for medical fraternities where training in medical education is perceived as inadequate, more so in the early stages of their academic career. Data suggests that only a third of academics in medical schools have formal training in medical education [ 16 ] which is a limitation. Thus, the credibility of alternatives, such as the AIs, is evaluated to generate appropriate course learning outcomes.

We observed that the AI platforms in the present study generated quality test items suitable for different types of assessment purposes. The AI-generated outputs were similar with minor variation. We have used generative AIs in the present study that could generate new content from their training dataset [ 17 ]. Problem-based and interactive learning approaches are referred to as “bottom-up” where learners obtain first-hand experience in solving the cases first and then indulge in discussion with the educators to refine their understanding and critical thinking skills [ 18 ]. We suggest that AI tools can be useful for this approach for imparting the core knowledge and skills related to Pharmacology and Therapeutics to undergraduate medical students. A recent scoping review evaluating the barriers to writing quality test items based on 13 studies has concluded that motivation, time constraints, and scheduling were the most common [ 19 ]. AI tools can be valuable considering the quick generation of quality test items and time management. However, as observed in the present study, the AI-generated test items nevertheless require scrutiny by faculty members for content validity. Moreover, it is important to train faculty in AI technology-assisted teaching and learning. The General Medical Council recommends taking every opportunity to raise the profile of teaching in medical schools [ 20 ]. Hence, both the academic faculty and the institution must consider investing resources in AI training to ensure appropriate use of the technology [ 21 ].

The AI outputs assessed in the present study had errors, particularly with A-type MCQs. One notable observation was that often the AI tools were unable to differentiate the differences between ACEIs and ARBs. AI platforms access several structured and unstructured data, in addition to images, audio, and videos. Hence, the AI platforms can commit errors due to extracting details from unauthenticated sources [ 22 ] created a framework identifying 28 factors for reconstructing the path of AI failures and for determining corrective actions. This is an area of interest for AI technical experts to explore. Also, this further iterates the need for human examination of test items before using them for assessment purposes.

There are concerns that AIs can memorize and provide answers from their training dataset, which they are not supposed to do [ 23 ]. Hence, the use of AIs-generated test items for summative examinations is debatable. It is essential to ensure and enhance the security features of AI tools to reduce or eliminate cross-contamination of test items. Researchers have emphasized that AI tools will only reach their potential if developers and users can access full-text non-PDF formats that help machines comprehend research papers and generate the output [ 24 ].

AI platforms may not always have access to all standard treatment guidelines. However, in the present study, it was observed that all three AI platforms generally provided appropriate test items regarding the choice of medications, aligning with recommendations from contemporary guidelines and standard textbooks in pharmacology and therapeutics. The prompts used in the study were specifically focused on the pre-clerkship phase of the undergraduate medical curriculum (and at the time of their graduation) and assessed fundamental core concepts, which were also reflected in the AI outputs. Additionally, the recommended first-line antihypertensive drug classes have been established for several decades, and information regarding their pharmacokinetics, ADRs, and indications is well-documented in the literature.

Different paradigms and learning theories have been proposed to support AI in education. These paradigms include AI- directed (learner as recipient), AI-supported (learner as collaborator), and AI-empowered (learner as leader) that are based on Behaviorism, Cognitive-Social constructivism, and Connectivism-Complex adaptive systems, respectively [ 25 ]. AI techniques have potential to stimulate and advance instructional and learning sciences. More recently a three- level model that synthesizes and unifies existing learning theories to model the roles of AIs in promoting learning process has been proposed [ 26 ]. The different components of our study rely upon these paradigms and learning theories as the theoretical underpinning.

Strengths and limitations

To the best of our knowledge, this is the first study evaluating the utility of AI platforms in generating test items related to a discipline in the undergraduate medical curriculum. We have evaluated the AI’s ability to generate outputs related to most types of assessment in the undergraduate medical curriculum. The key lessons learnt for improving the AI-generated test item quality from the present study are outlined in Table  7 . We used a structured framework for assessing the content validity of the test items. However, we have demonstrated using a single case study (hypertension) as a pilot experiment. We chose to evaluate anti-hypertensive drugs as it is a core learning objective and one of the most common disorders relevant to undergraduate medical curricula worldwide. It would be interesting to explore the output from AI platforms for other common (and uncommon/region-specific) disorders, non-/semi-core objectives, and disciplines other than Pharmacology and Therapeutics. An area of interest would be to look at the content validity of the test items generated for different curricula (such as problem-based, integrated, case-based, and competency-based) during different stages of the learning process. Also, we did not attempt to evaluate the generation of flowcharts, algorithms, or figures for generating test items. Another potential area for exploring the utility of AIs in medical education would be repeated procedural practices such as the administration of drugs through different routes by trainee residents [ 27 ]. Several AI tools have been identified for potential application in enhancing classroom instructions and assessment purposes pending validation in prospective studies [ 28 ]. Lastly, we did not administer the AI-generated test items to students and assessed their performance and so could not comment on the validity of test item discrimination and difficulty indices. Additionally, there is a need to confirm the generalizability of the findings to other complex areas in the same discipline as well as in other disciplines that pave way for future studies. The conceptual framework used in the present study for evaluating the AI-generated test items needs to be validated in a larger population. Future studies may also try to evaluate the variations in the AI outputs with repetition of the same queries.

Notwithstanding ongoing discussions and controversies, AI tools are potentially useful adjuncts to optimize instructional methods, test blueprinting, test item generation, and guidance for test standard-setting appropriate to learners’ stage in the medical program. However, experts need to critically review the content validity of AI-generated output. These challenges and caveats are to be addressed before the use of widespread use of AIs in medical education can be advocated.

Data availability

All the data included in this study are provided as Electronic Supplementary Materials.

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Sridharan, K., Sequeira, R.P. Artificial intelligence and medical education: application in classroom instruction and student assessment using a pharmacology & therapeutics case study. BMC Med Educ 24 , 431 (2024). https://doi.org/10.1186/s12909-024-05365-7

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