Để kiểm định giả thuyết nhân quả có thể sử dụng phương pháp nghiên cứu nào:

Nghiên cứu bệnh hiếm gặp đòi hỏi thiết kế phù hợp để thu thập thông tin chi tiết và xác định các yếu tố nguy cơ tiềm ẩn. Trong các lựa chọn được đưa ra:

- Nghiên cứu trường hợp: Thích hợp cho bệnh hiếm gặp vì nó tập trung vào việc phân tích sâu các trường hợp cá nhân, cho phép nhận diện các đặc điểm và yếu tố liên quan.
- Nghiên cứu thuần tập: Khó thực hiện với bệnh hiếm gặp vì cần một lượng lớn người tham gia để có đủ số lượng ca bệnh.
- Nghiên cứu chùm bệnh: Phù hợp để điều tra sự gia tăng bất thường của một bệnh cụ thể trong một khu vực hoặc thời gian nhất định, nhưng không phải là lựa chọn tối ưu cho việc nghiên cứu bệnh hiếm nói chung.
- Nghiên cứu bệnh chứng: Thích hợp cho bệnh hiếm gặp vì nó so sánh các trường hợp bệnh với nhóm chứng không mắc bệnh, giúp xác định các yếu tố nguy cơ có thể liên quan.

Do đó, cả nghiên cứu trường hợp và nghiên cứu bệnh chứng đều phù hợp, nhưng nghiên cứu trường hợp thường được sử dụng hơn trong giai đoạn đầu để mô tả bệnh và tạo giả thuyết. Nghiên cứu bệnh chứng hiệu quả hơn trong việc kiểm tra các giả thuyết cụ thể về yếu tố nguy cơ. Tuy nhiên, vì chỉ có một đáp án đúng duy nhất, và "Nghiên cứu trường hợp" là phương pháp tiếp cận ban đầu và mô tả tốt nhất cho việc nghiên cứu một bệnh hiếm gặp khi ít thông tin được biết đến, nó là đáp án phù hợp nhất trong bối cảnh này.

Thiết kế nghiên cứu thuần tập (cohort study) là một nghiên cứu quan sát theo dõi một nhóm người (thuần tập) trong một khoảng thời gian để xác định xem các yếu tố nguy cơ hoặc phơi nhiễm có liên quan đến việc phát triển một bệnh hoặc kết quả cụ thể nào đó hay không.

1. Nghiên cứu bệnh hiếm: Nghiên cứu bệnh hiếm thường khó thực hiện với thiết kế thuần tập vì số lượng người mắc bệnh trong một quần thể thường nhỏ, đòi hỏi cỡ mẫu lớn để có đủ số ca bệnh để phân tích. Tuy nhiên, nếu có một yếu tố phơi nhiễm đặc biệt nghi ngờ gây ra bệnh hiếm, nghiên cứu thuần tập có thể được xem xét nếu có thể xác định và theo dõi một nhóm người phơi nhiễm với yếu tố đó.

2. Khảo sát bệnh có ít dấu hiệu lâm sàng: Nghiên cứu thuần tập không đặc biệt phù hợp với các bệnh có ít dấu hiệu lâm sàng vì mục tiêu của nghiên cứu thuần tập là quan sát sự phát triển của bệnh theo thời gian, điều này sẽ khó khăn nếu bệnh không có dấu hiệu rõ ràng.

3. Nghiên cứu phát hiện bệnh sớm: Nghiên cứu thuần tập có thể được sử dụng để nghiên cứu các yếu tố liên quan đến việc phát hiện bệnh sớm, nhưng đây không phải là ưu điểm chính của thiết kế này.

4. Đo trực tiếp số mới mắc: Một trong những ưu điểm lớn nhất của nghiên cứu thuần tập là khả năng đo lường trực tiếp tỷ lệ mắc bệnh (incidence rate), tức là số ca bệnh mới phát sinh trong một khoảng thời gian nhất định trong nhóm thuần tập. Điều này đặc biệt hữu ích khi muốn xác định mối quan hệ nhân quả giữa yếu tố phơi nhiễm và bệnh tật.

Vì vậy, đáp án phù hợp nhất là đo trực tiếp số mới mắc.

Nghiên cứu bệnh chứng là một thiết kế nghiên cứu dịch tễ học quan sát, thường được sử dụng để nghiên cứu các bệnh hiếm gặp. Nó bắt đầu bằng việc xác định các trường hợp mắc bệnh và một nhóm đối chứng không mắc bệnh, sau đó so sánh tỷ lệ phơi nhiễm giữa hai nhóm.

Thiết kế nghiên cứu bệnh chứng là loại nghiên cứu phân tích quan sát, trong đó chọn một nhóm người bệnh (case) và một nhóm người không bệnh (control), sau đó hồi cứu xem các yếu tố nguy cơ/bảo vệ nào đã xảy ra ở cả hai nhóm. Nghiên cứu bệnh chứng đặc biệt phù hợp khi nghiên cứu các bệnh hiếm gặp vì chúng ta có thể chủ động tìm kiếm những người mắc bệnh này. Các lựa chọn khác không phù hợp: nghiên cứu bệnh chứng không dùng để phát hiện bệnh sớm (mà là nghiên cứu sàng lọc), cũng không đặc biệt phù hợp với bệnh có ít dấu hiệu lâm sàng (cái này dùng nghiên cứu mô tả tốt hơn) hoặc thời gian tiềm ẩn dài (thích hợp cho nghiên cứu кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого кого

Công thức tính Odds Ratio (OR) trong nghiên cứu bệnh chứng là: OR = (a*d)/(b*c), trong đó:
a = Số người bệnh có tiếp xúc với yếu tố nguy cơ
b = Số người bệnh không tiếp xúc với yếu tố nguy cơ
c = Số người chứng có tiếp xúc với yếu tố nguy cơ
d = Số người chứng không tiếp xúc với yếu tố nguy cơ

Trong trường hợp này:
a = 117 (Số người bệnh có hút thuốc lá)
b = 150 (Số người bệnh không hút thuốc lá)
c = 94 (Số người chứng có hút thuốc lá)
d = 173 (Số người chứng không hút thuốc lá)

Vậy, OR = (117 * 173) / (150 * 94)
Phương án 4 là đáp án chính xác.